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

Autor: Stroeks SLVM; Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands., Hellebrekers DMEI; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Claes GRF; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Tayal U; National Heart Lung Institute, Imperial College London, London, United Kingdom.; Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom., Krapels IPC; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Vanhoutte EK; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., van den Wijngaard A; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Henkens MTHM; Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands., Ware JS; National Heart Lung Institute, Imperial College London, London, United Kingdom.; Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, United Kingdom., Heymans SRB; Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.; Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium., Brunner HG; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.; GROW Institute for Developmental Biology and Cancer, Maastricht University, Maastricht, The Netherlands.; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Verdonschot JAJ; Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands. job.verdonschot@mumc.nl.; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. job.verdonschot@mumc.nl.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Nov; Vol. 23 (11), pp. 2186-2193. Date of Electronic Publication: 2021 Jun 30.
DOI: 10.1038/s41436-021-01255-1
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
Databáze: MEDLINE
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