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.
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.
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.
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.
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The data that support the findings of this study are available from the corresponding author on request.
Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–47.
Japp AG, Gulati A, Cook SA, Cowie MR, Prasad SK. The diagnosis and evaluation of dilated cardiomyopathy. J Am Coll Cardiol. 2016;67:2996–3110.
Verdonschot JAJ et al. Implications of genetic testing in dilated cardiomyopathy. Circ Genom Precis Med. 2020;13:476–87.
Gigli M et al. Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2019;74:1480–90.
Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19:192–203.
Richards S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Kelly MA et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genet Med. 2018;20:351–59.
Morales A et al. Variant interpretation for dilated cardiomyopathy: refinement of the American College of Medical Genetics and Genomics/ClinGen guidelines for the DCM Precision Medicine Study. Circ Genom Precis Med. 2020;13:e002480.
Mazzarotto F et al. Reevaluating the genetic contribution of monogenic dilated cardiomyopathy. Circulation. 2020;141:387–98.
Pinto YM et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic nondilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37:1850–58.
Verdonschot JAJ et al. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum Mutat. 2020;41:1091–111.
Thomson KL et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet Med. 2019;21:1576–84.
Manrai AK et al. Genetic misdiagnoses and the potential for health disparities. N Engl J Med. 2016;375:655–65.
Ingles J et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med. 2019;12:e002460.
Hosseini SM et al. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome. Circulation. 2018;138:1195–205.
Adler A et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT Syndrome. Circulation. 2020;141:418–28.
Jordan E et al. An evidence-based assessment of genes in dilated cardiomyopathy. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.120.053033.
Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517–24.
Harris KM et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006;114:216–25.
Sen-Chowdhry S, Jacoby D, Moon JC, McKenna WJ. Update on hypertrophic cardiomyopathy and a guide to the guidelines. Nat Rev Cardiol. 2016;13:651–75.
Kalia SS et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55.
Hershberger RE et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:899–909.
Bean LJH et al. Diagnostic gene sequencing panels: from design to report-a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22:453–61.
The authors are grateful to Pablo Garcia-Pavia and Juan Pablo Ochoa (Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain) for their input and revising of the manuscript. J.W.: This work was supported by Wellcome Trust [107469/Z/15/Z], Medical Research Council (UK), British Heart Foundation [RE/18/4/34215], NIHR Royal Brompton Cardiovascular Biomedical Research Unit, and the NIHR Imperial College Biomedical Research Centre. S.H.: The research leading to these results has received funding from the European Union Commission’s Seventh Framework program under grant agreement number 305507 (HOMAGE). This paper has been possible thanks to the support of the the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21. The views expressed in this work are those of the authors and not necessarily those of the funders.
The study was performed according to the declaration of Helsinki and was approved by the institutional Medical Ethics Committee of the Maastricht University Medical Center. All patients gave written informed consent.
The authors declare no competing interests.
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Stroeks, S.L.V.M., Hellebrekers, D.M.E.I., Claes, G.R.F. et al. Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy. Genet Med (2021). https://doi.org/10.1038/s41436-021-01255-1