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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.hrthm.2018.03.015
Journal or Publication Title: Heart Rhythm
Volume: 15
Number: 7
Page Range: pp. 1051-1057
Date: 2018
Divisions: Cardio Genomics
Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1016/j.hrthm.2018.03.015
ISSN: 15475271
Date Deposited: 03 Jan 2021 23:01
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.

Keywords: Brugada Syndrome; Genotype-phenotype correlation; Reclassification; SADS; SCN1B; Sudden cardiac death.

Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Creators:
Creators
Email
Gray, Belinda
UNSPECIFIED
Hasdemir, Can
UNSPECIFIED
Ingles, Jodie
UNSPECIFIED
Aiba, Takeshi
UNSPECIFIED
Makita, Naomasa
UNSPECIFIED
Probst, Vincent
UNSPECIFIED
Wilde, Arthur A.M.
UNSPECIFIED
Newbury-Ecob, Ruth
UNSPECIFIED
Sheppard, Mary N.
UNSPECIFIED
Semsarian, Christopher
UNSPECIFIED
Sy, Raymond W.
UNSPECIFIED
Behr, Elijah R.
UNSPECIFIED
Last Modified: 03 Jan 2021 23:01
URI: https://eprints.centenary.org.au/id/eprint/496

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