Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Background-Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. Methods and Results-The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years ) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. Conclusions-Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.(Circ Cardiovasc Genet. 2013;6:533-542.)

Implantable Cardioverter‐Defibrillator Therapy in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Predictors of Appropriate Therapy, Outcomes, and Complications

“…Our results are also consistent with the results of prior studies that have reported that men are at higher arrhythmia risk than women 17, 19, 22, 23. Finally, our results are also consistent with prior studies that have reported that T‐wave inversions on precordial leads of the ECG13, 15, 20 and a PVC count of ≥1000 on 24‐hour Holter15 are predictors of appropriate ICD therapy for VT/VF.…”

Arrhythmogenic Cardiomyopathy

“…6) [59]. Comprehensive exonic sequence analysis of the known desmosomal AC-related genes currently identifies approximately 50 % of AC probands [60][61][62][63]. The most commonly defective AC gene is PKP2 (10-45 %), followed by DSP (10-15 %), DSG2 (7-10 %) and DSC2, JUP (1-2 %).…”

“…The inheritance pattern of AC is more complex than previously appreciated, with frequent requirement for more than one 'hit' for fully penetrant disease [60,61,66,67]. The low penetrance of AC may be explained by a "recessive-like" inheritance pattern, based on the fact that AC probands often carry homozygous or compound heterozygous variants in the same gene, or digenic/oligogenic variants in a cluster of desmosomal genes.…”

A Case of Dna-Diagnostics Application for Arrhythmogenic Right Ventricle Cardiomyopathy

“…Это связано с тем, что экспрессивность и пенетрантность заболева-ния очень вариабельны даже у членов одной семьи -носителей мутации. Кроме того, по всей видимости, значительную роль в формировании фенотипа играют различные факторы, такие как пол (мужской пол явля-ется дополнительным фактором риска ВСС [18,19]), возраст, уровень физических нагрузок, сопутствующие инфекционные заболевания, гормональный фон, эмо-циональный стресс [20].…”

“…В 2009г Bhuiyan, et al описали дигенные формы АКПЖ, вызванные мутациями в генах DSC2 и DSG2 [21]. Дальнейшие исследования подтвердили, что множественные мутации в генах десмосом ассоциированы с более тяжелым течением заболевания и являются дополнительным фактором риска ВСС, выявление которого, в сочетании с дру-гими факторами, расширяет показания к импланта-ции ИКД [19]. Описано, что у имеющих мутации в гене десмоплакина достоверно чаще развивается систолическая дисфункция ЛЖ (40%) и ХСН (13%), нежели у лиц с мутацией в гене плакофилина [22].…”