Reclassification of genetic variants in children with long QT syndrome
Abstract 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 r...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1300 |
| _version_ | 1797301148857663488 |
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| author | Dominik S. Westphal Tobias Burkard Alexander Moscu‐Gregor Roman Gebauer Gabriele Hessling Cordula M. Wolf |
| author_facet | Dominik S. Westphal Tobias Burkard Alexander Moscu‐Gregor Roman Gebauer Gabriele Hessling Cordula M. Wolf |
| author_sort | Dominik S. Westphal |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T23:17:17Z |
| format | Article |
| id | doaj.art-bea25f40d7734b32b2036bf1a9bb5831 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:17:17Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-bea25f40d7734b32b2036bf1a9bb58312024-02-21T10:24:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-09-0189n/an/a10.1002/mgg3.1300Reclassification of genetic variants in children with long QT syndromeDominik S. Westphal0Tobias Burkard1Alexander Moscu‐Gregor2Roman Gebauer3Gabriele Hessling4Cordula M. Wolf5Institute of Human Genetics Technical University of Munich Munich GermanyDepartment of Congenital Heart Disease and Pediatric Cardiology German Heart Center Munich, Technical University of Munich Munich GermanyCenter for Human Genetics and Laboratory Diagnostics Martinsried GermanyDepartment of Pediatric Cardiology Heart Center Leipzig, University of Leipzig Leipzig GermanyDepartment of Congenital Heart Disease and Pediatric Cardiology German Heart Center Munich, Technical University of Munich Munich GermanyDepartment of Congenital Heart Disease and Pediatric Cardiology German Heart Center Munich, Technical University of Munich Munich GermanyAbstract 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.https://doi.org/10.1002/mgg3.1300ACMGcardiogeneticslong QT syndromeSchwartz scorevariant classification |
| spellingShingle | Dominik S. Westphal Tobias Burkard Alexander Moscu‐Gregor Roman Gebauer Gabriele Hessling Cordula M. Wolf Reclassification of genetic variants in children with long QT syndrome Molecular Genetics & Genomic Medicine ACMG cardiogenetics long QT syndrome Schwartz score variant classification |
| title | Reclassification of genetic variants in children with long QT syndrome |
| title_full | Reclassification of genetic variants in children with long QT syndrome |
| title_fullStr | Reclassification of genetic variants in children with long QT syndrome |
| title_full_unstemmed | Reclassification of genetic variants in children with long QT syndrome |
| title_short | Reclassification of genetic variants in children with long QT syndrome |
| title_sort | reclassification of genetic variants in children with long qt syndrome |
| topic | ACMG cardiogenetics long QT syndrome Schwartz score variant classification |
| url | https://doi.org/10.1002/mgg3.1300 |
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