Pediatric cardiomyopathy illustrates the importance of reinterpreting the significance of genetic variants

Abstract

Background

Clinical genetic testing is increasingly being utilized to establish a molecular diagnosis to help manage children with cardiomyopathy and to assess the risk of cardiomyopathy among family members. However, as evidence and guidelines evolve, variant classification can change with the potential to impact counseling and family screening.

Objectives

The main purpose of this study was to investigate whether variants in cardiomyopathy genes previously interpreted by clinical genetic testing laboratories would be reclassified under current guidelines for the interpretation of sequence variants.

Methods

In 211 children enrolled in the Pediatric Cardiomyopathy Registry, we compared the results of previous clinical genetic testing with the results of research testing in 37 cardiomyopathy genes.

Results

The mean time difference between initial testing and reinterpretation was 7 years. Using the 2015 American College of Medical Genetics and Genomics guidelines for the interpretation of sequence variants, we found that 18 % of the tested population had a change in variant classification. Ninety-two percent of the initial classifications were performed before the publication of the guidelines, with 82 % of reclassifications resulting in a variant downgrade. Most of these were changes from the pathogenic or likely pathogenic category to a variant of uncertain significance. Reclassification frequency was similar across types of cardiomyopathy.

Conclusion

Our results highlight that a portion of variants get downgraded, and periodic reinterpretation of genetic testing results is necessary for all types of cardiomyopathy—particularly for variant interpretations prior to 2015. Importantly, variant reclassification has potential impact on the clinical management of at-risk patients.