Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy

Abstract

AimsTo investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). Methods and resultsWe screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 % ) ARVC patients and in 39 (15 % ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del-DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P , 0.001), cardiac transplantation (18 % vs. 2 % , P , 0.001), and a family history for sudden cardiac death (SCD) at , 50 years (36 % vs. 16 % , P ¼ 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 % ) R14del+ ARVC samples, but in only one of nine (11 % ) R14del+ DCM samples (P ¼ 0.03). ConclusionsThe PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.--

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

“…Among the inherited cardiomyopathies, this benefit is probably most pronounced for DCM because it can be an end-stage presentation of HCM in a minority of cases 6 and has some clinical overlap with ARVC. 7,8 Our analysis confirmed earlier reports that pathogenic variation in desmosomal Original research article genes contributes a portion of pathogenic variation in DCM patients. It remains to be shown whether such cases represent misdiagnosed ARVC or whether desmosomal variants can cause both disorders.…”

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

“…2008; van der Zwaag et al. 2012). Accurate clinical diagnosis can be challenging and it has not been surprising that pathogenic variation in desmosomal genes contribute to a portion of disease‐causing variation in DCM patients (Elliott et al.…”

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

“…[11][12][13] In certain populations, specific mutations can be found often due to a founder effect, such as the PLN p.Arg14del and PKP2 p.Arg79* mutations in the Netherlands and the TMEM43 p.Ser358Leu mutation in Newfoundland, Canada. [14][15][16] ARVC patients carrying more than one disease-associated mutation often show a more severe phenotype, characterized by a younger age of onset and worse prognosis, suggesting a gene-dosage effect. 5,13,17,18 It is to be expected that the use of NGS techniques will result in the identification of an increasing number of patients with such complex genotypes.…”