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

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.

• Authors: Conor M Lane, John R Giudicessi, Dan Ye, David J Tester, Ram K Rohatgi, J Martijn Bos, Michael J Ackerman
• Journal: Heart rhythm (Heart Rhythm) Vol. 15 Issue 8 Pg. 1223-1230 (08 2018) ISSN: 1556-3871 [Electronic] United States
• PMID: 29625280 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

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

Topics

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