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Published on: January 16, 2019
Predicted Risk of Ventricular Arrhythmias in a Genome-First Population With Genetic Risk for Arrhythmogenic Right
Eric D Carruth1, Brittney Murray2, Crystal Tichnell2
1Department of Genomic Health (E.D.C.), Geisinger, Danville, PA.
Insights
Population genomic screening identifies individuals with desmosome variants linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). The predicted 5-year risk for ventricular arrhythmia (VA) is low, but varies by gene and clinical criteria.
Area of Science:
- Cardiovascular Genetics
- Genomics
- Clinical Cardiology
Background:
- Population genomic screening aids in identifying desmosome gene variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC).
- Risk stratification for individuals with diagnosed ARVC is possible using a validated risk calculator.
- The utility of this risk calculator for individuals identified through genomic screening has not been previously explored.
Purpose of the Study:
- To assess the predicted risk of ventricular arrhythmia (VA) in individuals identified through population genomic screening for desmosome variants.
- To compare predicted VA risk with actual outcomes within a 5-year follow-up period.
- To explore how genetic factors and clinical criteria influence predicted VA risk.
Main Methods:
- Identified individuals with pathogenic/likely pathogenic variants in desmosome genes (PKP2, DSP, DSG2, DSC2) via genomic screening.
- Applied the ARVC risk calculator to patients with subsequent right ventricular function evaluation.
- Compared predicted 5-year VA risk with observed outcomes in individuals followed for up to 5 years post-genetic result disclosure.
Main Results:
- Of 113 individuals with variants and no prior sustained VA, 8% met criteria for definite ARVC diagnosis.
- The median 5-year predicted VA risk was 3.9% (1.6% for fast VA), significantly lower than the calculator's derivation cohort.
- Predicted VA risk was higher in those with non-genetic ARVC Task Force Criteria (6.3%) and DSP variants (6.1%) compared to others.
- No sustained VA events were observed during a median 3.0-year follow-up.
Conclusions:
- Individuals identified via population genomic screening for desmosome variants have a low predicted 5-year risk of VA.
- Predicted VA risk is influenced by the specific gene involved and the presence of additional ARVC Task Force Criteria.
- The findings suggest a potentially lower risk profile in screened populations compared to clinically diagnosed cohorts.
Background:
Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARVC risk calculator offers a novel means to risk stratify individuals with diagnosed ARVC, but predicted risk in the context of genomic screening identification has not been explored.
Methods:
Individuals harboring a pathogenic/likely pathogenic variant in a desmosome gene (PKP2, DSP, DSG2, or DSC2) were identified through the Geisinger MyCode Genomic Screening and Counseling program. The ARVC risk calculator was applied to patients with a subsequent evaluation of right ventricular function. This predicted risk was compared with outcomes in the first 5 years (range, 0.3-5.0 years) after genetic result return.
Results:
Of 254 individuals with a clinically confirmed pathogenic/likely pathogenic desmosome variant, 113 (median age, 56 [interquartile range, 42-66]; 71% female) had cardiac imaging in follow-up and no prior sustained ventricular arrhythmia (VA). Eighty-two (73%) had no ARVC task force criteria (TFC) besides the variant (possible diagnosis), 22 (19%) had a single additional minor criterion (borderline diagnosis), and 9 (8%) met criteria for definite diagnosis. The median 5-year predicted VA risk was 3.9% (2.3%-6.6%), notably lower than that of the calculator derivation cohort (20.6%). The risk of fast VA was 1.6% (1.0%-2.9%). The predicted VA risk was higher in individuals with any nongenetic ARVC task force criteria (6.3% [2.5-13.2%]) versus those without (3.7% [2.2-5.6%]; P=0.01), and in individuals with DSP variants (6.1% [3.9-7.8%] versus PKP2 3.4% [2.2-5.3%]; P=0.01). Over a median 3.0 years of follow-up (≤5 years only), no sustained VA events were observed in this cohort.
Conclusions:
The predicted 5-year risk of VA in individuals ascertained via population genomic screening for desmosome variants is low (3.9%; 1.6% for fast VA) but may vary by affected gene and ARVC task force criteria burden.
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