Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy

S.L.V.M. Stroeks, D.M.E.I. Hellebrekers, G.R.F. Claes, U. Tayal, I.P.C. Krapels, E.K. Vanhoutte, A. van den Wijngaard, M.T.H.M. Henkens, J.S. Ware, S.R.B. Heymans, H.G. Brunner, J.A.J. Verdonschot*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose Accurate interpretation of variants detected in dilated cardiomyopathy (DCM) is crucial for patient care but has proven challenging. We applied a set of proposed refined American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria for DCM, reclassified all detected variants in robust genes, and associated these results to patients' phenotype. Methods The study included 902 DCM probands from the Maastricht Cardiomyopathy Registry who underwent genetic testing. Two gene panel sizes (extended n = 48; and robust panel n = 14) and two standards of variant classification (standard versus the proposed refined ACMG/AMP criteria) were applied to compare genetic yield. Results A pathogenic or likely pathogenic (P/LP) variant was found in 17.8% of patients, and a variant of uncertain significance (VUS) was found in 32.8% of patients when using method 1 (extended panel (n = 48) + standard ACMG/AMP), compared to respectively 16.9% and 12.9% when using method 2 (robust panel (n = 14) + standard ACMG/AMP), and respectively 14% and 14.5% using method 3 (robust panel (n = 14) + refined ACMG/AMP). Patients with P/LP variants had significantly lower event-free survival compared to genotype-negative DCM patients. Conclusion Stringent gene selection for DCM genetic testing reduced the number of VUS while retaining ability to detect similar P/LP variants. The number of genes on diagnostic panels should be limited to genes that have the highest signal to noise ratio.
Original languageEnglish
Pages (from-to)2186-2193
Number of pages8
JournalGenetics in Medicine
Issue number11
Early online date30 Jun 2021
Publication statusPublished - Nov 2021



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