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Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants.

Gray, B; Hasdemir, C; Ingles, J; Aiba, T; Makita, N; Probst, V; Wilde, AAM; Newbury-Ecob, R; Sheppard, MN; Semsarian, C; et al. Gray, B; Hasdemir, C; Ingles, J; Aiba, T; Makita, N; Probst, V; Wilde, AAM; Newbury-Ecob, R; Sheppard, MN; Semsarian, C; Sy, RW; Behr, ER (2018) Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants. Heart Rhythm, 15 (7). pp. 1051-1057. ISSN 1556-3871 https://doi.org/10.1016/j.hrthm.2018.03.015
SGUL Authors: Behr, Elijah Raphael Sheppard, Mary Noelle

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Abstract

BACKGROUND: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.

Item Type: Article
Additional Information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Brugada Syndrome, Genotype-phenotype correlation, Reclassification, SADS, SCN1B, Sudden cardiac death, Brugada Syndrome, Genotype-phenotype correlation, Reclassification, SADS, SCN1B, Sudden cardiac death, 1102 Cardiovascular Medicine And Haematology, 0903 Biomedical Engineering
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Heart Rhythm
ISSN: 1556-3871
Language: eng
Dates:
DateEvent
July 2018Published
11 May 2018Published Online
5 March 2018Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
1122330National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
100833National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
1059156National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
PubMed ID: 29758173
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109874
Publisher's version: https://doi.org/10.1016/j.hrthm.2018.03.015

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