The Establishment Of Long QT Interval Syndrome Gene Variants Database And The Screen Of Gene Variants In Ten Chinese Families

Abstract:Long QT syndrome (LQTS) is a group of familial disorders characterized by a striking prolongation of the QT-interval on a 12-lead surface electrocardiogram (ECG), abnormal T wave, easily predisposing to ventricular arrhythmias, especially an atypical polymorphic ventricular tachycardia known as Torsade de Pointes (TdP), syncope, seizures and sudden cardiac death in the setting of a structurally normal heart and otherwise healthy individual. There are two types of LQTS according to the pathogenicity:congenital LQTS and acquired LQTS. Acquired LQTS usually caused by cardiac ischemia, bradycardia, electrolyte abnormalities and some medicines. Four clinical types of congenital LQTS have been described:(1) Romano-Ward syndrome (RWS); (2)Jervell-Lange Nielsen syndrome (JLNS); (3)Andersen syndrome (AS); (4) Timothy syndrome (TS).The advance of molecular genetics revealed the mechanism of QT interval prolongation:a reduction in the outward potassium current during phase 3 of the action potential in myocardial cells; or an augmented late entry of sodium or calcium ions into the myocytes due to malfunctioning sodium or calcium channels.12 genes that associated with LQTS in total have been revealed, which are KCNQ1,KCNH2,SCN5A, KCNE1, KCNE2, KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1 and CAV3. With the development of medical genetics, genetic diagnosis is becoming available to clinics abroad in recent years. According to the data from NCBI website (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests), genetic diagnosis has been applied to 1,658 genetic diseases in clinical and 259 genetic diseases are still in the process of experimental study as of 2010/3/9.A great deal of mutation variants have been reported, thereafter a huge amount of information has been produced. However the description of these variants is protean, which is inconvenient to the communication and sharing of the data. In 2008, the International Human variome project (HVP) made unified format database. The database is based on the Leiden Open Variation Database (LOVD) system, which is a web-based database format designed to collect and display DNA variants in specific genes. However, LQTS-associated 12 genes'database in LOVD format hasn' t been built up yet. Therefore, our lab started to establish the LQTS online database since March 2009. We submit 2,976 entries in total. As of February 2010, the database contains 1740 unique variants in 12 genes. A total of 950 variants are considered pathogenic,266 are possible pathogenic,131 are unknown/unclassified, and 293 have no known pathogenicity. The website of our database is: http://www.china-hvp.org/introduction/introduction.htm. The database contains the most comprehensive variant data available from the published literature, including the entire corpus of Chinese literature on the subject.In the second part of study, we collected ten suspected inherited arrhythmias Chinese families, including 6 LQTS families,2 Brugada syndrome families, and 2 sick sinus syndrome. The KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes have been amplified and sequenced in these ten probands. After the results were checked in our database, we found two reported pathogenic variants (c.246₂52delATCGCGCAG in KCNH2 and c.3823G>A in SCN5A) in two LQTS families; a novel mutation near the splice site, c.4296G>A in SCN5A was found in a sick sinus syndrome family; a possible pathogenic variant, c.2690A>C in KCNH2 in a LQTS family. In addition to these pathogenic variants, many polymorphisms were also screened out:c.3575G>A in SCN5A, c.1673A>G in SCN5A, c.112A>G in KCNE1 and c.1141-3C>A in SCN5A. These data were also submitted to our database. The creative points of our work:1) Set up a comprehensive up-to-date LQTS database based on LOVD for the first time in the world;2) Find a novel possible pathogenic variant c.4296G>A in SCN5A in a sick sinus syndrome family.