Netherlands Heart Journal

, Volume 18, Issue 12, pp 583–591

Recurrent and founder mutations in the Netherlands

Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia
  • 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
Original Article

DOI: 10.1007/s12471-010-0839-5

Cite this article as:
van der Zwaag, P., Cox, M., van der Werf, C. et al. Neth Heart J (2010) 18: 583. doi:10.1007/s12471-010-0839-5
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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 

Copyright information

© Springer Media / Bohn Stafleu van Loghum 2010

Authors and Affiliations

  • P.A. van der Zwaag
    • 1
  • M.G.P.J. Cox
    • 3
  • C. van der Werf
    • 4
  • A.C.P. Wiesfeld
    • 5
  • J.D.H. Jongbloed
    • 2
  • D. Dooijes
    • 6
  • H. Bikker
    • 7
  • R. Jongbloed
    • 8
  • A.J.H. Suurmeijer
    • 9
  • M.P. van den Berg
    • 10
  • R.M.W. Hofstra
    • 2
  • R.N.W. Hauer
    • 3
  • A.A.M. Wilde
    • 11
  • J.P. van Tintelen
    • 12
  1. 1.Department of GeneticsUniversity Medical Center GroningenRB Groningenthe Netherlands
  2. 2.Department of GeneticsUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
  3. 3.Department of CardiologyUniversity Medical Center Utrecht, Utrecht, and Interuniversity Cardiology Institute of the NetherlandsUtrechtthe Netherlands
  4. 4.Heart Failure Research Center, Department of Cardiology, Academic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
  5. 5.Department of CardiologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
  6. 6.Department of Medical GeneticsUniversity Medical Center UtrechtUtrechtthe Netherlands
  7. 7.Department of Clinical Genetics, Academic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
  8. 8.Department of Clinical GeneticsMaastricht University Medical CenterMaastrichtthe Netherlands
  9. 9.Department of PathologyUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
  10. 10.Department of Cardiology, and Interuniversity Cardiology Institute of the NetherlandsUniversity Medical Center Groningen, University of Groningen, GroningenUtrechtthe Netherlands
  11. 11.Heart Failure Research Center, Department of Cardiology, Academic Medical CenterUniversity of AmsterdamUtrechtthe Netherlands
  12. 12.Department of GeneticsUniversity Medical Center Groningen, University of Groningen, Groningen, and Interuniversity Cardiology Institute of the NetherlandsUtrechtthe Netherlands

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