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Deleterious protein-altering mutations in the SCN10A voltage-gated sodium channel gene are associated with prolonged QT.
Abou Ziki, M D; Seidelmann, S B; Smith, E; Atteya, G; Jiang, Y; Fernandes, R G; Marieb, M A; Akar, J G; Mani, A.
Afiliação
  • Abou Ziki MD; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Seidelmann SB; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Smith E; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Atteya G; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Jiang Y; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Fernandes RG; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Marieb MA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Akar JG; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • Mani A; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Clin Genet ; 93(4): 741-751, 2018 04.
Article em En | MEDLINE | ID: mdl-28407228
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Arritmias Cardíacas / Síncope / Síndrome do QT Longo / Canal de Sódio Disparado por Voltagem NAV1.8 Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Genet Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Arritmias Cardíacas / Síncope / Síndrome do QT Longo / Canal de Sódio Disparado por Voltagem NAV1.8 Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Genet Ano de publicação: 2018 Tipo de documento: Article