Familial AF study: identifying pathogenic genetic variants underlying electropa-thology in familial atrial fibrillation

Atrial Fibrillation (AF) is the most common sustained cardiac tachyarrhythmia
with an estimated prevalence in the European Union of 17,9 million patients in
2060. The prognosis of AF patients is determined by serious complications such
as cognitive impairment, stroke, heart failure and increased mortality.
AF onset and progression have been associated with risk factors including
hypertension, obesity, ageing and diabetes. Interestingly, 10-20% of the
patients present with AF onset at young age, as well as absence of (extra)
cardiovascular comorbidities, nor known risk factors, suggesting
familial/genetic character. In some instances, the number of individuals in a
pedigree presenting AF at young age is large and its pattern of inheritance is
highly suggestive of substantial genetic contribution through a monogenic mode
- autosomal dominant -. Nevertheless, there is only an expert*s opinion-based
suggestion to consider a limited diagnostic genetic screening according to the
HRS/EHRA expert consensus statement on genetic testing for AF. This fact
prompts us to investigate and substantiate the genetic contribution to AF
development.

Primary Objectives are to
• identify novel (likely) pathogenic genetic variants in familial or young AF
patients.
• investigate the relation between genetic profiles and electrical (AF)
phenotypes.
• develop a specific gene panel for AF
• construct a blood biobank from (likely) pathogenic genetic variants carriers
for iPSC generation and biomarker research.
• implement an AF specific gene screening in a dedicated outpatient clinic for
patients with familial or young AF.
• characterize electrophysiological features of patients with familial or young
AF
• correlate electrical profiles with genetic profiles

Secondary Objectives are to:
• unravel electromyopathy-related mechanistic pathways underlying familial or
young AF.
• identify genetic targets for novel tailored therapy in genetic AF.

The current proposal is a prospective interventional study in Erasmus Medical
Centre, with a planned duration of 5 years. After signing a written informed
consent, patients with suspected or diagnosed familial AF referred to a
dedicated EMC cardiology outpatient clinic. If indicated, also patients* family
members will be screened.
At the moment of inclusion at the outpatient cardiology clinic, clinical
characteristics are collected.
Routine examinations are performed to rule out other cardiovascular or
metabolic diseases underlying AF, including echocardiography, exercise testing,
Holter monitoring, CT or MRI and Ajmaline testing on indication according to
the ESC guidelines 4.
In addition to these routine clinical investigations, blood samples are
collected in patients with confirmed familial or young AF. These samples will
be used for genetic testing (after pretest counseling). After genetic testing
has been completed, patients will return to the outpatient clinic to discuss
results and potential relevance for family screening and further cardiological
follow-up. Also, additional blood samples will be collected for preclinical
research on proteostasis markers and gene-specific pathway alterations using
induced pluripotent stem cells (iPSC).
If a patient is referred for ablation therapy of AF, endocardial atrial
electro-anatomical mapping studies will be performed during sinus rhythm and/or
AF, in accordance with common practice in ablation therapy. Electro-anatomical
activation maps will be collected for constructing electrical profiles.

Burden for participants consists of time investment and venapunction (18ml
total).