Genotype–phenotype relationship and risk stratification in loss‐of‐function <i><scp>SCN</scp>5A</i> mutation carriers

Robyns, Tomas; Nuyens, Dieter; Vandenberk, Bert; Kuipéri, Cuno; Corveleyn, Anniek; Breckpot, Jeroen; Garweg, Christophe; Ector, Joris; Willems, Rik

doi:10.1111/anec.12548

Cited by 8 publications

(10 citation statements)

References 44 publications

(83 reference statements)

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“…Another possibility is incomplete penetrance despite the presence of the mutated gene or variable expressivity (Giudicessi and Ackerman, 2013). Whilst the genetic epidemiology of BrS has been extensively studied in Western populations (Meregalli et al, 2009;Hu et al, 2014;Baruteau et al, 2018;Robyns et al, 2018), data from Asian countries are less complete.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong

et al. 2020

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Background: The aim of this study is to report on the genetic composition of Brugada syndrome (BrS) patients undergoing genetic testing in Hong Kong. Methods: Patients with suspected BrS who presented to the Hospital Authority of Hong Kong between 1997 and 2019, and underwent genetic testing, were analyzed retrospectively. Results: A total of 65 subjects were included (n = 65, 88% male, median presenting age 42 [30-54] years old, 58% type 1 pattern). Twenty-two subjects (34%) showed abnormal genetic test results, identifying the following six novel, pathogenic or likely pathogenic mutations in SCN5A: c.674G > A, c.2024-11T > A, c.2042A > C, c.4279G > T, c.5689C > T, c.429del. Twenty subjects (31%) in the cohort suffered from spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and 18 (28%) had incident VT/VF over a median follow-up of 83 [Q1-Q3: 52-112] months. Univariate Cox regression demonstrated that syncope (hazard ratio [

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…Until now, whether the SCN5A mutation status is an independent predictor of risk in BrS still remains controversial. More importantly, some of previous studies included asymptomatic SCN5A-positive family members of BrS probands, 12,[19][20][21][22][23][24][25] which might lead to patient selection bias and further alleviate the results because SCN5A mutations seemly do not elevate the arrhythmic risks in asymptomatic patients. 13,21,26 To reduce selection bias, we performed this study to fully characterize the relationship between the SCN5A mutation status and the phenotypic features in unrelated and consecutive patients with BrS.…”

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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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“…Late potentials in high resolution ECG were more frequently observed in SCN5A mutation carriers 31 .…”

Section: Paralogs or Paralogous Genesmentioning

confidence: 96%

Brugada syndrome: current concepts and genetic background

Pérez‐Riera

Mendes

Silva

et al. 2021

jhgd

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Brugada syndrome (BrS) is a hereditary clinical-electrocardiographic arrhythmic entity with low worldwide prevalence. The syndrome is caused by changes in the structure and function of certain cardiac ion channels and reduced expression of Connexin 43 (Cx43) in the Right Ventricle (RV), predominantly in the Right Ventricular Outflow Tract (VSVD), causing electromechanical abnormalities. The diagnosis is based on the presence of spontaneous or medicated ST elevation, characterized by boost of the J point and the ST segment ≥2 mm, of superior convexity "hollow type" (subtype 1A) or descending rectilinear model (subtype 1B). BrS is associated with an increased risk of syncope, palpitations, chest pain, convulsions, difficulty in breathing (nocturnal agonal breathing) and/or Sudden Cardiac Death (SCD) secondary to PVT/VF, unexplained cardiac arrest or documented PVT/VF or Paroxysmal atrial fibrillation (AF) in the absence of apparent macroscopic or structural heart disease, electrolyte disturbance, use of certain medications or coronary heart disease and fever. In less than three decades since the discovery of Brugada syndrome, the concept of Mendelian heredity has come undone. The enormous variants and mutations found mean that we are still far from being able to concretely clarify a genotype-phenotype relationship. There is no doubt that the entity is oligogenetic, associated with environmental factors, and that there are variants of uncertain significance, especially the rare variants of the SCN5A mutation, with European or Japanese ancestors, as well as a spontaneous type 1 or induced pattern, thanks to gnomAD (coalition) researchers who seek to aggregate and harmonize exome and genome sequencing data from a variety of large scale sequencing projects and make summary data available to the scientific community at large). Thus, we believe that this in depth analytical study of the countless mutations attributed to BrS may constitute a real cornerstone that will help to better understand this intriguing syndrome.

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Genotype–phenotype relationship and risk stratification in loss‐of‐function SCN5A mutation carriers

Cited by 8 publications

References 44 publications

RETRACTED: Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong

RETRACTED: Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong

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

Brugada syndrome: current concepts and genetic background

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