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Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Barc, Julien; Tadros, Rafik; Glinge, Charlotte; Chiang, David Y; Jouni, Mariam; Simonet, Floriane; Jurgens, Sean J; Baudic, Manon; Nicastro, Michele; Potet, Franck; Offerhaus, Joost A; Walsh, Roddy; Choi, Seung Hoan; Verkerk, Arie O; Mizusawa, Yuka; Anys, Soraya; Minois, Damien; Arnaud, Marine; Duchateau, Josselin; Wijeyeratne, Yanushi D; Muir, Alison; Papadakis, Michael; Castelletti, Silvia; Torchio, Margherita; Ortuño, Cristina Gil; Lacunza, Javier; Giachino, Daniela F; Cerrato, Natascia; Martins, Raphaël P; Campuzano, Oscar; Van Dooren, Sonia; Thollet, Aurélie; Kyndt, Florence; Mazzanti, Andrea; Clémenty, Nicolas; Bisson, Arnaud; Corveleyn, Anniek; Stallmeyer, Birgit; Dittmann, Sven; Saenen, Johan; Noël, Antoine; Honarbakhsh, Shohreh; Rudic, Boris; Marzak, Halim; Rowe, Matthew K; Federspiel, Claire; Le Page, Sophie; Placide, Leslie; Milhem, Antoine; Barajas-Martinez, Hector; Beckmann, Britt-Maria; Krapels, Ingrid P; Steinfurt, Johannes; Winkel, Bo Gregers; Jabbari, Reza; Shoemaker, Moore B; Boukens, Bas J; Å korić-Milosavljević, Doris; Bikker, Hennie; Manevy, Federico; Lichtner, Peter; Ribasés, Marta; Meitinger, Thomas; Müller-Nurasyid, Martina; Veldink, Jan H; van den Berg, Leonard H; Van Damme, Philip; Cusi, Daniele; Lanzani, Chiara; Rigade, Sidwell; Charpentier, Eric; Baron, Estelle; Bonnaud, Stéphanie; Lecointe, Simon; Donnart, Audrey; Le Marec, Hervé; Chatel, Stéphanie; Karakachoff, Matilde; Bézieau, Stéphane; London, Barry; Tfelt-Hansen, Jacob; Roden, Dan; Odening, Katja E; Cerrone, Marina; Chinitz, Larry A; Volders, Paul G; van de Berg, Maarten P; Laurent, Gabriel; Faivre, Laurence; Antzelevitch, Charles; Kääb, Stefan; Arnaout, Alain Al; Dupuis, Jean-Marc; Pasquie, Jean-Luc; Billon, Olivier; Roberts, Jason D; Jesel, Laurence; Borggrefe, Martin; Lambiase, Pier D; Mansourati, Jacques; Loeys, Bart; Leenhardt, Antoine; Guicheney, Pascale; Maury, Philippe; Schulze-Bahr, Eric; Robyns, Tomas; Breckpot, Jeroen; Babuty, Dominique; Priori, Silvia G; Napolitano, Carlo; de Asmundis, Carlo; Brugada, Pedro; Brugada, Ramon; Arbelo, Elena; Brugada, Josep; Mabo, Philippe; Behar, Nathalie; Giustetto, Carla; Molina, Maria Sabater; Gimeno, Juan R; Hasdemir, Can; Schwartz, Peter J; Crotti, Lia; McKeown, Pascal P; Sharma, Sanjay; Behr, Elijah R; Haissaguerre, Michel; Sacher, Frédéric; Rooryck, Caroline; Tan, Hanno L; Remme, Carol A; Postema, Pieter G; Delmar, Mario; Ellinor, Patrick T; Lubitz, Steven A; Gourraud, Jean-Baptiste; Tanck, Michael W; George, Alfred L; MacRae, Calum A; Burridge, Paul W; Dina, Christian; Probst, Vincent; Wilde, Arthur A; Schott, Jean-Jacques; Redon, Richard; Bezzina, Connie R
PMID: 35474365
ISSN: 1546-1718
CID: 5205632

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Barc, Julien; Tadros, Rafik; Glinge, Charlotte; Chiang, David Y; Jouni, Mariam; Simonet, Floriane; Jurgens, Sean J; Baudic, Manon; Nicastro, Michele; Potet, Franck; Offerhaus, Joost A; Walsh, Roddy; Choi, Seung Hoan; Verkerk, Arie O; Mizusawa, Yuka; Anys, Soraya; Minois, Damien; Arnaud, Marine; Duchateau, Josselin; Wijeyeratne, Yanushi D; Muir, Alison; Papadakis, Michael; Castelletti, Silvia; Torchio, Margherita; Ortuño, Cristina Gil; Lacunza, Javier; Giachino, Daniela F; Cerrato, Natascia; Martins, Raphaël P; Campuzano, Oscar; Van Dooren, Sonia; Thollet, Aurélie; Kyndt, Florence; Mazzanti, Andrea; Clémenty, Nicolas; Bisson, Arnaud; Corveleyn, Anniek; Stallmeyer, Birgit; Dittmann, Sven; Saenen, Johan; Noël, Antoine; Honarbakhsh, Shohreh; Rudic, Boris; Marzak, Halim; Rowe, Matthew K; Federspiel, Claire; Le Page, Sophie; Placide, Leslie; Milhem, Antoine; Barajas-Martinez, Hector; Beckmann, Britt-Maria; Krapels, Ingrid P; Steinfurt, Johannes; Winkel, Bo Gregers; Jabbari, Reza; Shoemaker, Moore B; Boukens, Bas J; Å korić-Milosavljević, Doris; Bikker, Hennie; Manevy, Federico C; Lichtner, Peter; Ribasés, Marta; Meitinger, Thomas; Müller-Nurasyid, Martina; Veldink, Jan H; van den Berg, Leonard H; Van Damme, Philip; Cusi, Daniele; Lanzani, Chiara; Rigade, Sidwell; Charpentier, Eric; Baron, Estelle; Bonnaud, Stéphanie; Lecointe, Simon; Donnart, Audrey; Le Marec, Hervé; Chatel, Stéphanie; Karakachoff, Matilde; Bézieau, Stéphane; London, Barry; Tfelt-Hansen, Jacob; Roden, Dan; Odening, Katja E; Cerrone, Marina; Chinitz, Larry A; Volders, Paul G; van de Berg, Maarten P; Laurent, Gabriel; Faivre, Laurence; Antzelevitch, Charles; Kääb, Stefan; Arnaout, Alain Al; Dupuis, Jean-Marc; Pasquie, Jean-Luc; Billon, Olivier; Roberts, Jason D; Jesel, Laurence; Borggrefe, Martin; Lambiase, Pier D; Mansourati, Jacques; Loeys, Bart; Leenhardt, Antoine; Guicheney, Pascale; Maury, Philippe; Schulze-Bahr, Eric; Robyns, Tomas; Breckpot, Jeroen; Babuty, Dominique; Priori, Silvia G; Napolitano, Carlo; de Asmundis, Carlo; Brugada, Pedro; Brugada, Ramon; Arbelo, Elena; Brugada, Josep; Mabo, Philippe; Behar, Nathalie; Giustetto, Carla; Molina, Maria Sabater; Gimeno, Juan R; Hasdemir, Can; Schwartz, Peter J; Crotti, Lia; McKeown, Pascal P; Sharma, Sanjay; Behr, Elijah R; Haissaguerre, Michel; Sacher, Frédéric; Rooryck, Caroline; Tan, Hanno L; Remme, Carol A; Postema, Pieter G; Delmar, Mario; Ellinor, Patrick T; Lubitz, Steven A; Gourraud, Jean-Baptiste; Tanck, Michael W; George, Alfred L; MacRae, Calum A; Burridge, Paul W; Dina, Christian; Probst, Vincent; Wilde, Arthur A; Schott, Jean-Jacques; Redon, Richard; Bezzina, Connie R
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
PMID: 35210625
ISSN: 1546-1718
CID: 5172442

Sudden cardiac death in the young: are we still missing the opportunity to prevent recurrencies in the family? [Editorial]

Priori, Silvia G; Marino, Maira; Couns, Gen
PMID: 34157372
ISSN: 1556-3871
CID: 4918362

Management of Congenital Long-QT Syndrome: Commentary From the Experts

Kaufman, Elizabeth S; Eckhardt, Lee L; Ackerman, Michael J; Aziz, Peter F; Behr, Elijah R; Cerrone, Marina; Chung, Mina K; Cutler, Michael J; Etheridge, Susan P; Krahn, Andrew D; Lubitz, Steven A; Perez, Marco V; Priori, Silvia G; Roberts, Jason D; Roden, Dan M; Schulze-Bahr, Eric; Schwartz, Peter J; Shimizu, Wataru; Shoemaker, M Benjamin; Sy, Raymond W; Towbin, Jeffrey A; Viskin, Sami; A M Wilde, Arthur; Zareba, Wojciech
While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
PMID: 34238011
ISSN: 1941-3084
CID: 4933462

Precision Medicine in Catecholaminergic Polymorphic Ventricular Tachycardia: JACC Focus Seminar 5/5

Priori, Silvia G; Mazzanti, Andrea; Santiago, Demetrio J; Kukavica, Deni; Trancuccio, Alessandro; Kovacic, Jason C
In this final of a 5-part Focus Seminar series on precision medicine, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT). This focus on CPVT allows us to take a "deep dive" and explore the full extent of the precision medicine opportunities for a single cardiovascular condition at a level that was not possible in the preceding articles. As a new paradigm presented in this article, it has become clear that CPVT can occur as either a typical or atypical form. Although there is a degree of overlap between the typical and atypical forms, it is notable that they arise due to different underlying genetic changes, likely exhibiting differing mechanisms of action, and presenting with different phenotypic features. The recognition of these differing forms of CPVT and their different etiologies and mechanisms is an important step toward implementing rapidly emerging precision medicine approaches that will tailor novel therapies to specific gene defects.
PMID: 34016269
ISSN: 1558-3597
CID: 4877582

Identification of Loss-of-function RyR2 Mutations Associated with Idiopathic Ventricular Fibrillation and Sudden Death

Zhong, Xiaowei; Guo, Wenting; Wei, Jinhong; Tang, Yijun; Liu, Yingjie; Zhang, Joe Z; Tan, Vern Hsen; Zhang, Lin; Wang, Ruiwu; Jones, Peter P; Napolitano, Carlo; Priori, Silvia G; Chen, S R Wayne
Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release in HEK293 cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.
PMID: 33825858
ISSN: 1573-4935
CID: 4839252

Left ventricular myocardial work in patients with severe aortic stenosis

Fortuni, Federico; Butcher, Steele C; van der Kley, Frank; Lustosa, Rodolfo P; Karalis, Ioannis; de Weger, Arend; Priori, Silvia G; van der Bijl, Pieter; Bax, Jeroen J; Delgado, Victoria; Marsan, Nina Ajmone
BACKGROUND:Left ventricular myocardial work (LVMW) is a novel method to assess LV function utilizing pressure-strain loops that takes into consideration LV afterload. The estimation of LV afterload in severe aortic stenosis (AS) may be challenging and no study so far has investigated LVMW in this setting. The aim of this study was to develop a method to calculate LVMW in severe AS and to analyze its relationship with heart failure (HF) symptoms. METHODS:Indices of LVMW were calculated in 120 patients with severe AS who underwent transcatheter aortic valve replacement and invasive LV and aortic pressure measurements. LV systolic pressure was also derived by adding the mean aortic valve gradient to the aortic systolic pressure. LV global longitudinal strain (GLS) and echocardiography-derived LV systolic pressure were then incorporated to construct pressure-strain loops of the LV. RESULTS:An excellent correlation was observed between LVMW indices calculated with the invasive and echocardiography-derived LV systolic pressure. Patients in NYHA class III-IV (n=97, 73%) had lower LV GLS, LV global work index (GWI), LV global constructive work (GCW), and right ventricular free-wall strain compared to those in NYHA class I-II. In contrast to LV GLS, LVGWI (OR per-100mmHg%-increase 0.91; 95%CI 0.85-0.98; P=0.012) and LVGCW showed an independent association with NYHA class III-IV HF symptoms. CONCLUSION/CONCLUSIONS:The calculation of echocardiography-based LVMW indices is feasible in patients with severe AS. In particular, LVGWI and GCW showed an independent association with HF symptoms and may provide additional information on myocardial remodeling and function in severe AS.
PMID: 33181281
ISSN: 1097-6795
CID: 4665452

Cardiac ryanodine receptor calcium release deficiency syndrome

Sun, Bo; Yao, Jinjing; Ni, Mingke; Wei, Jinhong; Zhong, Xiaowei; Guo, Wenting; Zhang, Lin; Wang, Ruiwu; Belke, Darrell; Chen, Yong-Xiang; Lieve, Krystien V V; Broendberg, Anders K; Roston, Thomas M; Blankoff, Ivan; Kammeraad, Janneke A; von Alvensleben, Johannes C; Lazarte, Julieta; Vallmitjana, Alexander; Bohne, Loryn J; Rose, Robert A; Benitez, Raul; Hove-Madsen, Leif; Napolitano, Carlo; Hegele, Robert A; Fill, Michael; Sanatani, Shubhayan; Wilde, Arthur A M; Roberts, Jason D; Priori, Silvia G; Jensen, Henrik K; Chen, S R Wayne
Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.
PMID: 33536282
ISSN: 1946-6242
CID: 4776502

Evolving determinants of carotid atherosclerosis vulnerability in asymptomatic patients from the MAGNETIC observational study

Catalano, Oronzo; Bendotti, Giulia; Mori, Alessia; De Salvo, Maria; Falconi, Marialuisa; Aloi, Teresa L; Tibollo, Valentina; Bellazzi, Riccardo; Bardile, Alberto Ferrari; Montagna, Stefano; Pesarin, Clara; Poggi, Paolo; Pedretti, Roberto F E; Priori, Silvia G
MRI can assess plaque composition and has demonstrated an association between some atherosclerotic risk factors (RF) and markers of plaque vulnerability in naive patients. We aimed at investigating this association in medically treated asymptomatic patients. This is a cross-sectional interim analysis (August 2013-September 2016) of a single center prospective study on carotid plaque vulnerability (MAGNETIC study). We recruited patients with asymptomatic carotid atherosclerosis (US stenosis > 30%, ECST criteria), receiving medical treatments at a tertiary cardiac rehabilitation. Atherosclerotic burden and plaque composition were quantified with 3.0 T MRI. The association between baseline characteristics and extent of lipid-rich necrotic core (LRNC), fibrous cap (CAP) and intraplaque hemorrhage (IPH) was studied with multiple regression analysis. We enrolled 260 patients (198 male, 76%) with median age of 71-y (interquartile range: 65-76). Patients were on antiplatelet therapy, ACE-inhibitors/angiotensin receptor blockers and statins (196-229, 75-88%). Median LDL-cholesterol was 78 mg/dl (59-106), blood pressure 130/70 mmHg (111-140/65-80), glycosylated hemoglobin 46 mmol/mol (39-51) and BMI 25 kg/m2 (23-28); moreover, 125 out of 187 (67%) patients were ex-smokers. Multivariate analysis of a data-set of 487 (94%) carotid arteries showed that a history of hypercholesterolemia, diabetes, hypertension or smoking did not correlate with LRNC, CAP or IPH. Conversely, maximum stenosis was the strongest independent predictor of LRNC, CAP and IPH (p < 0.001). MRI assessment of plaque composition in patients on treatment for asymptomatic carotid atherosclerosis shows no correlation between plaque vulnerability and the most well-controlled modifiable RF. Conversely, maximum stenosis exhibits a strong correlation with vulnerable features despite treatment.
PMCID:7840938
PMID: 33504842
ISSN: 2045-2322
CID: 4767372

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Walsh, Roddy; Lahrouchi, Najim; Tadros, Rafik; Kyndt, Florence; Glinge, Charlotte; Postema, Pieter G; Amin, Ahmad S; Nannenberg, Eline A; Ware, James S; Whiffin, Nicola; Mazzarotto, Francesco; Å korić-Milosavljević, Doris; Krijger, Christian; Arbelo, Elena; Babuty, Dominique; Barajas-Martinez, Hector; Beckmann, Britt M; Bézieau, Stéphane; Bos, J Martijn; Breckpot, Jeroen; Campuzano, Oscar; Castelletti, Silvia; Celen, Candan; Clauss, Sebastian; Corveleyn, Anniek; Crotti, Lia; Dagradi, Federica; de Asmundis, Carlo; Denjoy, Isabelle; Dittmann, Sven; Ellinor, Patrick T; Ortuño, Cristina Gil; Giustetto, Carla; Gourraud, Jean-Baptiste; Hazeki, Daisuke; Horie, Minoru; Ishikawa, Taisuke; Itoh, Hideki; Kaneko, Yoshiaki; Kanters, Jørgen K; Kimoto, Hiroki; Kotta, Maria-Christina; Krapels, Ingrid P C; Kurabayashi, Masahiko; Lazarte, Julieta; Leenhardt, Antoine; Loeys, Bart L; Lundin, Catarina; Makiyama, Takeru; Mansourati, Jacques; Martins, Raphaël P; Mazzanti, Andrea; Mörner, Stellan; Napolitano, Carlo; Ohkubo, Kimie; Papadakis, Michael; Rudic, Boris; Molina, Maria Sabater; Sacher, Frédéric; Sahin, Hatice; Sarquella-Brugada, Georgia; Sebastiano, Regina; Sharma, Sanjay; Sheppard, Mary N; Shimamoto, Keiko; Shoemaker, M Benjamin; Stallmeyer, Birgit; Steinfurt, Johannes; Tanaka, Yuji; Tester, David J; Usuda, Keisuke; van der Zwaag, Paul A; Van Dooren, Sonia; Van Laer, Lut; Winbo, Annika; Winkel, Bo G; Yamagata, Kenichiro; Zumhagen, Sven; Volders, Paul G A; Lubitz, Steven A; Antzelevitch, Charles; Platonov, Pyotr G; Odening, Katja E; Roden, Dan M; Roberts, Jason D; Skinner, Jonathan R; Tfelt-Hansen, Jacob; van den Berg, Maarten P; Olesen, Morten S; Lambiase, Pier D; Borggrefe, Martin; Hayashi, Kenshi; Rydberg, Annika; Nakajima, Tadashi; Yoshinaga, Masao; Saenen, Johan B; Kääb, Stefan; Brugada, Pedro; Robyns, Tomas; Giachino, Daniela F; Ackerman, Michael J; Brugada, Ramon; Brugada, Josep; Gimeno, Juan R; Hasdemir, Can; Guicheney, Pascale; Priori, Silvia G; Schulze-Bahr, Eric; Makita, Naomasa; Schwartz, Peter J; Shimizu, Wataru; Aiba, Takeshi; Schott, Jean-Jacques; Redon, Richard; Ohno, Seiko; Probst, Vincent; Behr, Elijah R; Barc, Julien; Bezzina, Connie R
PURPOSE/OBJECTIVE:Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS:We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS:). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION/CONCLUSIONS:Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
PMID: 32893267
ISSN: 1530-0366
CID: 4588752