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J Cardiovasc Transl Res. 2013 Feb;6(1):94-103. doi: 10.1007/s12265-012-9401-8. Epub 2012 Sep 7.

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

Author information

1
MRC Clinical Sciences Centre, Imperial College London, London, UK. j.ware@imperial.ac.uk

Abstract

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.

PMID:
22956155
PMCID:
PMC3546298
DOI:
10.1007/s12265-012-9401-8
[Indexed for MEDLINE]
Free PMC Article

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