J Mol Diagn. 2019 Feb 4. pii: S1525-1578(18)30177-6. doi: 10.1016/j.jmoldx.2019.01.004. [Epub ahead of print]
Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting.
Daoud H1, Ghani M2, Nfonsam L2, Potter R2, Ordorica S2, Haslett V2, Santos N2, Derksen H2, Lahey D2, McGill M2, Trudel V2, Antoniuk B2, Vasli N2, Chisholm C2, Mettler G2, Sinclair-Bourque E2, McGowan-Jordan J3, Smith A3, Roberts R4, Jarinova O3.
Inherited cardiomyopathies (ICs) are a major cause of heart disease. Given their marked clinical and genetic heterogeneity, the content and clinical utility of IC multi-gene panels has been the topic of continuous debate. Our genetics diagnostic laboratory has been providing clinical diagnostic testing for ICs since 2012. We began by testing nine genes, and expanded our panel by 5-fold in 2015. Here, we describe the implementation of a cost-effective next-generation sequencing (NGS)-based assay for testing of IC genes, including a protocol that minimizes the amount of Sanger sequencing required to confirm variants identified via NGS, which reduces the cost and time of testing. The NGS assay was developed for the simultaneous analysis of 45 IC genes, and assessed for the impact of panel expansion on variant detection, turn-around-time (TAT), and cost of testing in a cohort of 993 patients. The assay led to a considerable reduction in test cost and TAT. However, only a marginal increase was observed in the diagnostic yield, whereas the rate of inconclusive findings increased considerably. These findings suggest that the ongoing evaluation of gene content and monitoring of clinical utility for multi-gene tests are essential to achieve maximum clinical utility of multi-gene tests in a publicly-funded health care setting.
Copyright © 2019. Published by Elsevier Inc.