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Deleterious protein-altering mutations in the SCN10A voltage-gated sodium channel gene are associated with prolonged QT.


ABSTRACT: 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.

SUBMITTER: Abou Ziki MD 

PROVIDER: S-EPMC5640462 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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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 MD   Seidelmann S B SB   Smith E E   Atteya G G   Jiang Y Y   Fernandes R G RG   Marieb M A MA   Akar J G JG   Mani A A  

Clinical genetics 20170518 4


<h4>Background</h4>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.<h4>Materials and methods</h4>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 seq  ...[more]

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