Deleterious protein-altering mutations in the SCN10A voltage-
gated sodium channel gene are associated with prolonged QT
M.D. Abou Ziki
| S.B. Seidelmann
| E. Smith
| G. Atteya
| Y. Jiang
| M.A. Marieb
| J.G. Akar
| A. Mani
Section of Cardiovascular Medicine,
Department of Internal Medicine, Yale
University School of Medicine, New Haven,
Cardiovascular Division, Department of
Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston,
Department of Genetics, Yale University
School of Medicine, New Haven, Connecticut
Dr Arya Mani, MD, Section of Cardiovascular
Medicine and Genetics, Yale University School
of Medicine, 333 Cedar Street, 3 FMP, PO Box
208017, New Haven, CT 06520-8017.
National Institutes of Health, Grant/Award
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
Conclusion: Our findings implicate SCN10A in LQT. The presence of frameshift mutations sug-
gests loss-of-function as the underlying disease mechanism. The common association with
atrial fibrillation suggests a unique mechanism of disease for this LQT gene.
cardiac conduction, cardiovascular genetics, electrophysiology, long QT syndrome, SCN10A,
sudden cardiac death
1 | INTRODUCTION
Long QT syndrome (LQT) is a pro-arrhythmogenic condition that
increases the risk of a unique life-threatening polymorphic ventricular
tachycardia known as “torsades de pointes,” and sudden cardiac
death (SCD). Congenital LQTs are inherited disorders caused by
mutations in cardiac conduction channels or associated proteins, and
are estimated to affect 0.005% to 0.05% of the general population.
LQT is also accounted for by QT prolonging drugs, electrolyte
ischemic heart disease
or structural heart disease; a
condition that is often referred to as acquired LQT. With the advent
of genome sequencing it is evident that genetic variants with small
effects also account for some, if not all, subclinical acquired LQTs
that manifest themselves in the presence of additional precipitating
It has also been estimated that 10% to 36% of patients
with LQT genotypes are silent mutation carriers.
To this date 15 different types of congenital LQT have been
characterized and account for about 80% of inherited long QT cases.
These correspond to mutations in genes encoding potassium
calcium signaling proteins,
Most of these genes have been established as
casual genes for LQT based on linkage or segregation analysis, or in
the case of KCNE2, CAV3, SNTA1 and CALM2 genes by association
Received: 13 February 2017 Revised: 27 March 2017 Accepted: 9 April 2017
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clinical Genetics. 2018;93:741–751. wileyonlinelibrary.com/journal/cge 741