布魯蓋達症候群--從臨床到基礎研究

Study on Brugada Syndrome--From Bedside to Bench

莊志明(Jyh-Ming Jimmy Juang)

指導教授 ： 賴亮全 ； 江福田

國立臺灣大學/醫學院/生理學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.11002

摘要

布魯蓋達症候群（Brugada syndrome, BrS）是一種突發性心臟性猝死（Sudden cardiac death, SCD）的疾病。流行病學研究顯示，本病可能是將近一半的突發性無器質性心臟疾病死亡的原因。這種疾病也是東南亞年輕人猝死最常見的原因。因此，我們進行了一系列的BrS研究，包括流行病學，臨床和遺傳表現，電腦程式的預測應用分析，帶有SCN5A基因突變BrS患者的長期預後分析，拷貝數變異(Copy Number Variation)和利用新一代定序(Next-Generation Sequencing)找尋新的BrS致病基因 。我們發現帶Brugada型心電圖患者並不少見。帶Brugada型心電圖患者若無暈厥或心臟猝死病史。我們分析台灣最大的BrS世代的SCN5A基因突變發生率。SCN5A基因突變的發生率顯著低於高加索人群。我們開發了一種新的方法通過組合多個電腦程式進行分析，在進行體外研究(in vitro)之前預測SCN5A基因可疑變異在BrS中的功能和結構變化。我們的結論是整合突變序列信息和預測蛋白質二級結構分子可於進行耗時的電生理研究前，幫助篩選極具可能變異的 BrS SCN5A突變位點。回到臨床，我們前瞻性地研究結論是SCN5A突變可能不是預測有症狀的BrS患者復發性心律失常事件的因子，而是心律失常事件的發生時間的預測因子。在進階的基因研究，我們在非家族性有症狀且沒有SCN5A基因變異的BrS患者身上發現兩種新的拷貝數缺失（GSTM3和NALCN），這表示篩檢CNV可以幫助診斷和預測SCN5A基因變異陰性患者的BrS 。另外，利用新一代定序找尋新的BrS致病基因，我們在15個無相關，非家族的BrS患者且沒有SCN5A基因突變或單核苷酸多態性進行疾病為導向多基因定序，包括130人離子通道的基因和12已報導的BrS基因。在三個BrS患者的四個基因（ SCNN1A ， KCNJ16 ， KCNB2和KCNT1 ）找到五個新的BrS致病突變。
從上面的研究結果，我們提供臺灣的BrS更深入的資料。 BrS在台灣並不少見，在台灣的BrS患者SCN5A基因突變的比例比在高加索人群要低得多。我們也發現幾個新的CNV或新的BrS致病突變值得進一步研究，以深入探討BrS致病機制。

關鍵字

布魯蓋達症候群 ； 突發性心臟性猝死

並列摘要

Brugada syndrome (BrS) is a hereditable sudden cardiac death (SCD) disease. Epidemiologic studies suggest that the disease might be responsible for nearly half of all sudden cardiac deaths in individuals without structural heart diseases. This disease is the most common cause of SCD in young persons in South Asia including Taiwan. As a result, we conducted a series of studies on BrS regarding epidemiology, clinical and genetic presentations, application of in silico analyses, long-term prognosis of BrS patients with SCN5A mutation, copy number variations and identification of novel genes using next-generation sequencing in BrS. We found that patients with Brugada-type ECGs are not rare in a hospital-based population. We investigated the prevalence of SCN5A mutation in the largest BrS cohort in Taiwan. The prevalence of SCN5A mutations was significantly lower than 20–25% in Caucasian populations. We developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies. Back to clinical implication, we prospectively investigated the recurrent events of symptomatic BrS patients with/without SCN5A mutations and concluded that SCN5A mutations may be not a predictor of recurrent arrhythmic events in symptomatic BrS patients, but a predictor of the timing of the onset of first cardiac event. In advanced genetic studies, we identifed two novel deletions in GSTM3 and NALCN in non-familial symptomatic BrS patients without SCN5A variants and five de novo mutations in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1).
With the findings from the above serial studies, we have had an more advanced understanding about BrS. BrS is not uncommon in Taiwanese population. Several novel CNVs or de novo BrS-causative genes were identified in our BrS patients that deserved for further studies to investigate the underlying mechanisms of development of BrS.

並列關鍵字

Brugada-type ECG ； sudden cardiac death ； all-cause mortality ； brugada syndrome ； SCN5A mutations ； Long-term prognosis ； sodium channael ； copy number variations ； Next-generation sequencing ； in silico analysis

參考文獻

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