Clinical manifestations and screening implications of the 4q25 cardiac syndrome

Background

Several heterozygous deletions at the 4q25 locus, disrupting regulatory elements near PITX2, have recently been identified as a novel autosomal-dominant cause of sinus node dysfunction (SND) through dysregulation of PITX2 expression in the right atrium. All variants overlapped within a shared minimal region of approximately 15 kb. In the initial report, carriers of this deletion exhibited a syndromic phenotype combining SND with diverse cardiovascular comorbidities (1).

Purpose

To provide a comprehensive clinical characterisation of this syndrome and to define clinical features that should prompt genetic screening for this deletion in practice.

Methods

Clinical characteristics of 73 deletion carriers from 10 families originating from France and Germany were analysed. Deletion screening was performed in 63 familial SND cases in which no pathogenic variants had been identified in known SND-associated genes.

Results

Ten families carried eight distinct 4q25 deletions (Figure 1A). At the last clinical follow-up, the median (IQR) age of the carriers was 44 [20–58] years; 65 (90%) were alive and 31 (43%) were male. SND was the most frequent manifestation, observed in 67 individuals (92%) with an age at onset of 8 [1–23] years, followed by atrial fibrillation (AF) in 31 (44%) at 39 [30–50] years (Figure 1B–C). Eighteen percent of SND cases were diagnosed in infancy and 89% before 40 years of age. Non-lethal ventricular arrhythmias occurred in 25 (42%), and repolarisation abnormalities on the electrocardiogram were documented in 37 (51%). Cardiovascular comorbidities observed in ≥2 families included atrial septal defect, mitral valve prolapse, azygos continuation of the inferior vena cava, pulmonary valve stenosis, ascending aortic dilatation, bicuspid aortic valve, and ventricular septal defect; overall, 48 individuals (66%) had at least one structural abnormality. Pacemaker implantation was required in 43 patients (59%) at 26 [11–43] years, and 8 (11%) underwent invasive treatment for structural disease. One young individual with a pacemaker experienced sudden death of undetermined cause.

Screening of genotype-unidentified familial SND cases revealed the same 4q25 deletion in four families (4.8% of the cohort) (Figure 1D).

Conclusions

The 4q25 cardiac syndrome is characterised by early-onset SND, frequently accompanied by AF and structural cardiac abnormalities. Individuals presenting with early-onset SND, with or without associated cardiovascular malformations, should be considered for genetic screening of this 4q25 deletion.Figure 1