Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis
| Autor: | Shubhayan Sanatani, Thomas M. Roston, Frances Perry, Glen F. Tibbits, Valentine Sergeev, Thomas W. Claydon |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male ERG1 Potassium Channel Benign early repolarization Long QT syndrome hERG 030204 cardiovascular system & hematology Pathology and Forensic Medicine 03 medical and health sciences Electrocardiography 0302 clinical medicine Channelopathy Recurrence Medicine Humans Genetic Testing Gene Exome sequencing Genetics biology business.industry Infant Sudden infant death syndrome medicine.disease Pedigree Long QT Syndrome 030104 developmental biology Child Preschool Mutation (genetic algorithm) Mutation biology.protein Female business Law Sudden Infant Death |
| Zdroj: | Forensic science international. 284 |
| ISSN: | 1872-6283 |
| Popis: | Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations. |
| Databáze: | OpenAIRE |
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