Repository logo

Next generation diagnostics in inherited arrhythmia syndromes : a comparison of two approaches.

Published version



Change log


Ware, James S 
John, Shibu 
Roberts, Angharad M 
Buchan, Rachel 
Gong, Sungsam 


Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.



Arrhythmias, Cardiac, DNA Mutational Analysis, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Heredity, High-Throughput Nucleotide Sequencing, Humans, Ion Channels, KCNQ1 Potassium Channel, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Polymerase Chain Reaction, Potassium Channels, Voltage-Gated, Predictive Value of Tests, Ryanodine Receptor Calcium Release Channel, Sensitivity and Specificity

Journal Title

J Cardiovasc Transl Res

Conference Name

Journal ISSN


Volume Title



Springer Science and Business Media LLC