Abstract 18124: The Role of SCN5A Mutations in J Wave Syndromes
Introduction: Brugada syndrome (BrS), Early repolarization syndrome (ERS), and some forms of ventricular fibrillation represent a continuous spectrum of phenotypic expression that we recently proposed be termed J wave syndromes (JWS). The present study examines the hypothesis that SCN5A gene mutations contribute to all forms of JWS.
Methods: Direct sequencing of all exons and intron borders of SCN5A was performed on 241 JWS probands and their family members.
Results: Forty-nine SCN5A mutations (35 missense, 5 nonsense, 6 frameshift, 3 splice site) were identified in a total of 90 patients, including 49 unrelated probands. Three probands carried more than one mutation in SCN5A, and 10 subjects had compound mutations in SCN5A and various other genes including CACNA1C (2), CACNB2b (2), KCNH2 (3), SUR2A (1), KCNJ2 (1) and KCNJ8 (1). Most SCN5A mutations were located in the P-loop (36.96%) and interdomain linker regions (17.39%). R1306H, G1391R, Q1695H, R1739G, G1740V, G1297GfsX22, E1105X, Q1185X and 3 splice site mutations are novel mutations. A family history of SCD was found in 66.67% of mutant carriers. SCN5A mutations were equally distributed between the two genders (male/female, 46/44), but males were much more likely to be symptomatic (35/13). Average age of the subjects was 32.06 ± 2.14 (8.89% were <2 y/o and 6.67% were 2-10 y/o). Young patients displayed more malignant manifestations than the adult carriers. Overall, 88.90%, 20.00%, 14.44%, 11.11%, 1.11% of subjects presented with clinical characteristics of BrS, conduction disease, ERS, bradycardia and IVF, respectively. Among those with ERS, J point elevation was observed in lateral (23.08%), inferior or inferolateral (46.15%), and global leads (30.77%). VT/VF ocurred in 12.22%, syncope in 44.44%, and aborted sudden cardiac death (SCD) in 15.56% of all SCN5A mutant carriers. Thirteen patients received an ICD.
Conclusions: Our study adds 11 novel SCN5A mutations associated with channelopathies to the public domain and is the first to point to the possible contribution of SCN5A mutations to ERS. Additional studies are needed to establish SCN5A as an ERS susceptibility gene and to determine the pathogenicity of the various mutations uncovered.
- © 2010 by American Heart Association, Inc.