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

Chua, Han Chow; Servatius, Helge Simon; Asatryan, Babken; Schaller, André; Rieubland, Claudine; Noti, Fabian; Seiler, Jens; Roten, Laurent; Baldinger, Samuel Hannes; Tanner, Hildegard; Fuhrer, Jürg; Häberlin, Andreas; Lam, Anna; Pless, Stephan A; Medeiros Domingo, Argelia (2018). Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results. Clinical research in cardiology, 107(8), pp. 670-678. Springer-Verlag 10.1007/s00392-018-1233-3

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Humangenetik
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie

UniBE Contributor:

Servatius, Helge Simon; Asatryan, Babken; Schaller, André; Rieubland, Claudine; Noti, Fabian; Seiler, Jens; Roten, Laurent; Baldinger, Samuel Hannes; Tanner, Hildegard; Fuhrer, Jürg; Häberlin, Andreas; Lam, Anna and Medeiros Domingo, Argelia

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1861-0684

Publisher:

Springer-Verlag

Language:

English

Submitter:

André Schaller

Date Deposited:

13 Mar 2019 13:59

Last Modified:

24 Oct 2019 01:57

Publisher DOI:

10.1007/s00392-018-1233-3

PubMed ID:

29582136

Uncontrolled Keywords:

Arrhythmia Genetics Ion channel Sudden cardiac death Ventricular fibrillation

BORIS DOI:

10.7892/boris.123116

URI:

https://boris.unibe.ch/id/eprint/123116

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