Abstract
Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1. The purpose of this study was to determine whether a discernible phenotype is associated with p.Asp85Asn-KCNE1 and whether relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing. Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing (33/1248 [2.6%] vs 1552/126,652 [1.2%]; P= .0001). In 19 of 33 patients (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; P = .01) and were less likely to experience syncope (0% vs 34%; P = .0007), receive β-blockers (53% vs 85%; P = .001), or require an implantable cardioverter-defibrillator (5.3% vs 33%; P= .01). However, they exhibited a similar degree of QT prolongation (QTc 460 ms vs 467 ms; P = NS). Whole exome sequencing of 2 commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His-KCNE1 demonstrated loss of function, with a 47% reduction in peak IKs current density in the heterozygous state. We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially proarrhythmic common variants (ie, functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance.
Highlights
Long QT syndrome (LQTS) is a heritable disorder of cardiac repolarization characterized clinically by QT-interval prolongation on electrocardiogram (ECG) and an increased risk of syncope, seizure, and sudden death.[1]
We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as “LQTS type 5 (LQT5)-Lite” to distinguish such potentially proarrhythmic common variants from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance
624 patients who underwent full LQTS genetic evaluation and had a 12-lead ECG available for review were included (Figure 1)
Summary
Long QT syndrome (LQTS) is a heritable disorder of cardiac repolarization characterized clinically by QT-interval prolongation on electrocardiogram (ECG) and an increased risk of syncope, seizure, and sudden death.[1]. Large-scale sequencing efforts have revealed that monogenic disease-causative genes, including those responsible for LQTS, tolerate a substantial amount of nonsynonymous genetic variation.[4,5,6] As a result, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) released a set of revamped variant interpretation and reporting guidelines in 2015, to help standardize the classification and reporting of genetic variants.[7] the current ACMG/AMP guidelines adequately address rare genetic variants, they provide little guidance regarding the classification and reporting of common genetic variants that occur too frequently in the general population to be designated as disease-causative for any reasonably penetrant monogenetic disease but may modify or result in circumstance-dependent expression of a Mendelian disease phenotype.[8] most relatively common genetic variants, including those with substantive functional and epidemiologic evidence to support a potential contribution in disease pathogenesis, have been designated as benign and excluded from commercial genetic testing reports.[8] As a result, potentially clinically relevant information is being withheld from both patients and providers. Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1
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