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'.--
Background-Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in Ϸ50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-One hundred forty-nine ARVD/C index patients (111 male patients; age, 49Ϯ13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44Ϯ13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligationdependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V 1 to V 3 , especially in mutation-carrying relatives Ͻ20 years of age. In 45% of screened families, Ն1 affected relatives were identified (90% with mutations). Conclusions-Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives. A rrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is histopathologically characterized by progressive fibrofatty replacement of myocardium, primarily of the right ventricle (RV). 1-3 Although familial occurrence was recognized in the first report, only in the last decade has the genetic substrate been identified in genes encoding desmosomal proteins. 1,4 -9 Desmosomes are protein complexes in the intercalated disk, among others responsible for mechanical coupling of cardiac myocytes. Their impairment leads to both mechanical and electric uncoupling of cardiomyocytes, followed by cell death with fibrofatty replacement. 10 -13 Both uncoupling and altered architecture result in activation delay, which is the pivotal mechanism for reentry and thus ventricular tachycardia (VT). 14 -16 Editorial see p 2661 Clinical Perspective on p 2700Arrhythmogenic right ventricular dysplasia/cardiomyopathy usually shows an autosomal dominant inheritance pattern, w...
Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) is a hereditary cardiomyopathy characterized by fibrofatty replacement of cardiomyocytes, ventricular tachyarrhythmias and sudden death. ARVD/C is mainly caused by mutations in genes encoding desmosomal proteins. However, the pathogenicity of variants is not always clear. Therefore, we created an online database (www.arvcdatabase.info), providing information on variants in ARVD/C-associated genes. We searched the literature using ARVD/C and its underlying genes as search terms. From the selected papers and our unpublished data, we collected details on the type of mutation and information provided at the protein level. A ''details page'' contains clinical data and references. To aid the interpretation of missense mutations, we provide data from in silico prediction methods. In May 2009 the database contained 481 variants in eight genes. A total of 144 variants are considered pathogenic, 73 are unknown/unclassified, and 264 have no known pathogenicity. The database was converted into the Leiden Open Variation Database (LOVD) format, a gene-centered collection of DNA variations. The ARVD/ C database will be useful for both researchers and clinicians. It can be searched to determine if variants have been published and whether they are considered pathogenic. External users are invited to add information to improve the quantity and quality of the data entered.
Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
Since the discovery of the first causative mutations for cardiomyopathies in the early 1990s, the importance of inherited genetic variants has been increasingly recognized. 1,2 These discoveries have led to a better understanding of disease pathogenesis and introduced genetic evaluation into clinical practice for affected individuals and their relatives. 2,3 Editorial see p 405 Clinical Perspective on p 465Early identification of asymptomatic mutation carriers via genetic cascade screening is potentially of major prognostic importance because cardiomyopathies can lead to sudden cardiac death (SCD) as a result of malignant ventricular arrhythmias even before the onset of any symptoms.2 Although our knowledge of the genetics of cardiomyopathies has expanded greatly, mutation carriers are mostly advised, among other as to lifestyle adjustments (ie, sports activity), and treated based on general guidelines based on their cardiac morphological and functional characteristics; there is little known about specific genotype-phenotype relationships. 2,4 Phospholamban (encoded by the PLN gene) is a transmembrane sarcoplasmic reticulum phosphoprotein and is a key Background-The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. Methods and Results-Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. Conclusions-Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and endstage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. regulator of calcium homeostasis. 5 Pathogenic mutations in PLN, mostly leading to inhibition of the calcium uptake into the sarcoplasmic reticulum, may cause inherited cardiomyopathy. 5 The pathogenic PLN R14del ...
Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.
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