Deleterious protein-altering mutations in the SCN10A voltage-gated sodium channel gene are associated with prolonged QT
| Autor: | R.G. Fernandes, Yuexin Jiang, Gourg Atteya, Joseph G. Akar, M.D. Abou Ziki, Mark Marieb, Emily Smith, Sara B. Seidelmann, Arya Mani |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Long QT syndrome DNA Mutational Analysis 030204 cardiovascular system & hematology medicine.disease_cause Bioinformatics Syncope Article Sudden cardiac death Frameshift mutation NAV1.8 Voltage-Gated Sodium Channel 03 medical and health sciences symbols.namesake 0302 clinical medicine Gene Frequency Cardiac conduction Genetics medicine Humans Missense mutation Genetic Predisposition to Disease Genetic Testing Frameshift Mutation Allele frequency Genetics (clinical) Aged Sanger sequencing Mutation business.industry Arrhythmias Cardiac Middle Aged medicine.disease Pedigree Long QT Syndrome Phenotype 030104 developmental biology symbols Female business |
| Zdroj: | Clinical Genetics. 93:741-751 |
| ISSN: | 0009-9163 |
| DOI: | 10.1111/cge.13036 |
| Popis: | Background Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life-threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. Materials and methods Eighteen patients with history of palpitations, pre-syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole-exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. Results Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. Conclusion Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss-of-function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene. |
| Databáze: | OpenAIRE |
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