A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore

作者：Tan, Boon Yew; Yong, Rita Yu Yin; Barajas-Martinez, Hector; Dumaine, Robert; Chew, Ying Xia; Wasan, Pavandip Singh; Ching, Chi Keong; Ho, Kah Leng; Gan, Linda Seo Hwee; Morin, Nathalie; Chong, Alicia Poh Leng; Yap, Shiao Hui; Neo, Jia Ling; Yap, Eric Peng Huat; Moochhala, Shabbir; Chong, Daniel Thuan Tee; Chow, Weien; Seow, Swee Chong; Hu, Dan^*; Uttamchandani, Mahesh^*; Teo, Wee Siong^*

来源：Europace, 2016, 18(6): 897-904.

DOI：10.1093/europace/euv058

• Brugada syndrome
• Channelopathy
• SCN5A
• Nav1.5
• Compound heterozygote

Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the alpha-subunit of the sodium ion channel Na(v)1.5, 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.
The 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 (I-Na) 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 I-Na of only 13% of WT (P < 0.01).
Our 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.

• 出版日期2016-6
• 单位武汉大学; 南阳理工学院