A different background of arrhythmia in siblings with a positive family history of sudden death at young age

Abstract We present two symptomatic sisters who had a positive family history of sudden death. None of them had structural heart disease. In the 25‐year‐old proband, complex ventricular arrhythmia, cardiac conduction system disease, and skeletal muscle weakness were found. Genetic examination showed a pathogenic intronic variant in the desmin gene in the proband only. In the elder sister with palpitations, complex ventricular arrhythmia (>46 000 ectopic beats) was removed by radiofrequency ablation. This family case shows that complex ventricular arrhythmia may have different background within one family, genetic examinations should be performed in a person with broadest spectrum of symptoms.


| INTRODUC TI ON
A history of sudden cardiac death (SCD) of young individuals raises an important question among their offspring in the family, especially when the offspring starts being symptomatic and are uneasy about the extension of SCD risk to them. Desmin is an integral component of Z-disk located within the sarcomere, both in heart and skeletal muscle, linking the Z-disks to one another and neighboring sarcomeres, thus forming myofibrils, the basic unit of muscle fibers. Its role in pathogenesis of all types of cardiomyopathies is well established (Arbustini et al., 2006). Furthermore, DES gene mutations have been identified in sudden cardiac arrest survivors (Brodehl et al., 2013;Elliott et al., 2008;Stepien-Wojno et al., 2018).

| Family case description
We present a family with two symptomatic sisters, whose father died suddenly at the age of 32 years, and their paternal father died at the age of 35 years (Figure 1). F I G U R E 1 The pedigree of the family with DES c.735 + 3A>G mutation F I G U R E 2 12-lead standard electrocardiogram in the proband. Sinus rhythm 63/min, PR 130ms, nonspecific intraventricular conduction delay, QRS 119 ms, QTc 401 ms One of these sisters was 25 years old. Her medical history revealed episodes of postural hypotension and presyncope on effort and during palpitations. Moreover, she reported limbs' weakness.
Physical examination did not show any heart failure signs. A standard 12-lead electrocardiogram showed sinus rhythm with heart rate 63 beats per minute and intraventricular conduction delay, QRS 119 ms We examined cardiologically other living first-degree family members and did not find any abnormalities (Figure 1).
It was decided to perform a genetic testing in younger sister due to presented symptoms and signs indicating involvement of the striated muscles and thus a syndromic disorder. DNA was extracted from the peripheral blood by phenol extraction. Next-generation sequencing (NGS) in proband was performed using TruSight One (TSO) sequencing panel. Selected genetic variants identified with NGS were followed up in proband and relatives with Sanger sequencing.
In proband, but not in her symptomatic sister, we identified the sub- and subsarcolemmal areas of some myofibers, that were strongly immunoreactive for desmin (Park et al., 2000). Deleterious effects were seen both in the cardiac and skeletal muscle of the carriers.
Although the temporary symptomatic status of the proband's sister made us to cautiously interpret the results of genetic testing in the family, the complete recovery of the proband's sister after RF ablation, maintained over 5-year follow-up confirmed a lack of causal relationship between the two types of ventricular arrhythmia present in sisters. In the meantime, in the proband we have been observing progressive course of the disease, especially with regard to cardiac conduction system disease and skeletal muscle weakness. During 5 years of follow-up, broadening of the QRS complex, second-degree atrioventricular block of Mobitz 2, episodes of ventricular arrhythmia were observed in our proband. Implantable cardioverter-defibrillator (ICD-DR) was implanted. During the same period of time, there was no recurrence of arrhythmia, or appearance F I G U R E 4 Cardiac magnetic resonance, 4-chamber view revealing normal heart morphology F I G U R E 5 A standard 12-lead ECG in the elder sister revealing sinus rhythm with frequent ventricular ectopy, also paired beats of LBBB morphology of conduction disturbances or muscle symptoms in the elder proband's sister after the ablation of arrhythmia. This siblings' case shows clinical difficulties in the diagnosis of the complex ventricular arrhythmia in the family with a history of sudden death and shows that genetic study should be performed in subjects with broadest clinical presentation.