2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655855摘要：嬰兒猝死症(sudden infant death syndrome, SIDS)常為初為人父母的夫妻帶來極大的震撼，根據健保資，SIDS 在台灣發生率約為0.36/1000，粗估每年約有70-80位嬰兒死於此症，而且一半以上發生在前三個月，一般相信，其中10-15%可能與QT 延長症候群(long QT syndrome, LQTS)有關，然而根據學童心電圖篩檢和三家醫學中心針對一個月新生兒的心電圖篩檢，分別顯示QTc 延長的比例分別為1/104 及1/100，在這之間的落差很可能與個體所帶的遺傳訊息有關。心電圖上的QT 間距代表了心臟再極化(repolarization)電氣活動時間的長短，QT 過長或過短都很容易造成心律不整或猝死的發生。過去研究發現QT 本身受到遺傳因素的影響有30%之多:包含了家族內的基因突變以及某些特定的基因多型性(SNP)的組合。如此一來，了解嬰兒是否帶有某些突變及關鍵SNP 的訊息對其本身QT interval 長短甚至是使用藥物發生心律不整或猝死症的影響和預測，就變得非常重要。然而，在台灣，這方面的訊息與研究都非常的少，而且都是停留在mutation screening 的階段。本研究希望從近3000 名新生兒著手，了解這些影響QT interval 的關鍵突變及SNPs 的真正分布，並進而探討在台灣的基因背景下，這些SNPs 和mutation如何影響QTc >450msec 嬰兒的臨床表現－包括心電圖的變化；QT intervalvariability； heart rate variability；運動心電圖上的micro-T wavealternas 及3-10 年間中長期監控的心電圖變化和是否遭遇癲癇或猝死等重要事件。方法：(一)回顧最近幾篇與QT 相關的GWAS 研究，加上這兩年在國科會補助下研究的成果，我們選定了7 個基因的104 個exons 及另外14 個位在intron 上的SNPs做為genotyping 的研究標的。(二)藉由過去四年及未來兩年，台大醫院、國泰醫院及亞東醫院所蒐集到的3000-3500 份1 個月大新生兒心電圖做分析，找出可能的30-50 位QT > 450msec 的嬰兒；設法連絡並抽取血液檢體，針對設定的基因標的做詳細的定序分析；同時這30-50 位病人亦再接受十二導程心電圖、24 小時心電圖heartrate variability 及運動心電圖等檢查，這些檢查的某些指標已被證實與longQT syndrome 的預後相關。(三) 作genotype 與phenotype 間的association study。分析臨床的表現與基因型間的關係，並了解這些受試者QTc 隨著年紀的變異情形預期成果：有了這些資料之後，便可以把mutation 和SNP 放在同一個框架下，評估它們與臨床變數及猝死風險因子的相關性；同時以基因型為基礎的QT 長期變化趨勢，亦可藉此研究而了解。這將會形成未來預防嬰兒及兒童猝死的重要基礎，也是藥物遺傳學的重要起點。<br> Abstract: BackgroundMolecular studies demonstrated 10-15% of case diagnosis as sudden infant deathsyndrome (SIDS) carried functionally significant genetic variants of LQTS genes.In Twaiwan, there were 70-80 victims of SIDS annually. However, the incidence of QTcprolongation was 1.5% in neonatal EKG screening from 3 medical centers and 1/104 inschool screening, respectively. The exact cause of such discrepancy between LQTs andSIDS is still unclear. Furthermore, The QT interval in electrocardiography (ECG), a measureof cardiac repolarization, is a genetically influenced quantitative trait, including mutations andpolymorphisms, with 30% heritability. Several large-scale screening and association studiesin Caucasian population had echoed this concept. Therefore, it becomes important to explorethe molecular epidemiology of such genetic mutations and variants in infants and to see theirimpact on the long-term development of life-threatening events such as SIDS and seizure.Aim(1) Clarify prevalence of LQTS mutations and the allelic frequencies of QT-associated SNPsin the infants of Taiwan(2) In infants with QTc > 440 msec, analyze correlation between genotypes (mutations &QT-associated SNPs) and phenotypes (ECG characteristics & risk of sudden death).(3) Understand the longitudinal changes of QT interval in the infant cohort.Methods(1) Retrospectively enroll the 43 infants with QTc > 450 msec found in screening from 3medical centers (2009-2012) and prospectively enroll infants aged 15-25 days in thefuture 2-3 years.(2) For each participant, genotyping (exons of ion-channel genes & QT-associated SNPs withMAF > 1%), ECG, heart rate variability, QT variability, Holter and (in some cases)Treadmill will be done.(3) Annual follow-up of ECG, Holter and life-threatening events will be done in the following2-3 years.(4) Analyze correlation between genotypes and phenotypes (ECG characteristics & risk ofsudden death).Anticipated Results(1) The allelic frequencies of QT-associated SNPs and prevalence of ion-channel mutations inTaiwan(2) Certain SNPs associated with longer QT interval or electrocardiographic risk factors oflife-threatening events such as sudden death.(3) Longitudinal ECG changes on the infants with QTc ≧ 440 msec