Evaluation of Genes Encoding for the Transient Outward Current (Ito) Identifies the
KCND2
Gene as a Cause of J-Wave Syndrome Associated With Sudden Cardiac Death
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abstract
Background—
J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I
to
)-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I
to
in patients with J waves on ECG.
Methods and Results—
Comprehensive mutational analysis was performed on I
to
-encoding
KCNA4
,
KCND2
, and
KCND3
genes, as well as the previously described J-wave–associated
KCNJ8
gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the
KCND2
gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type
KCND2
with
KChIP2
in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I
to
density of 48% (
P
<0.05) in the heterozygous state. Using computer modeling, this increase in I
to
resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural I
to
gradient. The previously described
KCNJ8
-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome.
Conclusions—
These findings are the first to implicate the
KCND2
gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I
to
-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.
