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Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

Published online by Cambridge University Press:  03 September 2019

Adam C. Kean Open the ORCID record for Adam C. Kean [Opens in a new window] ,
Benjamin M. Helm ,
Matteo Vatta ,
Mark D. Ayers ,
John J. Parent  and
Robert K. Darragh
Adam C. Kean*
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, Indianapolis, IN, USA
Benjamin M. Helm
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Epidemiology, Fairbanks School of Public Health, Indiana University School of Medicine, Indianapolis, IN, USA
Matteo Vatta
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Mark D. Ayers
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, Indianapolis, IN, USA
John J. Parent
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
Robert K. Darragh
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
*
Author for correspondence: Assistant Professor A. C. Kean, Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, 705 Riley Hospital Drive, Riley Research Room 127, Indianapolis, IN 46202-5225, USA. Tel.: +1 317 274 8906; Fax: +1 317 274 4022; E-mail: akean@iu.edu
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Abstract

Introduction:

The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.

Methods:

A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.

Results:

All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.

Conclusions:

There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.

Keywords

SCN5Asudden cardiac arrestdilated cardiomyopathy
Type
Original Article
Information
Cardiology in the Young , Volume 29 , Issue 10 , October 2019 , pp. 1257 - 1263
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Copyright
© Cambridge University Press 2019 

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Footnotes

*

These authors contributed equally to this work.

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