A novel SCN5A gene mutation causing LQT3 with unique phenotype in a large canadian kindred

Abstract

Abstract Background SCN5A gene mutations are associated with diverse clinical phenotypes including Long QT (LQT) Syndrome, Brugada Syndrome, progressive conduction system disease and cardiomyopathy. Objective We identified a novel SCN5A variant (T731I) in a pedigree affected by QT prolongation and ventricular arrhythmia. Clinical phenotype and co-segregation with genotype within the pedigree were characterized. Methods Family members were invited to attend clinics held in their indigenous community. All subjects underwent a history, physical exam, 12 lead ECG and had blood samples collected for genetic testing. Patients were assessed by an adult or pediatric cardiologist and genetic counselors over a six year period. There were 86 females and 69 males ranging in age from 1 to 82 years (mean 36 years) at the time of first assessment. ECG analysis was performed by a cardiac electrophysiologist blinded to patient identity and genotype. The QTc was calculated using Bazett's formula. Results One hundred and fifty five family members were evaluated (86 (55%) female; mean age 36 years (range 1 to 82 years). Mean QTc was 461 + 21 ms for the gene positive group and 419 + 22 ms for the gene negative group (P<0.001) (Figure). There was no significant difference in age or sex between the gene positive and gene negative groups. Gene positive family members were also noted to have low right atrial p waves and frequent unifocal ventricular ectopy and non-sustained monomorphic ventricular tachycardia. One gene positive individual developed dilated cardiomyopathy with high burden ventricular tachycardia and required cardiac transplantation. Conclusion This novel SCN5A variant co-segregated with an abnormal phenotype consisting of significant QTc prolongation, low atrial rhythm, and ventricular arrhythmia. This pedigree highlights the phenotypic heterogeneity of SCN5A gene mutations and the importance of cascade family screening to identify at risk family members. Figure 1. QTc intervals Funding Acknowledgement Type of funding source: None