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Updated: Oct 3, 2026
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Cardiologist-Delivered Genetic Testing in 482 Patients With Cardiomyopathy: The Infrastructure Needed for Mainstream
Omid Kiamanesh1, Susan Christian2, Robert Miller1
1Broderick Cardiomyopathy Program, Libin Cardiovascular Institute, University of Calgary, Canada (O.K., R.M., K.L., J.H., L.H., L.A., N.M.).
Background:
Mainstream cardiac genetic testing, in which the treating cardiologist orders and returns multigene panel results without a traditional genetic counseling session, may expand access, but no mainstream program has quantified the operational burden. We quantified high-risk genotypes, variant reclassification, and carrier findings in a mainstream cardiomyopathy testing program to characterize the infrastructure required for safe scale-up.
Methods:
We retrospectively analyzed 482 consecutive patients with dilated cardiomyopathy (n=338), nondilated left ventricular cardiomyopathy (n=84), or hypertrophic cardiomyopathy (n=60) who underwent multigene panel testing ordered by cardiologists at the Broderick Cardiomyopathy Program (January 2022 to February 2026). Variant classifications used each laboratory's most current interpretation.
Results:
Diagnostic pathogenic/likely pathogenic variants were identified in 95 of 482 patients (yield, 19.7% [95% CI, 16.4%-23.5%]) across 21 genes. Three categories of results required program-level infrastructure: (1) 18 of 95 genotype-positive patients (18.9%) had high-risk genotypes (DSP, LMNA, FLNC [truncating], RBM20, DES) requiring genotype-specific management; (2) 8 of 12 reclassified variants (12/743 total, 1.6%) crossed the pathogenic/likely pathogenic threshold, including 7 variant of uncertain significance-to- pathogenic/likely pathogenic upgrades converting nondiagnostic patients to genotype-positive; and (3) carrier findings comprised 26 of 121 pathogenic/likely pathogenic variants (21.5%), inflating apparent yield to 23.7% if carrier findings were not distinguished from diagnostic results based on gene inheritance pattern. Variants of uncertain significance were reported in 295 patients (61.2%).
Conclusions:
These data identify 5 capabilities that support safe mainstream scale-up: high-risk genotype pathways for the 1 in 5 diagnostic patients with a high-risk variant, variant surveillance with recontact capacity for the 1 in 60 patients affected by actionable reclassification, recognition of gene inheritance pattern for the 1 in 19 patients with a carrier finding, a defined referral pathway to medical genetics, and standardized family screening infrastructure for all result categories.
