Functional testing for variant prioritization in a family with long QT syndrome.
Mol Genet Genomics
; 296(4): 823-836, 2021 Jul.
Article
en En
| MEDLINE
| ID: mdl-33876311
ABSTRACT
Next-generation sequencing platforms are being increasingly applied in clinical genetic settings for evaluation of families with suspected heritable disease. These platforms potentially improve the diagnostic yield beyond that of disease-specific targeted gene panels, but also increase the number of rare or novel genetic variants that may confound precise diagnostics. Here, we describe a functional testing approach used to interpret the results of whole exome sequencing (WES) in a family presenting with syncope and sudden death. One individual had a prolonged QT interval on electrocardiogram (ECG) and carried a diagnosis of long QT syndrome (LQTS), but a second individual did not meet criteria for LQTS. Filtering WES results for uncommon variants with arrhythmia association identified four for further analyses. In silico analyses indicated that two of these variants, KCNH2 p.(Cys555Arg) and KCNQ1 p.(Arg293Cys), were likely to be causal in this family's LQTS. We subsequently performed functional characterization of these variants in a heterologous expression system. The expression of KCNQ1-Arg293Cys did not show a deleterious phenotype but KCNH2-Cys555Arg demonstrated a loss-of-function phenotype that was partially dominant. Our stepwise approach identified a precise genetic etiology in this family, which resulted in the establishment of a LQTS diagnosis in the second individual as well as an additional asymptomatic family member, enabling personalized clinical management. Given its ability to aid in the diagnosis, the application of functional characterization should be considered as a value adjunct to in silico analyses of WES.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
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Canal de Potasio ERG1
Tipo de estudio:
Prognostic_studies
Límite:
Female
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Humans
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Middle aged
Idioma:
En
Año:
2021
Tipo del documento:
Article