Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome,Brugada Syndrome,and Conduction Defect

Background: phenotypic overlap of type 3 long qt syndrome (lqt3),brugada syndrome (brs),cardiac conduction disease (ccd),and sinus node dysfunction (snd) is observed with scn5a mutations. scn5a-e1784k is the most common mutation associated with brs and lqts3. the present study examines the genotype-phenotype relationship in a large family carrying scn5a-e1784k and scn5a-h558r polymorphism.methods and results: clinical work-up,follow-up,and genetic analysis were performed in 35 family members. seventeen were scn5a-e1784k positive. they also displayed qtc prolongation,and either brs,ccd,or both. one carrier exhibited snd. the presence of scn5a-h558r did not significantly alter the phenotype of scn5a-e1784k carriers. fourteen scn5a-e1784k patients underwent implantable cardioverter-defibrillator (icd) implantation; 4 developed vf and received appropriate icd shocks after 8±3 months of follow-up. one patient without icd also developed vf after 6.7 years. these 5 cases carried both scn5a-e1784k and scn5a-h558r. functional characterization was achieved by expressing scn5a variants in tsa201 cells. peak (ina,p) or late (ina,l) sodium currents were recorded using whole-cell patch-clamp techniques. co-expression of scn5a-e1784k and scn5a-wt reduced ina,p to 70.03% of wt,shifted steady-state inactivation by -11.03 mv,and increased ina,l from 0.14% to 1.86% of ina,p. similar changes were observed when scn5a-e1784k was co-expressed with scn5a-h558r.conclusions: we demonstrate a strong genotype-phenotype correlation with complete penetrance for brs,lqts,or ccd in the largest family harboring scn5a-e1784k mutation described so far. phenotype of lqts is present during all decades of life,whereas ccd develops with increasing age. phenotypic overlap may explain the high event rate in carriers. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.