title: Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing.
abstract: OBJECTIVE
  The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients.
  
  
  BACKGROUND
  BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events.
  
  
  METHODS
  Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only).
  
  
  RESULTS
  Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men<20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval.
  
  
  CONCLUSIONS
  We identified putative pathogenic mutations in ∼20% of our BrS cohort, with BrS genes 2 through 12 accounting for <5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval.
authors: Department of Lung, Blood, and Heart, Section of Cardiology, University of Pavia, Pavia, Italy.
authors: Lia
authors: L
authors: Crotti
authors: Cherisse A
authors: CA
authors: Marcou
authors: David J
authors: DJ
authors: Tester
authors: Silvia
authors: S
authors: Castelletti
authors: John R
authors: JR
authors: Giudicessi
authors: Margherita
authors: M
authors: Torchio
authors: Argelia
authors: A
authors: Medeiros-Domingo
authors: Savastano
authors: S
authors: Simone
authors: Melissa L
authors: ML
authors: Will
authors: Federica
authors: F
authors: Dagradi
authors: Peter J
authors: PJ
authors: Schwartz
authors: Michael J
authors: MJ
authors: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053840:Brugada Syndrome / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D004247:DNA / Q000032:analysis*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D015995:Prevalence; D055815:Young Adult
chemical_list: D004247:DNA