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Westphal, D.S. ; Burkard, T.* ; Moscu-Gregor, A.* ; Gebauer, R.* ; Hessling, G.* ; Wolf, C.M.*

Reclassification of genetic variants in children with long QT syndrome.

Mol. Genet. Genomic Med. 8:e1300 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acmg ; Cardiogenetics ; Long Qt Syndrome ; Schwartz Score ; Variant Classification; Founder Mutations; Risk
ISSN (print) / ISBN 2324-9269
e-ISSN 2324-9269
Zeitschrift Molecular genetics and genomic medicine
Quellenangaben Band: 8, Heft: 9, Seiten: , Artikelnummer: e1300 Supplement: ,
Verlag Wiley
Verlagsort [Hoboken, NJ]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)