Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant

Heart Rhythm. 2018 Aug;15(8):1223-1230. doi: 10.1016/j.hrthm.2018.03.038. Epub 2018 Apr 3.

Abstract

Background: Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Arrhythmia; Genetics; LQT5-Lite; Long QT syndrome; Sudden death.

MeSH terms

  • Alleles
  • DNA / genetics*
  • DNA Mutational Analysis
  • Electrocardiography*
  • Exome Sequencing
  • Female
  • Follow-Up Studies
  • Genetic Testing
  • Genetic Variation
  • Genotype
  • Heterozygote
  • Humans
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Male
  • Mutation*
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • Potassium Channels, Voltage-Gated / genetics*
  • Potassium Channels, Voltage-Gated / metabolism
  • Retrospective Studies
  • Young Adult

Substances

  • KCNE1 protein, human
  • Potassium Channels, Voltage-Gated
  • DNA

Supplementary concepts

  • Long Qt Syndrome 5