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DOI: 10.1055/s-0040-1705528
Reclassification of Genetic Variants in Children with Long QT Syndrome
Publication History
Publication Date:
13 February 2020 (online)
Objectives: Genes encoding for ion channel or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS), a major cause of life-threatening arrhythmias in the young. The genetic detection rate in patients with clinically proven LQTS is at 75 to 80% maximum. Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. Sometimes, classification of variants can change during follow-up due to new insights or can even differ between analysis performing laboratories. We therefore aimed to evaluate the rate of change in variant classification based on mostly used interpretation standards.
Methods: Medical charts of patients aged between 0 and 18 years and a diagnosis of LQTS presenting at the German heart center in Munich and Leipzig between 2001 and 2008 were reviewed. Clinical and genetic data were extracted. Only patients with available moleculargenetic diagnosis report were included for further analysis. Reinterpretation of the originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the “Standards and Guidelines for the Interpretation of Sequence Variants” by the ACMG 2015.
Result: A total of 84 distinct (likely) pathogenic variants were identified in 123 patients and were reinterpretated based on current ACMG guidelines. In 12 variants (12/84, 14.3%), the classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele that contributes to the LQTS phenotype but escapes the classification as disease causing by the ACMG criteria. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz’s scores and QTc intervals compared with individuals with unchanged variant characterization.
Conclusion: A remarkable proportion of variants that were originally reported to the patients as causative for LQTS were reclassified to VUS according to current standards. This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling especially in LQTS patients with minor clinical criteria.
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No conflict of interest has been declared by the author(s).