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Recurrent and founder mutations in the Netherlands |
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| Authors: | P.A. van der Zwaag M.G.P.J. Cox C. van der Werf A.C.P. Wiesfeld J.D.H. Jongbloed D. Dooijes H. Bikker R. Jongbloed A.J.H. Suurmeijer M.P. van den Berg R.M.W. Hofstra R.N.W. Hauer A.A.M. Wilde J.P. van Tintelen |
| Affiliation: | 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 ventricularcardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetranceand a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene(PKP2) are detected in about 50% of ARVC/D patients. Thep.Arg79X mutation in PKP2 has been identified in Europe and North America and has beenfunctionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 inthe Dutch population.Methods. Twelve index patients and 41 family memberswere evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D wasestablished according to the recently revised Task Force Criteria. Segregation of thep.Arg79X mutation was studied and haplotypes were reconstructed to determine whether thep.Arg79X mutation was a recurrent or a founder mutation.Results. The p.Arg79X mutation in PKP2 wasidentified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutchp.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had afirst- 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 nosignificant difference in symptom-free survival and event-free survival between men andwomen.Conclusion. We have identified the largest series ofpatients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79Xmutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance oftenseen in ARVC/D. (Neth Heart J 2010;18:583–91.) |
| Keywords: | Cardiomyopathy ARVC/D Genetics PKP2 Founder Mutation |
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