BabyScreen+ newborn screening

Gene: JUP

I don't know

Discussed potentially just screening for bi-allelic disease as can be earlier onset, more severe.

Discussed further with a paediatric cardiologist: variable age of onset and penetrance, therefore does not meet criteria.

Created: 1 Feb 2023, 7:13 a.m. | Last Modified: 29 Mar 2023, 1:24 a.m.

Panel Version: 0.2128

Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes.

ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.

Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended.

Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation.

Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:

• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
• Electrocardiography
• Cardiovascular imaging.

Penetrance:
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.

Created: 29 Dec 2022, 10:22 p.m. | Last Modified: 29 Dec 2022, 10:22 p.m.

Panel Version: 0.1756

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Arrhythmogenic right ventricular dysplasia 12 MIM# 611528; Naxos disease MIM# 601214