Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease.
Primary electrical disease (PED) is characterized by cardiac arrhythmias, which can lead to sudden cardiac death in the absence of detectable structural heart disease. PED encompasses a diversity of inherited syndromes, predominantly Brugada syndrome, early repolarization syndrome, long QT syndrome, short QT syndrome, arrhythmogenic right ventricular cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia. To overcome the diagnostic challenges imposed by the clinical and genetic heterogeneity of PED, we developed a targeted gene panel for next-generation sequencing of 51 PED genes. The amplified samples were sequenced on MiSeq. To validate the panel, 20 Human Polymorphism Study Center samples and 19 positive control samples were used, with a total of 1479 variants. An analytical sensitivity and specificity of 100% and 99.9% were obtained. After validation, we applied the assay to 114 PED patients. We identified 107 variants in 36 different genes, 18 of which were classified as pathogenic or likely pathogenic, 54 variants were of unknown significance, and 35 were classified as likely benign. We can conclude that the PED Multiplex Amplification of Specific Targets for Resequencing Plus assay is a proficient and highly reliable test to routinely screen patients experiencing primary arrhythmias.
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Dorien
D
Proost
Department of Cardiology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Johan
J
Saenen
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Geert
G
Vandeweyer
Multiplicom, Niel, Belgium.
Annelies
A
Rotthier
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Maaike
M
Alaerts
Department of Cardiology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Emeline M
EM
Van Craenenbroeck
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Joachim
J
Van Crombruggen
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Geert
G
Mortier
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Wim
W
Wuyts
Department of Cardiology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Christiaan
C
Vrints
Multiplicom, Niel, Belgium.
Jurgen
J
Del Favero
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Bart
B
Loeys
Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium. Electronic address: lut.vanlaer@uantwerp.be.
Lut
L
Van Laer
D001145:Arrhythmias, Cardiac / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics