title: End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome.
abstract: BACKGROUND
  Genetic variants represent benign single-nucleotide polymorphisms, disease causing mutations or variants of unknown significance (VUS). Resting, exercise, and recovery QTc intervals have been utilized to detect long-QT syndrome (LQTS) mutations. We sought to provide clinical data that may assist in classifying the presented VUS as disease causing/benign and to determine whether resting and/or end-recovery QT parameters can evaluate the significance of VUS.
  
  
  RESULTS
  Twenty-six patients with a VUS in genes associated with LQTS (15 females, age 38 ± 16 years) and 26 age and gender matched controls (age 37 ± 20 years) were included. There were 10 VUS (5 KCNQ1, 4 KCNH2, 1 KCNE1) in 12 families. All but 1 VUS was associated with sudden cardiac death (SCD), aborted SCD or Torsade de pointes. A Schwartz score of ≥3.5 was observed in at least 1 family member with each VUS. Resting QTc was marginally longer in VUS patients compared with controls (458 ± 48 vs 437 ± 25, P = 0.052). A prolonged resting QTc (>470 ms males, >480 ms females) identified 6 VUS carriers and 1 control. VUS carriers had a substantially longer end-recovery QTc (502 ± 68 vs 427 ± 17, P < 0.01) with an end-recovery QTc > 445 ms in 20/26 VUS patients compared to 2/26 controls (P < 0.01). The area under the receiver operating characteristic curve for resting QTc was 0.68 (95% CI, 0.53-0.83, P = 0.03) compared to the end-recovery QTc of 0.88 (95% CI, 0.76-0.99, P < 0.0001).
  
  
  CONCLUSIONS
  Variants in the current study appear to be disease causing. The end-recovery QTc is a useful metric when interpreting LQT VUS.
authors.affiliation: Division of Cardiology, University of Western Ontario, London, Ontario, Canada. manojobey@yahoo.com
authors.forename: Manoj N
authors.initials: MN
authors.lastname: Obeyesekere
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Sy
authors.forename: George J
authors.initials: GJ
authors.lastname: Klein
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Gula
authors.forename: Simon
authors.initials: S
authors.lastname: Modi
authors.forename: Susan
authors.initials: S
authors.lastname: Conacher
authors.forename: Peter
authors.initials: P
authors.lastname: Leong-Sit
authors.forename: Allan C
authors.initials: AC
authors.lastname: Skanes
authors.forename: Raymond
authors.initials: R
authors.lastname: Yee
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009864:Ontario; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D013997:Time Factors; D016171:Torsades de Pointes / Q000235:genetics; D055815:Young Adult