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Updated: Dec 13, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy
Danielle S Burstein1, J William Gaynor2, Heather Griffis3
1Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. bursteind@email.chop.edu.
Insights
Increased genetic variant burden, including variants of unknown significance (VUS), is linked to worse outcomes in pediatric dilated cardiomyopathy (DCM) but not hypertrophic cardiomyopathy (HCM). This finding may improve risk stratification for children with these heart conditions.
Area of Science:
- Cardiology
- Genetics
- Pediatrics
Background:
- Previous genetic research in pediatric cardiomyopathy (CM) primarily focused on pathogenic variants for diagnosis.
- Limited data exists on genotype-outcome correlations in pediatric CM.
- This study investigated the association between overall genetic variant burden and clinical outcomes.
Purpose of the Study:
- To determine if a higher burden of genetic variants (pathogenic and variants of unknown significance, VUS) correlates with worse clinical outcomes in pediatric dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).
- To explore the potential of incorporating VUS into risk stratification models for pediatric CM.
Main Methods:
- Retrospective analysis of 338 children with DCM or HCM who underwent multigene testing between 2010 and 2018.
- Composite endpoint defined as freedom from major adverse cardiac events (MACE).
- Statistical analysis to correlate genetic variant burden (pathogenic variants and VUS) with MACE in DCM and HCM cohorts.
Main Results:
- Pathogenic variants alone were not significantly associated with MACE in either DCM or HCM.
- In DCM, VUS alone (OR 4.0, 95% CI 1.9-8.3) and the combination of pathogenic variants with VUS (OR 5.2, 95% CI 1.7-15.9) were associated with MACE.
- VUS alone or in combination with pathogenic variants was not associated with MACE in HCM.
Conclusions:
- Increased genetic variant burden, including VUS, is associated with worse clinical outcomes in pediatric DCM, but not HCM.
- Genomic variants influencing DCM onset may differ from those driving disease progression.
- Incorporating both pathogenic variants and VUS may enhance risk stratification for pediatric CM.
Background:
Previous genetic research in pediatric cardiomyopathy (CM) has focused on pathogenic variants for diagnostic purposes, with limited data evaluating genotype-outcome correlations. We explored whether greater genetic variant burden (pathogenic or variants of unknown significance, VUS) correlates with worse outcomes.
Methods:
Children with dilated CM (DCM) and hypertrophic CM (HCM) who underwent multigene testing between 2010 and 2018 were included. Composite endpoint was freedom from major adverse cardiac event (MACE).
Results:
Three hundred and thirty-eight subjects were included [49% DCM, median age 5.7 (interquartile range (IQR) 0.2-13.4) years, 51% HCM, median age 3.0 (IQR 0.1-12.5) years]. Pathogenic variants alone were not associated with MACE in either cohort (DCM p = 0.44; HCM p = 0.46). In DCM, VUS alone [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.9-8.3] and in addition to pathogenic variants (OR 5.2, 95% CI 1.7-15.9) was associated with MACE. The presence of VUS alone or in addition to pathogenic variants were not associated with MACE in HCM (p = 0.22 and p = 0.33, respectively).
Conclusion:
Increased genetic variant burden (pathogenic variants and VUS) is associated with worse clinical outcomes in DCM but not HCM. Genomic variants that influence DCM onset may be distinct from those driving disease progression, highlighting the potential value of universal genetic testing to improve risk stratification.
Impact:
In pediatric CM, inconsistent findings historically have been shown between genotype and phenotype severity when only pathogenic variants have been considered. Increased genetic variant burden (including both pathogenic variants and VUS) is associated with worse clinical outcomes in DCM but not HCM. Genomic variants that influence CM onset may be distinct from those variants that drive disease progression and influence outcomes in phenotype-positive individuals. Incorporation of both pathogenic variants and VUS may improve risk stratification models in pediatric CM.
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