Jordan, Elizabeth and Peterson, Laiken and Ai, Tomohiko and Asatryan, Babken and Bronicki, Lucas and Brown, Emily and Celeghin, Rudy and Edwards, Matthew and Fan, Judy and Ingles, Jodie and James, Cynthia A. and Jarinova, Olga and Johnson, Renee and Judge, Daniel P. and Lahrouchi, Najim and Lekanne Deprez, Ronald H. and Lumbers, R. Thomas and Mazzarotto, Francesco and Medeiros Domingo, Argelia and Miller, Rebecca L. and Morales, Ana and Murray, Brittney and Peters, Stacey and Pilichou, Kalliopi and Protonotarios, Alexandros and Semsarian, Christopher and Shah, Palak and Syrris, Petros and Thaxton, Courtney and van Tintelen, J. Peter and Walsh, Roddy and Wang, Jessica and Ware, James and Hershberger, Ray E. (2021) Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation, 144 (1). pp.7-19. ISSN 0009-7322
Full text not available from this repository.Abstract
BACKGROUND: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. METHODS: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. RESULTS: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. CONCLUSIONS: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 31 Jul 2021 05:09 |
| Last Modified: | 31 Jul 2021 05:09 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1086 |
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