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Recurrent and founder mutations in the Netherlands |
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| Authors: | PA van der Zwaag MGPJ Cox C van der Werf ACP Wiesfeld JDH Jongbloed D Dooijes H Bikker R Jongbloed AJH Suurmeijer MP van den Berg RMW Hofstra RNW Hauer AAM Wilde JP van Tintelen |
| Institution: | 1. Department of Genetics, University Medical Center Groningen, 30.001, 9700, RB Groningen, the Netherlands 3. Department of Cardiology, University Medical Center Utrecht, Utrecht, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands 4. Heart Failure Research Center, Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 5. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 6. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands 7. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 8. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands 9. Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 10. Department of Cardiology, and Interuniversity Cardiology Institute of the Netherlands, University Medical Center Groningen, University of Groningen, Groningen, Utrecht, the Netherlands 11. Heart Failure Research Center, Department of Cardiology, Academic Medical Center, University of Amsterdam, Utrecht, the Netherlands 12. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands |
| Abstract: | Background. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population.Methods. Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation.Results. The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women.Conclusion. We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583–91.) |
| Keywords: | Cardiomyopathy ARVC/D Genetics PKP2 Founder Mutation |
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