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Functional testing for variant prioritization in a family with long QT syndrome.
- Source :
-
Molecular genetics and genomics : MGG [Mol Genet Genomics] 2021 Jul; Vol. 296 (4), pp. 823-836. Date of Electronic Publication: 2021 Apr 19. - Publication Year :
- 2021
-
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.
- Subjects :
- AMP-Activated Protein Kinases genetics
Amino Acid Substitution genetics
DNA Mutational Analysis methods
Electrocardiography
Family
Female
Genetic Testing methods
HEK293 Cells
Heart Function Tests methods
Humans
KCNQ1 Potassium Channel genetics
Middle Aged
Mutation
Pedigree
Phenotype
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Protein Serine-Threonine Kinases genetics
Exome Sequencing
ERG1 Potassium Channel genetics
Long QT Syndrome genetics
Long QT Syndrome physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1617-4623
- Volume :
- 296
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular genetics and genomics : MGG
- Publication Type :
- Academic Journal
- Accession number :
- 33876311
- Full Text :
- https://doi.org/10.1007/s00438-021-01780-3