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A novel three base-pair deletion in domain two of the cardiac sodium channel causes Brugada syndrome
Tan Boon Yew
Wang Luokai
Uttamchandani Mahesh
Barajas Martinez Hector
Dumaine Robert
Morin Nathalie
Ching Chi Keong
Ho Kah Leng
Chong Daniel Thuan Tee
Chow Weien
Yap Eric Peng Huat
Moochhala Shabbir
Hu Dan
Yong Rita Yu Yin
Teo Wee Siong
Journal of Electrocardiology, 2018, 51(4): 667-673.
Summary
Introduction: Mutations within SCN5A are found in a significant proportion (15-30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members.
Methods and results: The proband at age 44 years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12 lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741_T742delinsl (c.2223_2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (INa). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A).
Conclusion: Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741_T742delinsl (c.2223_2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification.
Keywords
Brugada syndrome; Channelopathy; Genetic testing; Nav1.5; SCN5A
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