Reclassification of genetic variants in children with long QT syndrome.
Adolescent
Calmodulin
/ genetics
Child
Child, Preschool
ERG1 Potassium Channel
/ genetics
Female
Gene Frequency
Humans
Infant
KCNQ1 Potassium Channel
/ genetics
Long QT Syndrome
/ classification
Male
Mutation
NAV1.5 Voltage-Gated Sodium Channel
/ genetics
Phenotype
Potassium Channels, Inwardly Rectifying
/ genetics
ACMG
Schwartz score
cardiogenetics
long QT syndrome
variant classification
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
28
10
2019
revised:
16
04
2020
accepted:
17
04
2020
pubmed:
10
5
2020
medline:
21
5
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32383558
doi: 10.1002/mgg3.1300
pmc: PMC7506994
doi:
Substances chimiques
CALM2 protein, human
0
Calmodulin
0
ERG1 Potassium Channel
0
KCNH2 protein, human
0
KCNJ2 protein, human
0
KCNQ1 Potassium Channel
0
KCNQ1 protein, human
0
NAV1.5 Voltage-Gated Sodium Channel
0
Potassium Channels, Inwardly Rectifying
0
SCN5A protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1300Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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