Prioritize Variant Reclassification in Pediatric Long QT Syndrome-Time to Revisit.
Pediatr Cardiol
; 45(5): 1023-1035, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38565666
ABSTRACT
Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome associated with sudden cardiac death. Accurate interpretation and classification of genetic variants in LQTS patients are crucial for effective management. All patients with LQTS with a positive genetic test over the past 18 years (2002-2020) in our single tertiary pediatric cardiac center were identified. Reevaluation of the reported variants in LQTS genes was conducted using the American College of Genetics and Genomics (ACMG) guideline after refinement by the US ClinGen SVI working group and guideline by Walsh et al. on genetic variant reclassification, under multidisciplinary input. Among the 59 variants identified. 18 variants (30.5%) were reclassified. A significant larger portion of variants of unknown significance (VUS) were reclassified compared to likely pathogenic (LP)/pathogenic (P) variants (57.7% vs 9.1%, p < 0.001). The rate of reclassification was significantly higher in the limited/disputed evidence group compared to the definite/moderate evidence group (p = 0.0006). All LP/P variants were downgraded in the limited/disputed evidence group (p = 0.0057). VUS upgrades are associated with VUS located in genes within the definite/moderate evidence group (p = 0.0403) and with VUS present in patients exhibiting higher corrected QT intervals (QTc) (p = 0.0445). A significant number of pediatric LQTS variants were reclassified, particularly for VUS. The strength of the gene-disease association of the genes influences the reclassification performance. The study provides important insights and guidance for pediatricians to seek for reclassification of "outdated variants" in order to facilitate contemporary precision medicine.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
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Pruebas Genéticas
Límite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Pediatr Cardiol
Año:
2024
Tipo del documento:
Article
País de afiliación:
China