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

Conor M. Lane, John R. Giudicessi, Dan Ye, David J. Tester, Ram K. Rohatgi, J. Martijn Bos, Michael John Ackerman

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalHeart Rhythm
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Long QT Syndrome
Phenotype
Genetic Testing
Pedigree
Exome
Penetrance
Implantable Defibrillators
Disease Susceptibility
Syncope
Alleles
Genotype
Demography
Genome
Databases
Genes

Keywords

  • Arrhythmia
  • Genetics
  • Long QT syndrome
  • LQT5-Lite
  • Sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Long QT syndrome type 5-Lite : Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. / Lane, Conor M.; Giudicessi, John R.; Ye, Dan; Tester, David J.; Rohatgi, Ram K.; Bos, J. Martijn; Ackerman, Michael John.

In: Heart Rhythm, 01.01.2018.

Research output: Contribution to journalArticle

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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.",
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T2 - Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant

AU - Lane, Conor M.

AU - Giudicessi, John R.

AU - Ye, Dan

AU - Tester, David J.

AU - Rohatgi, Ram K.

AU - Bos, J. Martijn

AU - Ackerman, Michael John

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N2 - 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.

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