Pathogenic Variants of SCN5A and KCNH2 Genes and Phenotypes

Study Questions:

What arrhythmia and electrocardiographic (ECG) phenotypes are associated with potentially pathogenic variants of the SCN5A and KCNH2 genes in a large unselected population examined through the electronic medical record?


This prospective cohort study included 2,022 individuals recruited for non-antiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics Project from seven US academic medical centers. Two molecular diagnostic laboratories and one research laboratory, all with expertise in ion channel gene variant evaluation, assessed potential pathogenicity of all missense and splice-site polymorphisms in SCN5A and KCNH2. All available ECG tracings from individuals with designated variants as well as available ECG tracings from age-, race-, and sex-matched individuals without pathogenic variants were manually reviewed by two independent cardiologists blinded to gene variant status.


Among the 2,022 study participants, 122 pathogenic variants of the SCN5A and KCNH2 genes were identified in 223 individuals (11% of the study cohort). There was low concordance across laboratories with only four variants (10%) designated by all three laboratories (Cohen κ = 0.26). An International Classification of Diseases, Ninth Revision (ICD-9) code for arrhythmia was found in 11 of 63 (17%) variant carriers vs. 264 of 1,959 (13%) of those without variants. ECG data were available for 1,270 participants (63%). Among these participants, corrected QT intervals were not different in variant carriers vs. those without (median, 429 vs. 439 ms; difference, -10 ms; 95% confidence interval, -16 to +3 ms; p = 0.17).


In an unselected population, pathogenic variants of the SCN5A and KCNH2 genes were not associated with an abnormal phenotype.


This is a very important study that draws attention to the potential limitations of ‘incidental genetic findings’ and the very low agreement in the assignment of pathogenic status to variants among expert laboratories. Indeed, in an accompanying editorial, Dr. Feero writes, ‘The lack of association among pathogenic variants and meaningful clinical outcomes in the study population calls into question how existing knowledge of genetic variants translates to predicting outcomes in unselected and ostensibly healthy individuals.’

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