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Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

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Abstract

Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

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Figure 1: Identification of PIGV mutations in individuals with HPMR syndrome.

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Acknowledgements

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 665) to S.M., by a grant from Bundesministerium für Bildung und Forschung (BMBF, project number 0313911) and an Australian National Health and Medical Research Council international research training fellowship to T.R., and by a grant of the Canadian Institutes of Health Research and Epilepsy Canada to M.D.T. We thank B. Fischer, U. Kornak, M. Ralser, E. van Beusekom, U. Marchfelder and D. Lefeber for their assistance in this project.

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Author notes

  1. Peter M Krawitz and Michal R Schweiger: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute for Molecular Genetics, Berlin, Germany

    Peter M Krawitz, Michal R Schweiger, Christian Rödelsperger, Melanie Isau, Axel Fischer, Andreas Dahl, Martin Kerick, Jochen Hecht, Stefan Mundlos & Peter N Robinson

  2. Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Berlin, Germany

    Peter M Krawitz, Michal R Schweiger, Christian Rödelsperger, Sebastian Bauer, Sebastian Köhler, Marten Jäger, Johannes Grünhagen, Birgit Jonske de Condor, Sandra Doelken, Denise Horn, Stefan Mundlos & Peter N Robinson

  3. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité -Universitätsmedizin Berlin, Berlin, Germany

    Peter M Krawitz, Christian Rödelsperger, Jochen Hecht, Stefan Mundlos & Peter N Robinson

  4. Department of Human Genetics, University Medical Centre St. Radboud, Nijmegen, The Netherlands

    Carlo Marcelis, Friederike Stephani, Han G Brunner & Tony Roscioli

  5. Institut für Medizinische Immunologie, Charité Universitätsmedizin Berlin, Berlin, Germany

    Uwe Kölsch & Christian Meisel

  6. Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    Taroh Kinoshita & Yoshiko Murakami

  7. Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany

    Peter Meinecke

  8. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany

    Eberhard Passarge

  9. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Miles D Thompson & David E Cole

  10. Department of Molecular and Clinical Genetics, University of Sydney, Sydney, Australia

    Tony Roscioli

Authors
  1. Peter M Krawitz
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  2. Michal R Schweiger
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  3. Christian Rödelsperger
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  4. Carlo Marcelis
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  5. Uwe Kölsch
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  6. Christian Meisel
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  7. Friederike Stephani
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  8. Taroh Kinoshita
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  9. Yoshiko Murakami
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  10. Sebastian Bauer
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  11. Melanie Isau
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  12. Axel Fischer
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  13. Andreas Dahl
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  14. Martin Kerick
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  15. Jochen Hecht
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  16. Sebastian Köhler
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  17. Marten Jäger
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  18. Johannes Grünhagen
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  19. Birgit Jonske de Condor
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  20. Sandra Doelken
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  21. Han G Brunner
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  22. Peter Meinecke
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  23. Eberhard Passarge
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  24. Miles D Thompson
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  25. David E Cole
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  26. Denise Horn
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  27. Tony Roscioli
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  28. Stefan Mundlos
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  29. Peter N Robinson
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Contributions

M.R.S., M.I. and A.D. performed targeted exome resequencing. P.M.K., C.R., A.F., M.K., S.B., S.K., M.J. and P.N.R. performed bioinformatic analysis. P.M.K., C. Marcelis, J.G., B.J.d.C., F.S. and T.R. performed mutation analysis and genotyping. D.H., C. Marcelis, M.D.T., D.E.C., S.D., P.M., E.P., T.R. and H.G.B. contributed to clinical evaluation of the affected individuals and delineation of the phenotype. P.M.K., U.K. and C. Meisel performed flow cytometric analysis. Y.M. and T.K. performed analysis of wild-type and A341E PIGV clones. P.M.K., M.R.S., D.H., J.H., H.G.B., P.N.R. and S.M. carried out the project planning and preparation of the manuscript.

Corresponding authors

Correspondence to Stefan Mundlos or Peter N Robinson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–7 (PDF 1270 kb)

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Krawitz, P., Schweiger, M., Rödelsperger, C. et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet 42, 827–829 (2010). https://doi.org/10.1038/ng.653

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  • DOI: https://doi.org/10.1038/ng.653

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