SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups

Baruteau, Alban‐Elouen; Kyndt, Florence; Behr, Elijah R.; Vink, Arja S.; Lachaud, Matthias; Joong, Anna; Schott, Jean Jacques; Horie, Minoru; Denjoy, Isabelle; Crotti, Lia; Shimizu, Wataru; Bos, J. Martijn; Stephenson, Elizabeth A.; Wong, Leonie C.H.; Abrams, Dominic J.; Davis, Andrew M.; Winbo, Annika; Dubin, Anne M.; Sanatani, Shubhayan; Liberman, Leonardo; Kaski, Juan Pablo; Rudic, Boris; Kwok, Sylvia Y. C. L.; Rieubland, Claudine; Tfelt-Hansen, Jacob; Hare, George F. Van; Guyomarc’h-Delasalle, Béatrice; Blom, Nico A.; Wijeyeratne, Yanushi D.; Gourraud, Jean‐Baptiste; Marec, Hervé Le; Ozawa, Junichi; Fressart, Véronique; Lupoglazoff, Jean‐Marc; Dagradi, Federica; Spazzolini, Carla; Aiba, Takeshi; Tester, David J.; Zahavich, Laura; Beauséjour-Ladouceur, Virginie; Jadhav, Mangesh; Skinner, Jonathan R.; Franciosi, Sonia; Krahn, Andrew D.; Abdelsayed, Mena; Ruben, Peter C.; Yung, TC; Ackerman, Michael J.; Wilde, Arthur A.M.; Schwartz, Peter J.; Probst, Vincent

doi:10.1093/eurheartj/ehy412

Cited by 32 publications

(23 citation statements)

References 39 publications

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“…Although there was a lower prevalence of 12-lead ECG abnormalities in patients <16 years of age, Holter monitoring was more frequently abnormal in younger patients, suggesting less manifest and more dynamic cardiac electric abnormalities at younger ages. This is in keeping with findings in cardiac sodium channel loss-of-function mutations, in which presentation with more severe conduction disease and atrial arrhythmia is commoner in childhood and adolescence, whereas a Brugada phenotype is commoner in adulthood, 34 suggesting an age-related penetrance to the disease. Although the cardiac abnormalities demonstrated in this study are not due to structural abnormalities detectable on echocardiography, it is theoretically possible that there may be structural abnormalities too subtle to be observed on echocardiography; additional investigations such as cardiac MRI with gadolinium contrast or histology from biopsies or postmortem heart tissue may provide further information.…”

Section: Discussionsupporting

confidence: 88%

Cardiac phenotype in ATP1A3 -related syndromes

Balestrini

Mikati²,

Álvarez-García-Rovés³

et al. 2020

Neurology

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Objective.To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.Methods.Patients meeting clinical diagnostic criteria for Rapid-onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS), with ATP1A3 genetic analysis, and had at least one cardiac assessment, were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death.Results.98 AHC, nine RDP, and three CAPOS patients (63 females, mean age 17 years) were included. Resting EKG abnormalities were found in 52/87 (60%) AHC, 2/3 (67%) CAPOS, and 6/9 (67%) RDP patients. Serial EKGs showed dynamic changes in 10/18 AHC patients. The first Holter EKG was abnormal in 24/65 (37%) AHC and RDP cases, with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3/98 (∼3%) AHC patients. In the mouse model, resting EKGs showed intra-cardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.Conclusions.We found increased prevalence of EKG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (∼3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases as well as neurological diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

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Section: Discussionsupporting

confidence: 88%

Cardiac phenotype in ATP1A3 -related syndromes

Balestrini

Mikati²,

Álvarez-García-Rovés³

et al. 2020

Neurology

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“…Thus, whether our findings in adults can be applicable to children needs further investigation. Meanwhile, the locations or types of SCN5A mutations, which may develop different severity of BrS phenotypes should be considered in further studies. Owing to a low sample size, a multivariate analysis to see if SCN5A mutations independently predict of cardiac arrest seems impossible.…”

Section: Limitationsmentioning

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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“…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%

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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SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups

Cited by 32 publications

References 39 publications

Cardiac phenotype in ATP1A3 -related syndromes

Cardiac phenotype in ATP1A3 -related syndromes

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

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

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