Reappraisal of Reported Genes for Sudden Arrhythmic Death

Hosseini, S. Mohsen; Kim, Raymond H.; Udupa, Sharmila; Costain, Gregory; Jobling, Rebekah; Liston, Eriskay; Jamal, Seema M.; Szybowska, Marta; Morel, Chantal F.; Bowdin, Sarah; Garcia, John; Care, Melanie; Sturm, Amy C.; Novelli, Valeria; Ackerman, Michael J.; Ware, James S.; Hershberger, Ray E.; Wilde, Arthur A.M.; Gollob, Michael H.

doi:10.1161/circulationaha.118.035070

Cited by 304 publications

(189 citation statements)

References 27 publications

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“…Most BrS patients are males, who have a higher risk of arrhythmic events than females . While more than 20 BrS‐associated genes have been identified, only SCN5A has sufficient genetic evidence suggesting that it is a genetic cause of disease, accounting for 20%‐25% of BrS cases, Despite these advances, genetic testing is still not recommended for BrS risk stratification . Although prior studies have investigated the role of SCN5A mutations in the prevalence, pathogenesis and prognosis of BrS, findings regarding phenotypic feature differences between SCN5A mutation carriers and non‐carriers are inconsistent across studies .…”

Section: Introductionmentioning

confidence: 99%

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

et al. 2019

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Whether the presence of SCN5A mutation is a predictor of BrS risk remains controversial, and patient selection bias may have weakened previous findings. Therefore, we performed this study to clarify the clinical characteristics and outcomes of BrS probands with SCN5A mutations. We systematically retrieved eligible studies published through October 2018. A total of 17 studies enrolling 1780 BrS patients were included. Overall, our results found that compared with BrS patients without SCN5A mutations, patients with SCN5A mutations exhibited a younger age at the onset of symptoms and higher rate of the spontaneous type-1 electrocardiogram pattern, more pronounced conduction or repolarization abnormalities, and increased atrial vulnerability. In addition, the presence of SCN5A mutations was associated with an elevated risk of major arrhythmic events in both Asian (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.07-3.11; P = .03) and Caucasian (OR = 2.24, 95% CI 1.02-4.90; P = .04) populations. In conclusions, patients with SCN5A mutations exhibit more pronounced electrophysiological defects and more severe prognosis.Clinicians should be cautious when utilizing genetic testing for risk stratification or treatment guidance before determining whether the causal relationship regarding SCN5A mutation status is an independent predictor of risk.

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Section: Introductionmentioning

confidence: 99%

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

et al. 2019

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“…Our report is the first exhaustive genetic interpretation of more than 40 minor genes associated with BrS. In a recent study, an evaluation of 21 genes currently tested by diagnostic for BrS, demonstrate only SCN5A as definitive BrS-causative, whereas all other genes were classified as limited evidence (Hosseini et al, 2018). Our comprehensive genetic study identified 135 additional rare variants, all potentially associated with a phenotype diagnosed as BrS.…”

Section: Discussionmentioning

confidence: 79%

“…Recent guidelines only recommend analysis of SCN5A in suspected BrS cases (Priori & Blomstrom-Lundqvist, 2015). A recent study evaluating the clinical validity of 21 genes for BrS diagnosis supports this single-gene approach in BrS patients (Hosseini et al, 2018). The authors conclude that only SCN5A…”

Section: Discussionmentioning

confidence: 93%

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Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

et al. 2019

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Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.

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“…This protein consists of 2016 residues with 24 membrane-spanning helices in four homologous domains ( Figure 1). Variants in SCN5A cause multiple distinct genetic arrhythmia syndromes: complete or partial loss of function variants are the most common genetic cause of Brugada Syndrome (BrS1) 1 and gain of function variants are the third most common genetic cause of congenital Long QT Syndrome (LQT3; Figure 1). 2 SCN5A variants have also been associated with isolated conduction system disease, atrial fibrillation, and dilated cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Glazer

Kroncke

Matreyek

et al. 2019

Preprint

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Variants in ion channel genes have classically been studied in lowthroughput by patch clamping. Deep Mutational Scanning (DMS) is a complementary approach that can simultaneously assess function of thousands of variants. We have developed and validated a method to perform a DMS of variants in SCN5A, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells. In preliminary experiments, challenge with three drugs (veratridine, brevetoxin, and ouabain) could discriminate wildtype channels from gain and loss of function pathogenic variants. High-throughput sequencing of the pre-and post-drug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The DMS scores identified 40 putative gain of function and 33 putative loss of function variants. For 8/9 variants, patch clamping data was consistent with the scores. These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.

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Reappraisal of Reported Genes for Sudden Arrhythmic Death

Abstract: Supplemental Digital Content is available in the text.

Cited by 304 publications

References 27 publications

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

Deep Mutational Scan of a cardiac sodium channel voltage sensor

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