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

Abstract

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.

Fig. 1. Proportion of DCM patients with either no variant, a variant of unknown significance, a likely pathogenic, or pathogenic variant as result after genetic testing.

The use of a restricted panel including robust genes with a high signal to noise ratio identified nearly all actionable variants, but greatly reduces the number of VUSs. Method 1 resembles the extended panel of 48 genes in which variants are classified according to the 2015 ACMG/AMP standards. Method 2 uses the robust panel of 14 DCM-associated genes and classified variants according to the 2015 ACMG/AMP standards. Method 3 uses the robust panel of 14 DCM-associated genes and classified them according to the 2020 DCM adaptation of the ACMG/AMP standards.

Fig. 2. Survival curves show freedom from combined endpoint (cardiac death or transplantation, heart failure hospitalization or life-threatening arrhythmia) stratified on genetic status.

Method 1 resembles the extended panel of 48 genes in which variants are classified according to the 2015 ACMG/AMP standards. Method 2 uses the robust panel of 14 DCM-associated genes and classified variants according to the 2015 ACMG/AMP standards. Method 3 uses the robust panel of 14 DCM-associated genes and classified them according to the 2020 DCM adaptation of the ACMG/AMP standards.