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Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy

Abstract

PURPOSE: We evaluated genome sequencing (GS) as an alternative to multigene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM). METHODS: Forty-two patients with familial DCM underwent PS and GS, and detection rates of rare single-nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed. RESULTS: GS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. GS identified all PS-identified pathogenic or likely pathogenic variants as well as two additional likely pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic. CONCLUSION: Our data support the use of GS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. GS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically actionable variants is limited by a paucity of genetic and functional evidence for DCM association.

Type Journal
ISBN 1530-0366 (Electronic) 1098-3600 (Linking)
Authors Minoche, A. E.; Horvat, C.; Johnson, R.; Gayevskiy, V.; Morton, S. U.; Drew, A. P.; Woo, K.; Statham, A. L.; Lundie, B.; Bagnall, R. D.; Ingles, J.; Semsarian, C.; Seidman, J. G.; Seidman, C. E.; Dinger, M. E.; Cowley, M. J.; Fatkin, D.
Responsible Garvan Author Dr Mark Cowley
Publisher Name GENETICS IN MEDICINE
Published Date 2018-07-02
Status Published in-print
DOI 10.1038/s41436-018-0084-7
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29961767