POSTER NO: 447

The molecular genetic investigation of congenital long QT syndrome

¹A. Polyakov, ¹E. Zaklyazminskaya, ¹T. Kovalevskaya, ¹S. Tverskaya, ¹S. Kozlova
¹Research Centre for Medical Genetics, Moskvorechie str, 1, 115478, Moscow, Russia, ²Russian Medical Academy of Postgraduate Educations, Moscow, Russia

Congenital long QT syndrome (LQTS) is an inherited cardiac disorder characterized by a prolonged QT interval (rate-corrected QT>460 ms), syncope due to polymorphous ventricular arrhythmias ('torsade de pointes') and high risk of sudden death. The physicians try to devote some clinical phenotypes for LQTS but it is impossible to do in a lot of patients. All known types of the disease are connected with ion channel disorder. At least the five genes when mutated produce this phenotype: KCNQ1, HERG, KCNE1, and KCNE2, which coded different parts of potassium channels and SCN5A, which coded the part of sodium channel. One hundred and twenty five patients with different types of LQTS from 60 unrelated Russian families were available for DNA analysis. All the patients were observed in Federal Child Center of Arrhythmias, Moscow. Diagnoses were confirmed using criteria according to Schwartz et al. (1993). DNA from all patients were tested for mutations in 4 genes: KCNQ1 (exons 2, 4, 5, 6, 7, 14), HERG (exons 2, 6, 7, 10), and KCNE2 using PCR-SSCP analysis. We have identified 32 mutations in 35 unrelated families and 3 SNPs. Seventeen mutations from these are novel and others have been reported yet. Missense mutations are represented the majority of genetic defects (90,6%), other abnormalities were splice errors. There are no differences between clinical and electrokardiographic symptoms in patients with both types of mutations. We did not find any mutations in 2 and 10 exons of HERG although it consists of about 25% of all known mutations in this gene by published date. It seems to us may be connected with populations differences. All patients who have mutations in KCNE1 gene revealed LQTS by electrocardiography (ECG) but have not syncopes in their anamnesis. The wide clinical polymorphism was observed in the family with A341V mutation in KCNQ1 gene revealed in mother and her three children: sick mother and one of the sons have LQT interval in ECG and syncope, another son has only LQTS in ECG but daughter has not LQTS and syncope both. We consider that some modifications and provocation factors may influence in clinical manifestation. The W585C substitution in seventh exon of HERG and the V107I substitution in KCNE1 were detected in the same proband with LQT1 and LQT2 both clinical phenotypes.