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

doi:10.1007/s00392-018-1233-3

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^*

^*Corresponding author for this work

5 Citations (Scopus)

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.

Original language	English
Journal	Clinical Research in Cardiology
Volume	107
Issue number	8
Pages (from-to)	670-678
Number of pages	9
ISSN	1861-0684
DOIs	https://doi.org/10.1007/s00392-018-1233-3
Publication status	Published - 1 Aug 2018

Keywords

Arrhythmia
Genetics
Ion channel
Sudden cardiac death
Ventricular fibrillation

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10.1007/s00392-018-1233-3

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Chua, H. C., Servatius, H., Asatryan, B., Schaller, A., Rieubland, C., Noti, F., Seiler, J., Roten, L., Baldinger, S. H., Tanner, H., Fuhrer, J., Haeberlin, A., Lam, A., Pless, S. A., & Medeiros-Domingo, A. (2018). Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results. Clinical Research in Cardiology, 107(8), 670-678. https://doi.org/10.1007/s00392-018-1233-3

Chua, HC, Servatius, H, Asatryan, B, Schaller, A, Rieubland, C, Noti, F, Seiler, J, Roten, L, Baldinger, SH, Tanner, H, Fuhrer, J, Haeberlin, A, Lam, A, Pless, SA & Medeiros-Domingo, A 2018, 'Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results', Clinical Research in Cardiology, vol. 107, no. 8, pp. 670-678. https://doi.org/10.1007/s00392-018-1233-3

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title = "Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results",

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 = "Arrhythmia, Genetics, Ion channel, Sudden cardiac death, Ventricular fibrillation",

author = "Chua, {Han Chow} and Helge Servatius and Babken Asatryan and Andr{\'e} Schaller and Claudine Rieubland and Fabian Noti and Jens Seiler and Laurent Roten and Baldinger, {Samuel H.} and Hildegard Tanner and Juerg Fuhrer and Andreas Haeberlin and Anna Lam and Pless, {Stephan A.} and Argelia Medeiros-Domingo",

year = "2018",

month = aug,

day = "1",

doi = "10.1007/s00392-018-1233-3",

language = "English",

volume = "107",

pages = "670--678",

journal = "Clinical Research in Cardiology",

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TY - JOUR

T1 - Unexplained cardiac arrest

T2 - a tale of conflicting interpretations of KCNQ1 genetic test results

AU - Chua, Han Chow

AU - Servatius, Helge

AU - Asatryan, Babken

AU - Schaller, André

AU - Rieubland, Claudine

AU - Noti, Fabian

AU - Seiler, Jens

AU - Roten, Laurent

AU - Baldinger, Samuel H.

AU - Tanner, Hildegard

AU - Fuhrer, Juerg

AU - Haeberlin, Andreas

AU - Lam, Anna

AU - Pless, Stephan A.

AU - Medeiros-Domingo, Argelia

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Arrhythmia

KW - Genetics

KW - Ion channel

KW - Sudden cardiac death

KW - Ventricular fibrillation

U2 - 10.1007/s00392-018-1233-3

DO - 10.1007/s00392-018-1233-3

M3 - Journal article

C2 - 29582136

AN - SCOPUS:85044445297

SN - 1861-0684

VL - 107

SP - 670

EP - 678

JO - Clinical Research in Cardiology

JF - Clinical Research in Cardiology

IS - 8

ER -

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

Abstract

Keywords

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