• Boon Yew Tan, Rita Yu Yin Yong, Hector Barajas-Martinez, Robert Dumaine, Ying Xia Chew, Pavandip Singh Wasan, Chi Keong Ching, Kah Leng Ho, Linda Seo Hwee Gan, Nathalie Morin, Alicia Poh Leng Chong, Shiao Hui Yap, Jia Ling Neo, Eric Peng Huat Yap, Shabbir Moochhala, Daniel Thuan Tee Chong, Weien Chow, Swee Chong Seow, Dan Hu, Mahesh Uttamchandani, and Wee Siong Teo.
• National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
• Europace. 2016 Jun 1; 18 (6): 897-904.

AimsBrugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the α-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members.Methods And ResultsThe proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01).ConclusionOur study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting.Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

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