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Pediatric Cardiology

, Volume 40, Issue 8, pp 1679–1687 | Cite as

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

  • Jeffrey S. Bennett
  • Madison Bernhardt
  • Kim L. McBride
  • Shalini C. Reshmi
  • Erik Zmuda
  • Naomi J. Kertesz
  • Vidu Garg
  • Sara Fitzgerald-Butt
  • Anna N. KampEmail author
Original Article

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.

Keywords

Genetics Arrhythmias Variants Long QT syndrome Genomics CPVT 

Notes

Funding

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

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest.

Informed consent

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jeffrey S. Bennett
    • 1
    • 2
  • Madison Bernhardt
    • 3
  • Kim L. McBride
    • 1
    • 4
    • 5
  • Shalini C. Reshmi
    • 1
    • 6
  • Erik Zmuda
    • 1
    • 6
  • Naomi J. Kertesz
    • 1
    • 2
  • Vidu Garg
    • 1
    • 2
    • 5
  • Sara Fitzgerald-Butt
    • 7
  • Anna N. Kamp
    • 1
    • 2
    Email author
  1. 1.Department of PediatricsThe Ohio State University College of MedicineColumbusUSA
  2. 2.The Heart CenterNationwide Children’s HospitalColumbusUSA
  3. 3.Department of Medical GeneticsSt. Luke’s Mountain States Tumor InstituteBoiseUSA
  4. 4.Division of Genetic and Genomic MedicineNationwide Children’s HospitalColumbusUSA
  5. 5.The Center for Cardiovascular ResearchNationwide Children’s HospitalColumbusUSA
  6. 6.Department of Pathology and Laboratory MedicineNationwide Children’s HospitalColumbusUSA
  7. 7.Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisUSA

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