Desmin gene (DES) variants have been previously reported in AC, but with insufficient evidence to support their pathogenicity. It is typically caused by mutations in desmosomal genes. The mutation that arose 575–825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.īackground: Arrhythmogenic Cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %). The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents’ places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers.
In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation.īy April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death. Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10–15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. Moreover, we discuss upcoming perspectives, and consequences of novel experimental approaches like genome editing technology, which might open a novel research field contributing to the development of efficient and mutation specific treatment options. In addition, we will summarize the genetic and clinical literature about DES mutations and will explain relevant cell and animal models. Here, we review the functions of desmin in health and disease with a focus on cardiomyopathies. Mutations in DES, encoding the muscle specific intermediate filament protein desmin, have been identified in different kinds of cardiac and skeletal myopathies.
However, detailed knowledge about the associated molecular patho-mechanism is essential for the development of efficient therapeutic strategies in future and genetic counseling. Because of the biochemical and cellular complexity, it is challenging to understand the clinical meaning or even the relevant patho-mechanisms of the majority of genetic sequence variants. Increasing usage of next-generation sequencing techniques pushed during the last decade cardiogenetic diagnostics leading to the identification of a huge number of genetic variants in about 170 genes associated with cardiomyopathies, channelopathies or syndromes with cardiac involvement. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the ACC and AHA and is accompanied by references and explanatory text, to provide essential context. Recommendations were developed and endorsed by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. PICO (Patient, Intervention, Comparison, Outcome) questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms.
The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation which may be associated with ventricular dilatation and/or impaired systolic function. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloid and sarcoidosis, Chagas' disease and left ventricular noncompaction. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive or valvular heart disease.