Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation
| Autor: | Óscar Díaz-Castro, Ramon Brugada, Alejandro Blanco-Verea, Bernardo López-Abel, Montserrat Santori, Helena Riuró, Guillermo J. Pérez, Fabiana S. Scornik, Maria Brion, Angel Carracedo, Rocio Gil |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male ERG1 Potassium Channel Heterozygote hERG Mutation Missense Context (language use) Bioinformatics Pathology and Forensic Medicine Sudden cardiac death 03 medical and health sciences 0302 clinical medicine Genotype Atrial Fibrillation Genetics Medicine Missense mutation Humans 030216 legal & forensic medicine Genetic testing Polymorphism Genetic medicine.diagnostic_test biology business.industry Homozygote Infant Atrial fibrillation Sudden infant death syndrome Middle Aged medicine.disease Pedigree 030104 developmental biology Phenotype biology.protein business Sudden Infant Death |
| Zdroj: | Forensic science international. Genetics. 43 |
| ISSN: | 1878-0326 |
| Popis: | Aims To assess the functional impact of two combined KCNH2 variants involved in atrial fibrillation, syncope and sudden infant death syndrome. Methods and results Genetic testing of a 4-month old SIDS victim identified a rare missense heterozygous in KCNH2 variant (V483I) and a missense homozygous polymorphism (K897T) which is often described as a genetic modifier. Electrophysiological characterisation of heterologous HERG channels representing two different KCNH2 genotypes within the family, showed significant differences in both voltage and time dependence of activation and inactivation with a global gain-of-function effect of mutant versus wild type channels and, also, differences between both types of recombinant channels. Conclusions The rare variant V483I in combination with K897T produces a gain-of-function effect that represents a pathological substrate for atrial fibrillation, syncope and sudden infant death syndrome events in this family. Ascertaining the genotype-phenotype correlation of genetic variants is imperative for the correct assessment of genetic testing and counselling. Translational perspective According to the current guidelines for clinical interpretation of sequence variants, functional studies are an essential tool for the ascertainment of variant pathogenicity. They are especially relevant in the context of sudden infant death syndrome and sudden cardiac death, where individuals cannot be clinically evaluated. The patch-clamp technique is a gold-standard for analysis of the biophysical mechanisms of ion channels. |
| Databáze: | OpenAIRE |
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