Homozygous Founder Mutation in Desmocollin-2 (
            <i>DSC2</i>
            ) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population

Gerull, Brenda; Kirchner, Florian; Chong, Jessica X.; Tagoe, Julia; Chandrasekharan, Kumaran; Strohm, Oliver; Waggoner, Darrel; Ober, Carole; Duff, Henry J.

doi:10.1161/circgenetics.113.000097

Cited by 51 publications

(41 citation statements)

References 37 publications

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“…The association between the DSC2 gene and ARVC was reported for the first time in 2006 [65]. Recently, the DSC2 gene was associated with a recessive pattern of inheritance with no cutaneous alterations [66]. In 2006, DSG2 was also associated in ARVC cases [51] with both dominant and recessive pattern of inheritance.…”

Section: Cadherinsmentioning

confidence: 99%

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

et al. 2014

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Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice.

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Section: Cadherinsmentioning

confidence: 99%

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

et al. 2014

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“…7). Founder mutations in both desmosomal and non-desmosomal encoding genes have been reported [53,64,65].…”

Section: Ac Genes/mutations and Diagnostic Implicationsmentioning

confidence: 99%

Arrhythmogenic Cardiomyopathy

Corrado

Basso

Judge

2017

Circulation Research

341

363

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Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50 % of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/ digenic heterozygosity was identified in up to 25 % of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis. AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC. Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.Arrhythmogenic Cardiomyopathy-key points summary

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“…[10][11][12][13][14][15] ARVC is an inherited cardiomyopathy clinically characterized by arrhythmias and predominately right ventricular dilatation leading to cardiac syncope, heart failure, or even sudden cardiac death (SCD). 16 It is well established that mutations in the genes coding for desmosomal plaque proteins cause ARVC [17][18][19] and rare forms of dilated cardiomyopathy. 20 In the cardiac muscle, desmin is found in costamers, the z-disk, and connected via plaque proteins to the cardiac desmosome within the ID.…”

Section: T He Intermediate Filament (If) Protein Desmin Is Encodedmentioning

confidence: 99%

The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

Brodehl¹,

Dieding²,

Klauke³

et al. 2013

Circ Cardiovasc Genet

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T he intermediate filament (IF) protein desmin is encodedby the gene DES and contributes to the mechanical stabilization of the sarcomeres and cell contacts within the cardiac intercalated disk (ID). Desmin is the predominant IF protein of striated muscles. It belongs to the type III IF proteins characterized by a uniform assembly mechanism. In the first step of the in vitro assembly, 2 coiled-coil dimers form an antiparallel tetramer.1 These tetramers are the essential building blocks of the IF. Eight tetramers anneal in lateral orientation into unit length filaments. In the longitudinal elongation step, these unit length filaments are assembled and radially compacted into IF.2 Since the first reports on DES mutations, [3][4][5] it became obvious that DES mutations cause skeletal myopathies and different forms of cardiomyopathies. 6,7 Clinical Perspective on p 623In the meantime, >60 different DES mutations distributed over the whole sequence are known, which lead to filament formation defects with deposition of cytoplasmic desmin aggregates in the majority of cases. 8,9 However, the pathomechanisms of desmin aggregation leading to skeletal or cardiac myopathies are mechanistically not understood in detail. Moreover, 10-15 ARVC is an inherited cardiomyopathy clinically characterized by arrhythmias and predominately right ventricular dilatation leading to cardiac syncope, heart failure, or even sudden cardiac death (SCD). 16 It is well established that mutations in the genes coding for desmosomal plaque proteins cause ARVC [17][18][19] and rare forms of dilated cardiomyopathy. 20 In the cardiac muscle, desmin is found in costamers, the z-disk, and connected via plaque proteins to the cardiac desmosome within the ID. The molecular processes contributing to the destabilization of the ID through desmin filaments are fragmentarily understood. Especially, it is not known, how and which of the desmin mutations impair the connection of the IF system to the cardiac desmosome. Background-TheIn this study, we report a novel pathogenic DES mutation (c.359C>A, p.A120D), which seems to interfere particularly with the connection of desmin IF to the ID. Furthermore, we investigate whether the DES variants p.A120D and p.H326R (c.977A>G) affect the IF formation using ectopic expression cell culture systems and atomic force microscopy (AFM). These data reveal that desmin-p.A120D but not desmin-p. H326R inhibits the longitudinal assembly step, confirming its pathogenic potential. Materials and Methods Clinical Description of the PatientsIn family A, the 34-year-old female index patient (III:24) presented with atrial flutter, variable atrioventricular conduction ( Figure I in the online-only Data Supplement), and dilated atria. The average ventricular frequency was 64 bpm, and the atrial frequency was 120 bpm. In the ECG, some polymorphic premature ventricular contractions (PVCs) with a frequency of 45 to 111 bpm were detected ( Figure I in the online-only Data Supplement). The cardiological evaluation including 2-dimensional, M-m...

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Homozygous Founder Mutation in Desmocollin-2 ( DSC2 ) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population

Cited by 51 publications

References 37 publications

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic Cardiomyopathy

The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

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