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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
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

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Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology

Sara Cherny1, Rachael Olson1, Kathryn Chiodo1

  • 1Division of Cardiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Journal of Genetic Counseling
|July 25, 2020
PubMed

Insights

Genetic testing for pediatric heart conditions shows increasing test volume and gene numbers. However, the proportion of variants of unknown significance (VUS) also rose, complicating interpretation and highlighting the need for genetic counselors.

Area of Science:

  • Cardiovascular Genetics
  • Pediatric Cardiology
  • Clinical Genomics

Background:

  • Genetic testing for inherited cardiac disorders is evolving rapidly.
  • Accurate variant classification is crucial for patient management.

Purpose of the Study:

  • To assess trends in variant classification for pediatric arrhythmia and cardiomyopathy genetic testing from 2006-2017.
  • To identify changes in test ordering, gene analysis, and variant interpretation over time.

Main Methods:

  • Retrospective review of genetic testing data from 583 patients.
  • Analysis of 914 variants classified by CLIA laboratories.
  • Spearman correlation used to assess trends over the 12-year study period.

Main Results:

  • Total genetic tests ordered increased significantly, accelerating after 2012.
  • Average number of genes tested per panel showed a strong positive correlation with year.
  • Variants of unknown significance (VUS) comprised over 50% of reported variants by 2011, and 21.5% of variants were reclassified over time.

Conclusions:

  • Genetic testing for pediatric cardiac conditions has expanded, interrogating more genes per panel.
  • The increasing proportion of VUS and variant reclassifications necessitate expert interpretation.
  • Inclusion of genetic counselors in pediatric electrophysiology and cardiomyopathy teams is recommended.

Keywords:
cascade testinggenetic counselinggenetic testinggenetics servicespediatricsvariant classificationvariants of uncertain significance (VUS)workforce

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