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Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors

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Abstract

Genetic testing is important to augment clinical diagnosis and inform management of inherited arrhythmias syndromes (IAS), but variants of uncertain significance (VUS) are common and remain a challenge in clinical practice. In 2015, American College of Medical Genetics (ACMG) published updated guidelines for interpretation of genetic results. Despite increasing understanding of human genomic variation, there are no guidelines for reinterpretation of prior genetic test results. Patients at a single tertiary children’s hospital with genetic testing for an IAS that demonstrated a VUS were re-evaluated using 2015 ACMG guidelines, clinical information, and publically available databases. Search of the electronic medical record identified 116 patients with genetic testing results available, and 24/116 (21%) harbored a VUS for an IAS. 23 unique VUS were evaluated from 12 genes. Over half of the VUS (12/23 (52%)) were reclassified using 2015 criteria, and 8 (35%) changed to pathogenic and 4 (17%) to benign. Relative risk of reclassification of VUS to a pathogenic variant in a patient with confirmed clinical diagnosis was 4.1 (95% CI 1.23–15.4). Reclassification was not associated with initial testing year. These data demonstrate 52% of VUS in children with IAS are reclassified with application of 2015 ACMG guidelines. Strength of phenotyping is associated with eventual pathogenic classification of genetic variants and periodic re-evaluation of VUS identified on genetic testing for IAS is warranted.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. Ms. Fitzgerald-Butt and Dr. Kamp have contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA

    Jeffrey S. Bennett, Kim L. McBride, Shalini C. Reshmi, Erik Zmuda, Naomi J. Kertesz, Vidu Garg & Anna N. Kamp

  2. The Heart Center, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, 43205, USA

    Jeffrey S. Bennett, Naomi J. Kertesz, Vidu Garg & Anna N. Kamp

  3. Department of Medical Genetics, St. Luke’s Mountain States Tumor Institute, Boise, ID, USA

    Madison Bernhardt

  4. Division of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

    Kim L. McBride

  5. The Center for Cardiovascular Research, Nationwide Children’s Hospital, Columbus, OH, USA

    Kim L. McBride & Vidu Garg

  6. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

    Shalini C. Reshmi & Erik Zmuda

  7. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Sara Fitzgerald-Butt

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  1. Jeffrey S. Bennett
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Correspondence to Anna N. Kamp.

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This study was a retrospective study exempt from informed consent. The study was approved by the Institutional Review Board of Nationwide Children’s Hospital, Columbus, OH.

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Bennett, J.S., Bernhardt, M., McBride, K.L. et al. Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors. Pediatr Cardiol 40, 1679–1687 (2019). https://doi.org/10.1007/s00246-019-02203-2

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