Whole exome sequencing in patients with Idiopathic Ventricular Fibrillation and familial Atrial Fibrillation

Ventricular fibrillation (VF) is a major cause of SCD and around 25% of the
patients with an out-of-hospital cardiac arrest (OHCA) show VF as initial
rhythm. Most of these are caused by ischemia in patients with coronary artery
disease.
The definition of idiopathic ventricular fibrillation (iVF) is an episode of
documented VF without a causal connection to the clinical circumstances. The
term idiopathic implies that up until present day, research has failed to
identify an underlying cause. In 95% of the patients with documented VF, an
underlying structural or primary electrical cardiac disease is found. 5% of all
patients with VF are diagnosed with iVF.
In several other forms of primary arrhythmia syndromes, a genetic cause has
been detected. For instance in the long QT syndrome (LQTS), once thought to be
idiopathic, 13 genes responsible for this disease have been identified.
Possibly this applies to iVF as well.
20% of the patients with iVF have a family history positive for sudden death.
This suggests a genetic origin in patients with familial iVF. Genetic testing
is becoming more important and new genes responsible for iVF have been
identified, such as the DPP6-haplotype. With the discovery of the
DPP6-haplotype, more evidence is becoming available that iVF does not exist,
but currently unknown genetic defects are responsible for a high susceptibility
for VF. In order to detect this genetic origin, Whole Exome Sequencing (WES)
should be performed in patients with iVF, where the regular genetic screening
has failed to detect a genetic cause.

Mostly AF is secondary to, or associated with cardiovascular conditions such as
hypertension, coronary artery disease, valvular disease and cardiomyopathies.
AF sometimes develops in a subset of young patients with no underlying
identifiable cardiopulmonary causes or other comorbid disease. This is referred
as *lone* or *idiopathic* AF. The diagnosis lone AF is made by excluding all
underlying causes. The true prevalence of lone AF is unknown. It varies between
1.6% and 30%, depending on the definition used for lone AF and the population
studied.
Lone AF can occur in patients with and without a positive family history of AF.
Increasing evidence is becoming available that familial lone AF has an
underlying genetic origin. 9 Multiple target genes responsible for AF have
been identified, such as KCNQ1, KCNE2, KCNJ2, SCN5A, GJA5, GJA1 and NPPA and
novel genes are still being identified.

Genotyping the population of patients with iVF and AF and detecting novel genes
associated with iVF and AF. Secondary endpoints are correlation of the presence
of gene defects and response to catheter ablation in AF patients and create a
better understanding in the pathophysiological mechanism and disease pathways
of iVF and familial lone AF.

The study is a single-center cohort study, where patients with iVF and familial
lone AF will undergo WES. If necessary, reference databases are used (such as
the genome of the Netherlands) to determine the pathogenicity of a found
genetic mutation.

Discovering the aetiology of iVF is a necessary first step to improve the
detection, treatment and follow-up in patients with iVF and to prevent the
occurrence of sudden cardiac death. In AF-patients, the knowledge of having
genetic predisposition to AF can be useful in risk-stratification and starting
prophylactic treatment to prevent morbidity, such as heart failure and stroke,
and mortality. WES has a relatively low burden and has no risks. In patients
where no DNA is available, it will be obtained by the withdrawal of 2x 10 mL of
blood by venepuncture. This is the only invasive study procedure. Information
on the possible outcomes of WES is provided, and the possibility of disclosure
of unsolicited findings is addressed as well, so all patients can make a
well-informed decision.