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• W2080856874 abstract "The Brugada syndrome (BrS) is an inherited arrhythmia disorder that emerged as a distinct clinical entity in the literature approximately 20 years ago.1Martini B. Nava A. Thiene G. et al.Ventricular fibrillation without apparent heart disease: a description of six cases.Am Heart J. 1989; 118: 1203-1209Abstract Full Text PDF PubMed Scopus (290) Google Scholar, 2Brugada P. Brugada J. 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. 1992; 20: 1391-1396Abstract Full Text PDF PubMed Scopus (2711) Google Scholar Characterized electrocardiographically by a coved-shape ST-segment elevation pattern in the right precordial leads, affected patients are susceptible to sudden cardiac death secondary to ventricular arrhythmias.3Roberts J.D. Gollob M.H. The genetic and clinical features of cardiac channelopathies.Future Cardiol. 2010; 6: 491-506Crossref PubMed Scopus (16) Google Scholar The first gene implicated in BrS, SCN5A, was identified in 1997 through a candidate gene approach.4Chen Q. Kirsch G.E. Zhang D. et al.Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392: 293-296Crossref PubMed Scopus (1523) Google Scholar The SCN5A gene encodes the α-subunit of Nav1.5, which mediates INa and is responsible for depolarization during Phase 0 of the cardiac action potential.5Katz A.M. Cardiac ion channels.N Engl J Med. 1993; 328: 1244-1251Crossref PubMed Scopus (100) Google Scholar Validation of SCN5A as a disease-causing gene for BrS has occurred over subsequent years from independent investigators around the world, and this gene may now be tested commercially in identified cases of BrS for the purpose of family cascade screening.6Gollob M.H. Blier L. Brugada R. et al.Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society join position paper.Can J Cardiol. 2011; 27: 232-245Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Approximately 20% of patients with BrS are genotype positive for culprit mutations within SCN5A. Since the initial discovery of SCN5A as a disease-causing gene, there have been a total of 11 different genes reported to be causative for the disorder, which collectively have been suggested to account for up to 40% of cases.6Gollob M.H. Blier L. Brugada R. et al.Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society join position paper.Can J Cardiol. 2011; 27: 232-245Abstract Full Text Full Text PDF PubMed Scopus (123) Google ScholarThe traditional and most reliable approach for identifying genes responsible for inherited disorders has been through linkage analysis which requires the presence of large families with multiple affected and unaffected members. Genes identified through linkage analysis provide strong evidence for disease association, as the culprit gene mutation is demonstrated to segregate with affected family members and is absent from healthy relatives (assuming complete disease penetrance). Although BrS is considered an autosomal dominant condition, reports of large affected families allowing for segregation analysis are rare, and sporadic cases account for a large proportion of affected patients. Thus, gene discovery for BrS (and many other conditions) has depended on the screening of biologically plausible candidate genes, and “proven” disease-association by the absence of the specific genetic variation from control cohorts. Such an approach is not without risk of false associations, because rare variants are by definition ‘rare,' and their absence from a control cohort may not be meaningful. It has been well established that even “healthy controls” harbour rare genetic variants in genes considered “biologically plausible” or known to be disease-causing for numerous conditions, including hereditary arrhythmia syndromes.7Kapa S. Tester D.J. Salisbury B.A. et al.Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.Circulation. 2009; 120: 1752-1760Crossref PubMed Scopus (275) Google Scholar, 8Kapplinger J.D. Landstrom A.P. Salisbury B.A. et al.Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.J Am Coll Cardiol. 2011; 57: 2317-2327Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Investigators will often argue that functional differences in the biologic behaviour of rare variants support their disease-causation. While often true, altered biological function alone cannot conclude disease-causation on all occasions, as even common polymorphisms may display altered function, yet by virtue of their frequency in the normal population are not disease-causing.9Anson B.D. Ackerman M.J. Tester D.J. et al.Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels.Am J Physiol Heart Circ Physiol. 2004; 286: H2434-H2441Crossref PubMed Scopus (113) Google Scholar, 10Tan B.H. Valdivia C.R. Rok B.A. et al.Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants.Heart Rhythm. 2005; 2: 741-747Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Despite these limitations, 9 of the 11 genes other than SCN5A currently believed to be associated with BrS have been identified by the candidate gene approach in the absence of linkage analysis and definitive familial segregation, and their disease-causation suggested by the absence of the specific rare variants from control cohorts.4Chen Q. Kirsch G.E. Zhang D. et al.Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392: 293-296Crossref PubMed Scopus (1523) Google Scholar, 11Antzelevitch C. Pollevick G.D. Cordeiro J.M. et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation. 2007; 115: 442-449Crossref PubMed Scopus (740) Google Scholar, 12Watanabe H. Koopmann T.T. Le Scouarnec S. et al.Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.J Clin Invest. 2008; 118: 2260-2268Crossref PubMed Scopus (395) Google Scholar, 13Delpon E. Cordeiro J.M. Nunez L. et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol. 2008; 1: 209-218Crossref PubMed Scopus (281) Google Scholar, 14Hu D. Barajas-Martinez H. Burashnikov E. et al.A mutation in the beta-3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet. 2009; 2: 270-278Crossref PubMed Scopus (215) Google Scholar, 15Medeiros-Domingo A. Tan B.H. Crotti L. et al.Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.Heart Rhythm. 2010; 7: 1466-1471Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 16Burashnikov E. Pfeiffer R. Barajas-Martinez H. et al.Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.Heart Rhythm. 2010; 7: 1872-1882Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 17Giudicessi J.R. Ye D. Tester D.J. et al.Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.Heart Rhythm. 2011; 8: 1024-1032Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 18Kattygnarath D. Maugenre S. Neyroud N. et al.MOG1: a new susceptibility gene for Brugada syndrome.Circ Cardiovasc Genet. 2011; 4: 261-268Crossref PubMed Scopus (138) Google ScholarThe present study by Holst et al., in this issue of the Canadian Journal of Cardiology, addresses the challenging issue of concluding disease-causation based on the rarity of a gene variant identified from a BrS patient cohort.19Holst A.G. Saber S. Houshmand M. et al.Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.Can J Cardiol. 2012; 28: 196-200Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The investigators utilize newly available genetic databases involving thousands of individuals without known disease, and review these databases as a resource to assess for the presence of specific, rare variants in genes reported to be associated with BrS. In their study, Holst and colleagues focus on 4 genes (SCN1B, SCN3B, KCND3, and MOG1) reported to be implicated in BrS pathogenesis. They screen an additional 3 genes (SCN2B, SCN4B, and CAV3) as biological candidates for BrS in their small BrS Danish and Iranian cohorts. The crux of this study deals with the assignment of genes as causative for BrS based on novel variants found within those genes in BrS cases. Based on the investigators own screening, and with reference to the newly available National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) exome sequencing database (http://evs.gs.washington.edu/EVS/), the authors question the reality of SCN3B, KCND3, and MOG1 as truly disease-causing BrS genes. Each of these genes were suggested to be BrS associated genes based on the observation of rare variants in relatively small series of BrS cases (0.4%-2% rare variant cases), the absence of the specific rare variants from local controls, and the demonstration of altered Nav1.5 channel behaviour in heterologous cells in the presence of the mutant.14Hu D. Barajas-Martinez H. Burashnikov E. et al.A mutation in the beta-3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet. 2009; 2: 270-278Crossref PubMed Scopus (215) Google Scholar, 17Giudicessi J.R. Ye D. Tester D.J. et al.Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.Heart Rhythm. 2011; 8: 1024-1032Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 18Kattygnarath D. Maugenre S. Neyroud N. et al.MOG1: a new susceptibility gene for Brugada syndrome.Circ Cardiovasc Genet. 2011; 4: 261-268Crossref PubMed Scopus (138) Google Scholar In each case, evidence for familial segregation of the gene variant with phenotype was absent, either due to a lack of family history or family members unavailable for testing. Holst and colleagues provide data from the exome database indicating that the previously reported BrS-associated mutations within SCN3B (Leu10Pro) and KCND3 (Gly600Arg and Leu450Phe) are noted to have been observed in this presumably healthy population of over 2000 individuals (4000 alleles), albeit at a low frequency. In regards to the MOG1 gene, the association with BrS stemming from the observation of a rare variant (Glu39Asp) found in 1/246 BrS cases, the authors note that a more radical genetic variation within this gene, Glu61X, which results in complete functional loss of the protein, is found in 1/200 healthy individuals. As pointed out by the authors, this observation suggests that loss-of-function mutations of MOG1 may be well tolerated, and not disease-causing.The bioinformatics approach used by Holst and colleagues highlights the potential value of newly generated large databases of human genome variations. While this study does not robustly disprove the association of SCN3B, KCND3, and MOG1 as genes causative for BrS, it does reasonably suggest cautious and reserved judgement in accepting their disease-causing nature. The last decade has seen an enormous increase in reports of novel genes implicated for various diseases, and many of these associations have occurred in the absence of the previous “gold standard” of linkage analysis and familial segregation. A common approach in recent years, as done in BrS, involves the screening of cohorts for rare variants in candidate genes and functional studies demonstrating altered biophysical function. These studies have justified a conclusion of disease-causation based on the absence of the specific rare variant from controls. We propose an alternative approach to safeguard against false associations. Candidate gene screening should include complete sequencing of the gene for both cases and controls, and a comparison of the number and nature of rare variants found in both populations. Functional studies should be performed on rare variants found in both cases and controls. Lastly, ideally, controls should be subsequently available for clinical phenotyping. While these measures may not ultimately provide ‘absolute proof’ of causality, the approach limits the risk of false associations and provides a more fair conclusion as to the relevance of rare variants identified in diseased cohorts.DisclosuresThe authors have no conflicts of interest to disclose. The Brugada syndrome (BrS) is an inherited arrhythmia disorder that emerged as a distinct clinical entity in the literature approximately 20 years ago.1Martini B. Nava A. Thiene G. et al.Ventricular fibrillation without apparent heart disease: a description of six cases.Am Heart J. 1989; 118: 1203-1209Abstract Full Text PDF PubMed Scopus (290) Google Scholar, 2Brugada P. Brugada J. 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. 1992; 20: 1391-1396Abstract Full Text PDF PubMed Scopus (2711) Google Scholar Characterized electrocardiographically by a coved-shape ST-segment elevation pattern in the right precordial leads, affected patients are susceptible to sudden cardiac death secondary to ventricular arrhythmias.3Roberts J.D. Gollob M.H. The genetic and clinical features of cardiac channelopathies.Future Cardiol. 2010; 6: 491-506Crossref PubMed Scopus (16) Google Scholar The first gene implicated in BrS, SCN5A, was identified in 1997 through a candidate gene approach.4Chen Q. Kirsch G.E. Zhang D. et al.Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392: 293-296Crossref PubMed Scopus (1523) Google Scholar The SCN5A gene encodes the α-subunit of Nav1.5, which mediates INa and is responsible for depolarization during Phase 0 of the cardiac action potential.5Katz A.M. Cardiac ion channels.N Engl J Med. 1993; 328: 1244-1251Crossref PubMed Scopus (100) Google Scholar Validation of SCN5A as a disease-causing gene for BrS has occurred over subsequent years from independent investigators around the world, and this gene may now be tested commercially in identified cases of BrS for the purpose of family cascade screening.6Gollob M.H. Blier L. Brugada R. et al.Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society join position paper.Can J Cardiol. 2011; 27: 232-245Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Approximately 20% of patients with BrS are genotype positive for culprit mutations within SCN5A. Since the initial discovery of SCN5A as a disease-causing gene, there have been a total of 11 different genes reported to be causative for the disorder, which collectively have been suggested to account for up to 40% of cases.6Gollob M.H. Blier L. Brugada R. et al.Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society join position paper.Can J Cardiol. 2011; 27: 232-245Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar The traditional and most reliable approach for identifying genes responsible for inherited disorders has been through linkage analysis which requires the presence of large families with multiple affected and unaffected members. Genes identified through linkage analysis provide strong evidence for disease association, as the culprit gene mutation is demonstrated to segregate with affected family members and is absent from healthy relatives (assuming complete disease penetrance). Although BrS is considered an autosomal dominant condition, reports of large affected families allowing for segregation analysis are rare, and sporadic cases account for a large proportion of affected patients. Thus, gene discovery for BrS (and many other conditions) has depended on the screening of biologically plausible candidate genes, and “proven” disease-association by the absence of the specific genetic variation from control cohorts. Such an approach is not without risk of false associations, because rare variants are by definition ‘rare,' and their absence from a control cohort may not be meaningful. It has been well established that even “healthy controls” harbour rare genetic variants in genes considered “biologically plausible” or known to be disease-causing for numerous conditions, including hereditary arrhythmia syndromes.7Kapa S. Tester D.J. Salisbury B.A. et al.Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.Circulation. 2009; 120: 1752-1760Crossref PubMed Scopus (275) Google Scholar, 8Kapplinger J.D. Landstrom A.P. Salisbury B.A. et al.Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.J Am Coll Cardiol. 2011; 57: 2317-2327Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Investigators will often argue that functional differences in the biologic behaviour of rare variants support their disease-causation. While often true, altered biological function alone cannot conclude disease-causation on all occasions, as even common polymorphisms may display altered function, yet by virtue of their frequency in the normal population are not disease-causing.9Anson B.D. Ackerman M.J. Tester D.J. et al.Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels.Am J Physiol Heart Circ Physiol. 2004; 286: H2434-H2441Crossref PubMed Scopus (113) Google Scholar, 10Tan B.H. Valdivia C.R. Rok B.A. et al.Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants.Heart Rhythm. 2005; 2: 741-747Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Despite these limitations, 9 of the 11 genes other than SCN5A currently believed to be associated with BrS have been identified by the candidate gene approach in the absence of linkage analysis and definitive familial segregation, and their disease-causation suggested by the absence of the specific rare variants from control cohorts.4Chen Q. Kirsch G.E. Zhang D. et al.Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392: 293-296Crossref PubMed Scopus (1523) Google Scholar, 11Antzelevitch C. Pollevick G.D. Cordeiro J.M. et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation. 2007; 115: 442-449Crossref PubMed Scopus (740) Google Scholar, 12Watanabe H. Koopmann T.T. Le Scouarnec S. et al.Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.J Clin Invest. 2008; 118: 2260-2268Crossref PubMed Scopus (395) Google Scholar, 13Delpon E. Cordeiro J.M. Nunez L. et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol. 2008; 1: 209-218Crossref PubMed Scopus (281) Google Scholar, 14Hu D. Barajas-Martinez H. Burashnikov E. et al.A mutation in the beta-3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet. 2009; 2: 270-278Crossref PubMed Scopus (215) Google Scholar, 15Medeiros-Domingo A. Tan B.H. Crotti L. et al.Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.Heart Rhythm. 2010; 7: 1466-1471Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 16Burashnikov E. Pfeiffer R. Barajas-Martinez H. et al.Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.Heart Rhythm. 2010; 7: 1872-1882Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 17Giudicessi J.R. Ye D. Tester D.J. et al.Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.Heart Rhythm. 2011; 8: 1024-1032Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 18Kattygnarath D. Maugenre S. Neyroud N. et al.MOG1: a new susceptibility gene for Brugada syndrome.Circ Cardiovasc Genet. 2011; 4: 261-268Crossref PubMed Scopus (138) Google Scholar The present study by Holst et al., in this issue of the Canadian Journal of Cardiology, addresses the challenging issue of concluding disease-causation based on the rarity of a gene variant identified from a BrS patient cohort.19Holst A.G. Saber S. Houshmand M. et al.Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.Can J Cardiol. 2012; 28: 196-200Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The investigators utilize newly available genetic databases involving thousands of individuals without known disease, and review these databases as a resource to assess for the presence of specific, rare variants in genes reported to be associated with BrS. In their study, Holst and colleagues focus on 4 genes (SCN1B, SCN3B, KCND3, and MOG1) reported to be implicated in BrS pathogenesis. They screen an additional 3 genes (SCN2B, SCN4B, and CAV3) as biological candidates for BrS in their small BrS Danish and Iranian cohorts. The crux of this study deals with the assignment of genes as causative for BrS based on novel variants found within those genes in BrS cases. Based on the investigators own screening, and with reference to the newly available National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) exome sequencing database (http://evs.gs.washington.edu/EVS/), the authors question the reality of SCN3B, KCND3, and MOG1 as truly disease-causing BrS genes. Each of these genes were suggested to be BrS associated genes based on the observation of rare variants in relatively small series of BrS cases (0.4%-2% rare variant cases), the absence of the specific rare variants from local controls, and the demonstration of altered Nav1.5 channel behaviour in heterologous cells in the presence of the mutant.14Hu D. Barajas-Martinez H. Burashnikov E. et al.A mutation in the beta-3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet. 2009; 2: 270-278Crossref PubMed Scopus (215) Google Scholar, 17Giudicessi J.R. Ye D. Tester D.J. et al.Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.Heart Rhythm. 2011; 8: 1024-1032Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 18Kattygnarath D. Maugenre S. Neyroud N. et al.MOG1: a new susceptibility gene for Brugada syndrome.Circ Cardiovasc Genet. 2011; 4: 261-268Crossref PubMed Scopus (138) Google Scholar In each case, evidence for familial segregation of the gene variant with phenotype was absent, either due to a lack of family history or family members unavailable for testing. Holst and colleagues provide data from the exome database indicating that the previously reported BrS-associated mutations within SCN3B (Leu10Pro) and KCND3 (Gly600Arg and Leu450Phe) are noted to have been observed in this presumably healthy population of over 2000 individuals (4000 alleles), albeit at a low frequency. In regards to the MOG1 gene, the association with BrS stemming from the observation of a rare variant (Glu39Asp) found in 1/246 BrS cases, the authors note that a more radical genetic variation within this gene, Glu61X, which results in complete functional loss of the protein, is found in 1/200 healthy individuals. As pointed out by the authors, this observation suggests that loss-of-function mutations of MOG1 may be well tolerated, and not disease-causing. The bioinformatics approach used by Holst and colleagues highlights the potential value of newly generated large databases of human genome variations. While this study does not robustly disprove the association of SCN3B, KCND3, and MOG1 as genes causative for BrS, it does reasonably suggest cautious and reserved judgement in accepting their disease-causing nature. The last decade has seen an enormous increase in reports of novel genes implicated for various diseases, and many of these associations have occurred in the absence of the previous “gold standard” of linkage analysis and familial segregation. A common approach in recent years, as done in BrS, involves the screening of cohorts for rare variants in candidate genes and functional studies demonstrating altered biophysical function. These studies have justified a conclusion of disease-causation based on the absence of the specific rare variant from controls. We propose an alternative approach to safeguard against false associations. Candidate gene screening should include complete sequencing of the gene for both cases and controls, and a comparison of the number and nature of rare variants found in both populations. Functional studies should be performed on rare variants found in both cases and controls. Lastly, ideally, controls should be subsequently available for clinical phenotyping. While these measures may not ultimately provide ‘absolute proof’ of causality, the approach limits the risk of false associations and provides a more fair conclusion as to the relevance of rare variants identified in diseased cohorts. DisclosuresThe authors have no conflicts of interest to disclose. The authors have no conflicts of interest to disclose." @default.
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