Recurrent and founder mutations in the Netherlands

Zwaag, Paul A. van der; Cox, Moniek G. P. J.; Werf, van der Christine; Wiesfeld, Ans C.P.; Jongbloed, Jan D. H.; Dooijes, Dennis; Bikker, Hennie; Jongbloed, Roselie; Suurmeijer, Albert; Berg, van den Maarten; Hofstra, Robert; Hauer, Richard N.W.; Wilde, Arthur A.M.; Tintelen, van Peter

doi:10.1007/s12471-010-0839-5

Cited by 34 publications

(8 citation statements)

References 32 publications

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“…Another 5 mutations (c.235C>T, c.397C>T, c.1211–1212dupT, c.2386T>C, and c.2489+1G>A) in PKP2 occurred at least as frequently in the Dutch ARVD/C cohort. Haplotype analysis and genealogy suggest that there may also be common founders contributing to these mutations, explaining the high prevalence of PKP2 mutations in Dutch ARVD/C patients [32,34]. …”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

et al. 2012

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Objectives: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. Methods: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. Results: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. Conclusions: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.

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Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

et al. 2012

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“…Studies in bold analysed mutations in all five desmosomal genes and data are displayed graphically in Fig. 2 the mutation originated in the northern part of the Netherlands [9]. In the present study we describe results from literature on the geographical distribution of mutation prevalence of diagnosed AC patients.…”

Section: Introductionmentioning

confidence: 95%

“…Loss-of-function mutations in five different desmosomal protein encoding genes, plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP), have been identified in AC [6]. The prevalence of these mutations might be related to ethnicity, founder mutations or founder populations [7][8][9] and therefore may be different in geographically distinct populations. For example, as shown by Van der Zwaag et al [9] 12 index patients carrying the same PKP2 mutation shared the same haplotype, indicative for a common founder.…”

Section: Introductionmentioning

confidence: 99%

“…The prevalence of these mutations might be related to ethnicity, founder mutations or founder populations [7][8][9] and therefore may be different in geographically distinct populations. For example, as shown by Van der Zwaag et al [9] 12 index patients carrying the same PKP2 mutation shared the same haplotype, indicative for a common founder. Geographical distribution of the index patients suggested that [33] 100 [19] 156 10 (6) 17 (11) 10 (6) 2 (1) a The population was first tested negative for mutations in PKP2 or DSP and then screened for mutations in DSG2.…”

Section: Introductionmentioning

confidence: 99%

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Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy

et al. 2012

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Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region.

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“…This high yield is partly explained by the occurrence of founder mutations in the Netherlands. Haplotype analysis suggested a founder effect of four different PKP2 mutations [38, 40]. On the other hand, there are geographical differences in the prevalence of AC-related gene mutations [13, 41].…”

Section: Molecular Genetic Background Of Acmentioning

confidence: 99%

Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management

et al. 2014

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Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.

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Recurrent and founder mutations in the Netherlands

Cited by 34 publications

References 32 publications

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management

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