Abstract
Inherited cardiac conditions (ICCs) are characterised by marked genetic and allelic heterogeneity and require extensive sequencing for genetic characterisation. We iteratively optimised a targeted gene capture panel for ICCs that includes disease-causing, putatively pathogenic, research and phenocopy genes (n = 174 genes). We achieved high coverage of the target region on both MiSeq (>99.8 % at ≥20× read depth, n = 12) and NextSeq (>99.9 % at ≥20×, n = 48) platforms with 100 % sensitivity and precision for single nucleotide variants and indels across the protein-coding target on the MiSeq. In the final assay, 40 out of 43 established ICC genes informative in clinical practice achieved complete coverage (100 % at ≥20×). By comparison, whole exome sequencing (WES; ∼80×), deep WES (∼500×) and whole genome sequencing (WGS; ∼70×) had poorer performance (88.1, 99.2 and 99.3 % respectively at ≥20×) across the ICC target. The assay described here delivers highly accurate and affordable sequencing of ICC genes, complemented by accessible cloud-based computation and informatics. See Editorial in this issue (DOI: 10.1007/s12265-015-9667-8).Electronic supplementary materialThe online version of this article (doi:10.1007/s12265-016-9673-5) contains supplementary material, which is available to authorized users.
Highlights
Inherited cardiac conditions (ICCs) are diseases of the heart and circulation with a combined prevalence of ∼1 %
The use of targeted sequencing and whole exome sequencing (WES) for the study of ICCs has increased, reflecting high-throughput capabilities and reduced per-base costs of Nextgeneration sequencing (NGS) when compared to conventional Sanger sequencing
Common pathogenic variants that are outside the captured region cannot be assessed by this assay, for instance, the 25 bp deletion in intron 32 of MYBPC3 that has been associated with hypertrophic cardiomyopathy (HCM) [36]
Summary
Inherited cardiac conditions (ICCs) are diseases of the heart and circulation with a combined prevalence of ∼1 %. ICCs include inherited arrhythmia syndromes, cardiomyopathies, aortopathies and hyperlipidaemias [1,2,3,4]. They most commonly exhibit autosomal dominant inheritance, though with highly variable expressivity and penetrance. Sequencing of ICC genes can be performed to confirm an ICC diagnosis, inform patient management/ cascade screening and be useful for molecular autopsy in the case of sudden unexplained death [5]. Sanger sequencing was used for ICC gene sequencing for both clinical and research applications, but this technique has limited throughput and is prohibitively.
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