Key result
Reinterpretation of 84 distinct variants in 127 children with long QT syndrome downgraded 14.3% (12/84) of variants from (likely) pathogenic to variant of unknown significance.
Why the study?
Complex pathophysiology and missing functional studies complicate variant interpretation and classification in inherited long QT syndrome, prompting evaluation of the rate of change in variant classification using current interpretation standards.
Observational (n=127)
Yes
Reevaluation of genetic variants in children with LQTS using updated guidelines frequently downgrades variants to VUS, particularly in patients with milder clinical phenotypes.
Answers are grounded in this paper and cite their sources.
Variant downgrading to VUS in pediatric LQTS supports periodic reevaluation; leaves open effects on prognosis and management.
BACKGROUND: Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. METHODS: Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of 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. RESULTS: About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. CONCLUSION: 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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Westphal et al. (2020) conducted an observational in Long QT syndrome (LQTS) (n=127). Reinterpretation of genetic variants based on ACMG 2015 guidelines vs. Unchanged variant characterization was evaluated on Rate of change in variant classification from (likely) pathogenic to variant of unknown significance (VUS). Reinterpretation of 84 distinct variants in 127 children with long QT syndrome downgraded 14.3% (12/84) of variants from (likely) pathogenic to variant of unknown significance.
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