European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases

Wilde, Arthur A.M.; Semsarian, Christopher; Márquez, Manlio F.; Shamloo, Alireza Sepehri; Ackerman, Michael J.; Ashley, Euan A.; Sternick, Eduardo Back; Barajas-Martinez, Héctor; Behr, Elijah R.; Bezzina, Connie R.; Breckpot, Jeroen; Charron, P.; Chockalingam, Priya; Crotti, Lia; Gollob, Michael H.; Lubitz, Steven A.; Makita, Naomasa; Ohno, Seiko; Ortiz-Genga, Martín; Sacilotto, Luciana; Schulze‐Bahr, Eric; Shimizu, Wataru; Sotoodehnia, Nona; Tadros, Rafik; Ware, James S.; Winlaw, David S.; Kaufman, Elizabeth S.; Aiba, Takeshi; Bollmann, A; Choi, Jong Il; Aarti, Dalal; Francisco, Darrieux; Giudicessi, John R.; Guerchicoff, Mariana; Hong, Kui; Krahn, Andrew D.; MacIntyre, Ciorsti; Mackall, Judith A.; Lluís, Mont; Carlo, Napolitano; Ochoa, Juan Pablo; Peichl, Petr; Pereira, Alexandre C.; Schwartz, Peter J.; Jon, Skinner; Stellbrink, Christoph; Tfelt-Hansen, Jacob; Deneke, Thomas

doi:10.1016/j.hrthm.2022.03.1225

Cited by 135 publications

(134 citation statements)

References 490 publications

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“…Genetic testing was performed in 161, and 36 cases carried a rare variant in the SCN5A gene (22.36%). This percentage is according to the widely accepted genetic yield in BrS [ 31 ], with SCN5A being the main gene currently associated with this arrhythmogenic syndrome [ 32 ]. Other minor genes encoding sodium subunits or associated proteins have been proposed as potential causes of BrS, but further studies should be conducted to conclude their definite role [ 3 ].…”

Section: Resultsmentioning

confidence: 99%

“…Of all the analyzed manuscripts concerning structural alterations, few were performed by expert cardiopathologists, and this fact may represent a limitation due to the particular technical difficulty of microscopic diagnosis. Some centers included cardiac magnetic resonance (CMR) as part of BrS assessment despite not being included in current guidelines [ 32 ]. Therefore, further studies focused on analyzing potential correlations between BrS and structural abnormalities are needed to clarify whether BrS can definitively be reclassified as a cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

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Structural Heart Alterations in Brugada Syndrome: Is it Really a Channelopathy? A Systematic Review

Oliva

Grassi

Pinchi

et al. 2022

JCM

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Brugada syndrome (BrS) is classified as an inherited cardiac channelopathy attributed to dysfunctional ion channels and/or associated proteins in cardiomyocytes rather than to structural heart alterations. However, hearts of some BrS patients exhibit slight histologic abnormalities, suggesting that BrS could be a phenotypic variant of arrhythmogenic cardiomyopathy. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. Our comprehensive analysis of structural findings did not reveal enough definitive evidence for reclassification of BrS as a cardiomyopathy. The collection and comprehensive analysis of new cases with a definitive BrS diagnosis are needed to clarify whether some of these structural features may have key roles in the pathophysiological pathways associated with malignant arrhythmogenic episodes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structural Heart Alterations in Brugada Syndrome: Is it Really a Channelopathy? A Systematic Review

Oliva

Grassi

Pinchi

et al. 2022

JCM

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“…To prevent overdiagnosis, substantiated suspicion of LQTS, based on the Schwartz score, is needed before patients are referred for detailed genetic testing [8][9][10][11]. The Schwartz score, based on ECG parameters, medical history and family history, scores a patient as having a low, intermediate, or high probability of LQTS.…”

Section: Introductionmentioning

confidence: 99%

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

Copier

Bootsma

et al. 2022

Preprint

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Background: Variants in KCNH2, encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods: A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2, (II) KCNH2-p.S906L alone (homozygous, Hm) or (III) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data. Results: Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2, or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared to KCNH2-WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%. Conclusion: The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

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“…Sudden deaths can be classified as sudden cardiac death (SCD) when SD has a cardiac primary origin or as SD from non-cardiac origin. In SCD cases, molecular screening for pathogenic mutations in SCD-related genes is common practice [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Those studies showed that less than 3% of total cases carried exonic pathogenic variants (P) and 26% likely pathogenic (LP) variants. Thus, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) in more than 70% of cases in the concurrent absence of clearly pathogenic mutations [ 1 , 2 ]. The presence of VUS variants is an uninformative genetic result in terms of clinical management, and genetic and clinical professionals cannot make informed clinical decisions based on such a classification.…”

Section: Introductionmentioning

confidence: 99%

Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

Coll

Fernández-Falgueras

Iglesias

et al. 2022

IJMS

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Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up.

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European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases

Cited by 135 publications

References 490 publications

Structural Heart Alterations in Brugada Syndrome: Is it Really a Channelopathy? A Systematic Review

Structural Heart Alterations in Brugada Syndrome: Is it Really a Channelopathy? A Systematic Review

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

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