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Deleterious protein‐altering mutations in the SCN10A voltage‐gated sodium channel gene are associated with prolonged QT
Author(s) -
Abou Ziki M.D.,
Seidelmann S.B.,
Smith E.,
Atteya G.,
Jiang Y.,
Fernandes R.G.,
Marieb M.A.,
Akar J.G.,
Mani A.
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13036
Subject(s) - missense mutation , frameshift mutation , long qt syndrome , sanger sequencing , medicine , genetics , mutation , brugada syndrome , exome sequencing , qt interval , gene , biology
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.