The Mutation Screening And Primary Functional Study On The Cadidate Gene Of Familial Progressive Cardiac Conduction Defect With Long QT Syndrome

Progressive cardiac conduction defect(PCCD) is one of the most common cardiac conduction abnormalities that is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block,and widening of QRS complexes,leading to complete atrio-ventricular block(AVB) and causing syncope and sudden death and the prevalence of PCCD is about 1%.Long QT syndrome(LQTS) is a prototypic arrhythmic disorder that is characterised by prolonged QT interval(or QTc) on electrocardiograms(ECGs),syncope,and sudden death from episodic ventricular tachyarrhythmias,specifically torsade de pointes.LQTS causes sudden deaths in young,otherwise healthy,individuals,and in many cases the first symptom is sudden death.However,PCCD with LQTS is rare except that only few cases were reported on coexistence of two-to-one AVB and LQTS. Heterozygous mutations in the cardiac voltage-gated sodium channelα-subunit gene(SCN5A) are related to cardiac arrhythmias such as conduction system disease,long-QT syndrome(LQTS),and Brugada syndrome.Here we report a single nucleotide polymorphism(SNP) R1193Q in SCN5A associated PCCD and LQTS in a four-generation Chinese pedigree.After investigating clinical data of the pedigree with information consent, we found that 6 out of 25(24%) family members were diagnosed as PCCD and LQTS was diagnosed in 2 out of 6 PCCD patients and borderline QTc was found in 1 family member with PCCD.During systematic survey of all SCN5A coding region and flanking intronic sequence,we identified a single base substitution(G to A transition;3578G→A) at the second nucleotide of codon R1193 of SCN5A, which resulted in a nonconservative replacement of arginine with glutamine (R/Q) in exon 20.SNP R1193Q was identified in 5 out of the 6 family members with PCCD and in the 3 family members with prolonged or borderline QTc.Moreover, we also found the presence of R1193Q polymorphism is up to 12%(36/281) in randomly selected control subjects consisting of Nan Chinese,while 0.2%in whites and 2%in Japanese.Based on the electrophysiological features of R1193Q that might increase susceptibility to LQTS for its carriers in whites,we would have to face the problem that quite a lot Chinese people were at the risk of LQTS due to 12%prevalence of R1193Q.For these carriers,if we should take some measurement or not,for example,avoiding administration of some medicine such as quinidine,sotalol and amiodarone,still needs further evidences.We randomly select 128 healthy people with electrocardiographic recordings. Their electrocardiographic recordings were measured and QTc durations were calculated by Bazett's formula.Moreover,genomic DNAs were amplified through a polymerace chain reaction(PCR) and the resulting PCR products were sequeced to be found out if R1193Q polymorphism was existed.The result showed that among the 128 subjects,R1193Q-carriers' average QTc is 428ms(n=21),while non-carriers' QTc is 41?ms(n=107).Female carriers group has a longer QTc duration(444ms) than female non-carrier group(422ms) with a statistical significance,and male carriers have a longer QTc tendency even though no statistical significance.In summary,we have found that R1193Q of the SCNSA gene may be associated with PCCD with LQTS by analyzing the four-generation Han Chinese family.We also found R1193Q is a common polymorphism in Han Chinese,and it is a risk factor for prolonging Chinese women's QTc.To our knowledge,this is the first time to report a case-control study on the relationship between R1193Q and QT duration.Even data have showed it might be a long QT mutation in other races,further studies will be needed to determine whether R1193Q indeed increases susceptibility to LQTS or other arrhythmias in Chinese population.