Key result
Genetic testing in phenotypically robust nonsyndromic long QT syndrome cases identifies a heterozygous pathogenic variant in approximately 75% of patients.
L ong QT syndrome (LQTS) is a clinically and genetically heterogenous disorder of myocardial repolarization that often manifests clinically as heart rate-corrected QT interval (QTc) prolongation on 12-lead ECG and increased risk of syncope and sudden cardiac death.1,2 Among phenotypically robust nonsyndromic LQTS cases (ie, persistent QTc prolongation ≥480 ms or Schwartz diagnostic score ≥3.5), ≈75% are anticipated to harbor a heterozygous pathogenic variant in 1 of the 3 major LQTS-susceptibility genes (KCNQ1/LQT1, ≈35%; KCNH2/LQT2, ≈30%; and SCN5A/LQT3, ≈10%).[2][3][4] As a result of established genotype-phenotype correlations, the identification of a putative pathogenic KCNQ1, KCNH2, or SCN5A genetic variant often enables use of genotype-guided approaches to risk stratification and clinical management.5 As such, current Heart Rhythm Society/European Heart Rhythm Association guidelines consider LQTS-specific genetic testing for individuals with a strong clinical suspicion of LQTS based on clinical/family history and electrocardiographic phenotype as a class I recommendation.6
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John R. Giudicessi (2017) conducted a review in Long QT syndrome. Machine learning for rare variant adjudication was evaluated. Genetic testing in phenotypically robust nonsyndromic long QT syndrome cases identifies a heterozygous pathogenic variant in approximately 75% of patients.
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