INTRODUCTION: 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. METHODS AND 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). CONCLUSION: Variants in the current study appear to be disease causing. The end-recovery QTc is a useful metric when interpreting LQT VUS.
INTRODUCTION: 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. METHODS AND 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). CONCLUSION: Variants in the current study appear to be disease causing. The end-recovery QTc is a useful metric when interpreting LQT VUS.
Authors: Rabia Faridi; Risa Tona; Alessandra Brofferio; Michael Hoa; Rafal Olszewski; Isabelle Schrauwen; Muhammad Z K Assir; Akhtar A Bandesha; Asma A Khan; Atteeq U Rehman; Carmen Brewer; Wasim Ahmed; Suzanne M Leal; Sheikh Riazuddin; Steven E Boyden; Thomas B Friedman Journal: Hum Mutat Date: 2018-12-12 Impact factor: 4.878