Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results

  • Han Chow Chua
  • Helge Servatius
  • Babken Asatryan
  • André Schaller
  • Claudine Rieubland
  • Fabian Noti
  • Jens Seiler
  • Laurent Roten
  • Samuel H. Baldinger
  • Hildegard Tanner
  • Juerg Fuhrer
  • Andreas Haeberlin
  • Anna Lam
  • Stephan A. Pless
  • Argelia Medeiros-Domingo
Original Paper

Abstract

Objective

Unexplained cardiac arrest (UCA) is often the first manifestation of an inherited arrhythmogenic disease. Genetic testing in UCA is challenging due to the complexities of variant interpretation in the absence of supporting cardiac phenotype. We aimed to investigate if a KCNQ1 variant [p.(Pro64_Pro70del)], previously reported as pathogenic, contributes to the long-QT syndrome phenotype, co-segregates with disease or affects KCNQ1 function in vitro.

Methods

DNA was extracted from peripheral blood of a 22-year-old male after resuscitation from UCA. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). Variants in 190 clinically relevant cardiac genes with minor allele frequency < 1% were analyzed according to the guidelines of the American College of Medical Genetics. Functional characterization was performed using site-directed mutagenesis, expression in Xenopus laevis oocytes using the two-electrode voltage-clamp technique.

Results

The 12-lead ECG, transthoracic echocardiography and coronary angiography after resuscitation showed no specific abnormalities. Two variants were identified: c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del), reported previously as pathogenic and c.2431C > A in PKP2 (p.Arg811Ser), classified as likely benign. Two asymptomatic family members with no evident phenotype hosted the KCNQ1 variant. Functional studies showed that the wild-type and mutant channels have no significant differences in current levels, conductance-voltage relationships, as well as activation and deactivation kinetics, in the absence and presence of the auxiliary subunit KCNE1.

Conclusions

Based on our data and previous reports, available evidence is insufficient to consider the variant KCNQ1:c.190_210del as pathogenic. Our findings call for cautious interpretation of genetic tests in UCA in the absence of a clinical phenotype.

Keywords

Ventricular fibrillation Ion channel Genetics Arrhythmia Sudden cardiac death 

Notes

Acknowledgements

This work was supported by the Swiss Heart Foundation (AMD). SAP was supported by a Lundbeck Foundation Fellowship (R139-2012-12390) and a Carlsberg Foundation Distinguished Associate Professor Fellowship (CF16-0504). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Han Chow Chua
    • 1
  • Helge Servatius
    • 2
  • Babken Asatryan
    • 2
  • André Schaller
    • 3
  • Claudine Rieubland
    • 3
  • Fabian Noti
    • 2
  • Jens Seiler
    • 2
  • Laurent Roten
    • 2
  • Samuel H. Baldinger
    • 2
  • Hildegard Tanner
    • 2
  • Juerg Fuhrer
    • 2
  • Andreas Haeberlin
    • 2
    • 4
  • Anna Lam
    • 2
  • Stephan A. Pless
    • 1
  • Argelia Medeiros-Domingo
    • 2
  1. 1.Center for Biopharmaceuticals, Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Cardiology, InselspitalBern University Hospital, University of BernBernSwitzerland
  3. 3.Division of Human Genetics, Department of Pediatrics, InselspitalBern University Hospital and University of BernBernSwitzerland
  4. 4.ARTORG Center for Biomedical Engineering ResearchUniversity of BernBernSwitzerland

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