Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors
| Autor: | Shalini C. Reshmi, Vidu Garg, Jeffrey S Bennett, Kim L. McBride, Anna Kamp, Madison Bernhardt, Naomi J. Kertesz, Erik Zmuda, Sara Fitzgerald-Butt |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Adolescent Genomics 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Internal medicine Clinical information Medicine Humans Genetic Predisposition to Disease Genetic Testing Child Uncertain significance Genetic testing Retrospective Studies medicine.diagnostic_test business.industry Electronic medical record Infant Arrhythmias Cardiac Syndrome Clinical Practice 030228 respiratory system Relative risk Child Preschool Pediatrics Perinatology and Child Health Practice Guidelines as Topic Medical genetics Female Cardiology and Cardiovascular Medicine business |
| Zdroj: | Pediatric cardiology. 40(8) |
| ISSN: | 1432-1971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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