Abriel, Hugues

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EDITORIALGenetic background of Brugada syndrome is morecomplex than what we would like it to be!Hugues Abriel*Department of Clinical Research, Ion Channel Research Group, University of Bern, Murtenstrasse 35, Bern 3010, SwitzerlandOnline publish-ahead-of-print 29 April 2015This editorial refers to ‘Role of common and rare variantsin SCN10A: results from the Brugada syndrome QRS locusgene discovery collaborative study’ by E.R. Behr et al.,pp. 520–529.Everythingmust be taken into account. If the fact will not fit the theory—letthe theory go.—Agatha Christie, The Mysterious Affair at StylesBrugada syndrome (BrS) has been named after the description of thedisease made by the Brugada brothers in 1992.1 BrS is clinically charac-terized by arrhythmic events, in particular ventricular fibrillation, result-ing in syncope and sudden cardiac arrestmainly inmiddle-agedmen. TheECG shows a peculiar down-sloping elevation of the ST segment in theright pre-cordial ECG leads with inversion of T-waves.2 Since 1998, agenetic component to BrS has been demonstrated.3 Over the pastyears, at least 20 genes have been proposed either to cause BrS or tobe BrS-susceptibility genes.4For several years, SCN5A, which encodes the ‘cardiac sodiumchannel’Nav1.5, was presented as a gene ‘causing’ BrS in 20% of the patients;however, this concept had to be revised due to recent findings. First,in some families where the probands were found to carry SCN5A rarevariants, other familymembersdiagnosedwithBrSdidnot carry the sup-posedly pathogenic variant.5,6 Second, a recent genome-wide associ-ation study (GWAS) led to the concept that BrS could no longer beconsidered a monogenic disease and it suggested a key role for thethree genes: SCN10A, SCN5A, and HEY2.7 Patients who accumulatedmore than four of the risk alleles in these genes had an odds ratio of.20 to have BrS. The two genes SCN5A and SCN10A, which encodetwo different voltage-gated sodium channels, were also implicated inother GWAS studies8 in physiological cardiac conduction, assessed asECGparameters. These findingsmotivated several groups to investigatethe, thus far, unknown role of the SCN10A gene product, the sodiumchannel Nav1.8, in cardiac electrical activity as this channel was onlythought to be important in the sensory nervous system.As it sometimes happens in science, this has led to controversialresults. The first unresolved question is the location of expression ofNav1.8 in cardiac tissues. Two hypotheses are currently debated. Onthe one hand, expression of Nav1.8 is proposed by one researchgroup to be specific to intracardiac neurons,9 while on the other hand,expression in cardiac myocytes of the myocardium and of the conduc-tionpathwaywas suggestedbyanother group.10The secondpointof dis-agreement is the role of genetic variants that were found in the geneSCN10A in patients with cardiac arrhythmias, in particular BrS. Upon in-vestigation of a population of 150 BrS probands and family members, arecent study by Hu et al.11 came to the conclusion that SCN10Agenetic variants may cause BrS in 16.7% of these probands, thusputting SCN10A as a major susceptibility gene of BrS.In the current issue of Cardiovascular Research, Dr E.R. Behr presents amulti-centre collaborative study,12 involving 156 SCN5Amutation nega-tive BrS probands where 7 candidate genes, including SCN10A, weresequenced. Contrary to the previous study by Hu et al.,11 while mostof the rare genetic variants were found in SCN10A, no statistical associ-ationwith these SCN10Avariants andBrSwasobserved.However,manyof these variants showed functional alterations, such as reduction inNav1.8-mediated sodium current when studied by patch clamping.Behr et al.12 did not investigate the functional consequences of theco-expression of the Nav1.8 with the Nav1.5 channel in the same cellsas done by Hu et al.11 Their rationale not to study it is based on the evi-dence that these two channels are not co-expressed in cardiomyo-cytes.9 This question of co-expression still remains unsolved, but onecan nevertheless note that proteomic studies13 performed usingmouse cardiac tissue only revealed significant amounts of Nav1.5 andNav1.4 peptides and none from Nav1.8. These observations by Behret al. suggest that, while these rare Nav1.8 variants and their functionaleffects are consistent with the observed role of this channel in cardiacconduction, they are not directly involved in the pathogenesis of BrS.The authors of the present study thus concluded that ‘rare variation inSCN10, particularly in SCN5A mutation negative cases, is unlikely tocause BrS’. Behr et al. discuss the possible origins of this discrepancyand propose that their studied BrS population is more focused(enriched), and that a more stringent ‘mutation’ definition had beenused. They also mention that by looking at larger control variant data-bases, only 2% of the SCN10A variants reported by Hu et al.11 shouldbe classified as ‘rare’. Here, one should also mention the recent studyby Le Scouarnec et al.4 from the Institut du Thorax in Nantes, wherethe burden of rare coding variants in 20 BrS genes was estimated.Using a ‘burden test’ for the exonic sequences of these genes from167 BrS probands, a significant enrichment in rare variants [with aThe opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.* Corresponding author. Tel: +41 31 6320928; fax: +41 31 6320946, Email: hugues.abriel@dkf.unibe.chPublished on behalf of the European Society of Cardiology. All rights reserved.& The Author 2015. For permissions please email: journals.permissions@oup.com.Cardiovascular Research (2015) 106, 351–352doi:10.1093/cvr/cvv135definition of the minor allele frequency (MAF) ,0.1% in an ethnicallymatched control population] was only observed for SCN5A, but notfor SCN10A. These results are in line with the ones of the currentstudy of Behr et al. in this issue of Cardiovascular Research. Importantly,these authors discuss that if Hu et al.11would also have used such a strin-gent rare variant definition of MAF,0.1% (instead of ,0.5%), the pro-portion of SCN10A carriers in BrS patients would have fallen to 7.3%instead of 16.7%. Thus, these two studies by Behr et al.12 and Le Scouar-nec et al.4 do not support the concept that SCN10A is a major suscepti-bility gene in BrS and propose plausiblemethodological explanations forthe discrepant results.There is no doubt that controversies are intrinsic to the scientificprocess; this is most likely a positive thing! However, in this case onehas to be extremely careful, since these findings may have importantconsequences, as they may be used for guiding the work-up of patientswith BrS and their family members. It is therefore important to replicatesimilar studies in larger populations (and similarly sized control popula-tions) as well as from other ethnic backgrounds, and use a cautious def-inition of ‘rare variant’ as proposed in study4 to sort through the role ofSCN10A in BrS and other genetic cardiac arrhythmias.AcknowledgementsD. Shy is thanked for her comments on this manuscript.Conflict of interest: none declared.FundingThis researchhas received funding fromtheEuropeanCommunity’s SeventhFramework Programme FP7/2007–2013 under grant agreement No.HEALTH-F2-2009-241526, EUTrigTreat (toH.A.). The groupofH.A. is sup-ported by a grant of the Swiss National Science Foundation 310030_14060.References1. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation andsudden cardiac death: a distinct clinical and electrocardiographic syndrome. Amulticen-ter report. J Am Coll Cardiol 1992;20:1391–1396.2. Mizusawa Y, Wilde AAM. Brugada syndrome. Circ Arrhythmia Electrophysiol 2012;5:606–616.3. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A,Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien RE,Schulze-Bahr E, Keating MT, Towbin JA,WangQ. Genetic basis and molecular mechan-ism for idiopathic ventricular fibrillation. Nature 1998;392:293–296.4. Le Scouarnec S, Karakachoff M, Gourraud JB, Lindenbaum P, Bonnaud S, Portero V,Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E,Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haissaguerre M, Kyndt F,Schmitt S, Bezieau S, Le MH, Dina C, Schott JJ, Probst V, Redon R. Testing the burdenof rare variation in arrhythmia-susceptibility genes provides new insights into moleculardiagnosis for Brugada syndrome. Hum Mol Genet 2015;24:2757–2763.5. Probst V,Wilde AAM, Barc J, Sacher F, Babuty D, Mabo P, Mansourati J, Le Scouarnec S,Kyndt F, Le Caignec C, Guicheney P, Gouas L, Albuisson J, Meregalli PG, Le Marec H,Tan HL, Schott JJ. SCN5A mutations and the role of genetic background in the patho-physiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552–557.6. Saber S, Amarouch MY, Fazelifar AF, Haghjoo M, Emkanjoo Z, Alizadeh A,Houshmand M, Gavrilenko AV, Abriel H, Zaklyazminskaya EV. Complex genetic back-ground in a large family with Brugada syndrome. Physiol Rep 2015;3:e12256.7. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, Verkerk AO,Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A,Antzelevitch C, Bartkowiak S, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R,Tfelt-Hansen J, Olesen MS, Kaab S, Beckmann BM, Weeke P, Watanabe H, Endo N,Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T,Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R,Coronel R, Boukens BJ, Bezieau S, Charpentier E, Chatel S, Despres A, Gros F,Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL,Roden DM, Christoffels VM, Marec HL, Wilde AA, Probst V, Schott JJ, Dina C,Redon R. Common variants at SCN5A-SCN10A and HEY2 are associated withBrugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet2013;45:1044–1049.8. van den Boogaard M, Barnett P, Christoffels VM. FromGWAS to function: genetic vari-ation in sodium channel gene enhancer influences electrical patterning. Trends CardiovascMed 2014;24:99–104.9. VerkerkAO,RemmeCA,SchumacherCA, SciclunaBP,WolswinkelR, de JB, BezzinaCR,Veldkamp MW. Functional Nav1.8 channels in intracardiac neurons: the link betweenSCN10A and cardiac electrophysiology. Circ Res 2012;111:333–343.10. Yang T, Atack TC, Stroud DM, Zhang W, Hall L, Roden DM. Blocking SCN10Achannels in heart reduces late sodium current and is antiarrhythmic. Circ Res 2012;111:322–332.11. Hu D, Barajas-Martinez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, Betzenhauser MJ,Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P,Marieb M, Nam GB, Bhatia A, Hasdemir C, Haissaguerre M, Veltmann C, Schimpf R,Borggrefe M, Viskin S, Antzelevitch C. Mutations in SCN10A are responsible for alarge fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014;64:66–79.12. Behr ER, Savio-Galimberti E, Barc J, Holst AG, Petropoulou E, Prins BP, Jabbari J,Torchio M, Berthet M, Mizusawa Y, Yang T, Nannenberg EA, Dagradi F, Weeke P,Bastiaenan R, Ackerman MJ, Haunso S, Leenhardt A, Kaab S, Probst V, Redon R,Sharma S, Wilde A, Tfelt-Hansen J, Schwartz P, Roden DM, Bezzina CR, Olesen M,Darbar D, Guicheney P, Crotti L, Jamshidi Y. Role of common and rare variants inSCN10A: results from the Brugada syndrome QRS locus gene discovery collaborativestudy. Cardiovasc Res 2015;106:520–529.13. Marionneau C, Lichti CF, Lindenbaum P, Charpentier F, Nerbonne JM, Townsend RRet al. Mass spectrometry-based identification of native cardiac Nav1.5 channel alphasubunit phosphorylation sites. J Proteome Res 2012;11:5994–6007.Editorial352

Genetic background of Brugada syndrome is more complex than what we would like it to be!

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Genetic background of Brugada syndrome is more complex than what we would like it to be!

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