Arrhythmias and atrial fibrillation in Kleefstra syndrome

An important study published in the scientific journal Europace brought to the foreground an aspect of Kleefstra Syndrome that until today had not been systematically studied: the probability of arrhythmias occurring, even in young individuals who do not have known structural heart disease.

The study entitled Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link analyzed data from the two largest available databases of individuals with Kleefstra syndrome, the registry of the Radboud University Medical Center in the Netherlands and the international GenIDA registry. Data from a total of 213 people, 50 from Radboudumc and 163 from GenIDA.

What we knew until today

Congenital heart defects are known to potentially be part of the Kleefstra syndrome phenotype. Atrial and ventricular septal defects, pulmonary valve stenosis, bicuspid aortic valve, aortic coarctation, and other structural abnormalities have been described, among others.

For this reason, an initial cardiological examination is already recommended after diagnosis. However, until recently there was much less data regarding the cardiac rhythm disorders and particularly as to whether arrhythmias can appear regardless of the presence of congenital heart disease.

The new study shows that we may need to pay more attention to this side of heart monitoring as well.

What the two large registries showed

In both groups approximately 4 in 10 individuals presented some cardiovascular abnormality, with congenital structural heart diseases constituting the majority of the findings.

In the Radboudumc registry, 20 out of 50 people had some form of cardiovascular anomaly. Among other things, atrial and ventricular septal defects, tetralogy of Fallot, and pulmonary valve stenosis were recorded.

Similarly, in GenIDA, 65 out of 163 individuals were reported to have some cardiovascular anomaly. Among the findings were structural heart diseases, valve disorders, vascular anomalies, and, in a small number of cases, cardiomyopathy.

However, the element that makes this specific research particularly important concerns arrhythmias.

Arrhythmias at a very young age

Researchers have identified cases atrial tachyarrhythmias in six young individuals with Kleefstra Syndrome, a number that corresponds approximately to 3% compared to the 213 participants in the two registries used as the reference population in the study.

Among the arrhythmias recorded was the atrial fibrillation, atrial tachycardia and other supraventricular tachycardias.

Even more remarkable is that at least four of the cases with atrial fibrillation or atrial tachycardia had no structural heart disease.

The ages at which some of these arrhythmias were detected were unusually young.

One patient was diagnosed with atrial fibrillation at 23 years of age, a second at 25, while another individual developed persistent atrial tachycardia at the age of 17. In all three of these cases, there was no apparent structural heart disease.

In one case, atrial fibrillation had such a significant impact that it was associated with a temporary decrease in left ventricular function and was ultimately treated with arrhythmia ablation.

Figure 1. Recording of ambulatory heart rate monitoring in an individual with Kleefstra syndrome, in which an episode of atrial fibrillation was recorded. Source: Vasireddi et al., Europace, 2024.

Why the absence of structural heart disease is important

Atrial fibrillation is much more common in older age groups and may be associated with hypertension, heart disease, and other risk factors.

Her appearance therefore in individuals with Kleefstra syndrome as early as adolescence or young adulthood, and moreover without apparent structural heart disease, raised a new research question.

Could the deficiency of EHMT1 does it affect not only neurodevelopment but also mechanisms related to the heart's electrical function?;

The authors consider this likely, although it has not yet been proven.

The potential connection to EHMT1

EHMT1 plays a central role in the epigenetic regulation of many other genes. Among these are genes involved in the development and maturation of heart cells.

Researchers hypothesize that reduced EHMT1 function could, directly or indirectly, affect ion channels, electrical connections between heart cells, cardiomyocyte metabolism, or other mechanisms involved in the generation of arrhythmias.

For now, it is biologically plausible hypothesis and not a proven mechanism. Special laboratory and clinical studies will be needed to determine whether there is indeed a particular electrophysiological vulnerability in Kleefstra syndrome.

What might this mean for monitoring

One of the most important messages of the publication concerns cardiological monitoring.

A normal echocardiogram does not rule out the possibility of a heart rhythm disorder. Furthermore, a simple electrocardiogram records only a few seconds and therefore may not detect an arrhythmia that occurs occasionally.

The authors of the study believe that individuals with Kleefstra syndrome may benefit from repeated heart rate monitoring with an electrocardiogram and, where appropriate, ambulatory monitoring such as a Holter monitor.

This takes on particular importance in Kleefstra, as some individuals may not be able to easily describe symptoms such as palpitations, dizziness, fatigue, or discomfort. Researchers point out that this communication difficulty can present an additional barrier to the timely recognition of an arrhythmia.

The study does not prove that all individuals with Kleefstra Syndrome will develop arrhythmia, nor does it yet establish a specific cardiac screening protocol. However, it highlights a potential clinical feature that may have been underrecognized to date and supports the need for greater attention to heart rate monitoring.