Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

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We thank the members of the families studied for their participation and members of the International Genetics of Learning Disability (IGOLD) study for their collaboration. This work was supported by grants from the Australian National Health and Medical Research Council Program Grant 400121 (I.E.S., S.F.B., J.C.M. and J.G.), Thyne-Reid Charitable Trusts (L.M.D.) and the Wellcome Trust. We also acknowledge support to J.F.G. from US National Institutes of Health grant GM061354 and D.H.G. from US National Institute of Mental Health U.S. grant R01 MH 64547. We are grateful for access to the tissues used in these studies from the Developmental Brain and Tissue Bank at University of Maryland funded by the US National Institutes of Health (National Institute of Child Health and Human Development contracts NO1-HD-4-3368 and NO1-HD-4-3383).

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Author notes

    • Leanne M Dibbens
    •  & Patrick S Tarpey

    These authors contributed equally to this work.


  1. Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.

    • Leanne M Dibbens
    • , Kim Hynes
    • , Marta A Bayly
    • , Lucianne Vandeleur
    • , Cheryl Shoubridge
    • , Grant R Sutherland
    • , Kathryn Friend
    • , Marie Shaw
    • , Mark Corbett
    • , Eric Haan
    • , John C Mulley
    •  & Jozef Gécz
  2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia.

    • Leanne M Dibbens
    • , Grant R Sutherland
    • , John C Mulley
    •  & Jozef Gécz
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Patrick S Tarpey
    • , Raffaella Smith
    • , Sarah Edkins
    • , Claire Stevens
    • , Sarah O'Meara
    • , Calli Tofts
    • , Syd Barthorpe
    • , Gemma Buck
    • , Jennifer Cole
    • , Kelly Halliday
    • , David Jones
    • , Rebecca Lee
    • , Mark Madison
    • , Tatiana Mironenko
    • , Jennifer Varian
    • , Sofie West
    • , Sara Widaa
    • , Paul Wray
    • , John Teague
    • , Ed Dicks
    • , Adam Butler
    • , Andrew Menzies
    • , Andrew Jenkinson
    • , Rebecca Shepherd
    • , P Andrew Futreal
    •  & Michael R Stratton
  4. School of Molecular & Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.

    • Kim Hynes
    • , Edwina Sutton
    • , Grant R Sutherland
    • , Paul Thomas
    • , Eric Haan
    • , John C Mulley
    •  & Jozef Gécz
  5. Epilepsy Research Centre and Department of Medicine, University of Melbourne, Level 1 Neurosciences Building, Heidelberg Repatriation Hospital, Austin Health, Banksia Street, Heidelberg West, Victoria 3081, Australia.

    • Ingrid E Scheffer
    • , Samantha J Turner
    • , Christopher P Derry
    •  & Samuel F Berkovic
  6. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.

    • Ingrid E Scheffer
  7. Program in Neurogenetics and Neurobehavioral Genetics, Neurology Department and Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769, USA.

    • Jamee Bomar
    •  & Daniel H Geschwind
  8. Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA and Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA.

    • James F Gusella
    • , Amos D Korczyn
    •  & Hyung-Goo Kim
  9. Department of Neurology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.

    • Zaid Afawi
    • , Aziz Mazarib
    •  & Miriam Y Neufeld
  10. Department of Neurology, Schneider Children's Medical Center, Petaq Tikvah 49202, Israel.

    • Sara Kivity
  11. Metabolic Neurogenetic Clinic, Wolfson Medical Center, 62 HaLohamim Street, Holon 58100, Israel.

    • Dorit Lev
    •  & Tally Lerman-Sagie
  12. AstraZeneca, 1800 Concord Pike, Wilmington, Delaware 19803, USA.

    • Stephen Ryan
  13. Northern Ireland Regional Genetics Service, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.

    • Shane McKee


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L.M.D. and P.S.T. contributed equally to this work. L.M.D. coordinated the project in concept and design, supervised molecular studies, managed collaborations, wrote the first draft of the manuscript and significantly edited successive manuscript drafts; P.S.T. supervised the X-chromosome gene sequencing and analysis; K. Hynes and M.A.B. carried out molecular studies. I.E.S., S.F.B., S.J.T., E.H., S.M., S.R., A. Mazarib, Z.A., M.Y.N., S.K., D.L., T.L.-S., A.D.K. and C.P.D. identified families and provided clinical information; R.S., S.E., C. Stevens, S.O., C.T., S.B., G.B., J.C., K. Halliday, D.J., T.M., J.V., S. West, S. Widaa, J.T., E.D., A.B., R.L., M.M., P.W., A. Menzies, A.J. and R.S. performed the X-chromosome gene sequencing and analysis of 737 genes. L.V. performed tissue culture work, J.B. and D.H.G. carried out and interpreted the human in situ hybridization analysis, K.F. performed and interpreted linkage analysis, M.S. and K. Hynes did X inactivation studies and their interpretation, and M.C. and C. Shoubridge contributed to the supervision of molecular and cell studies. H.-G.K. and J.F.G. contributed to segregation analysis. E.S. and P.T. performed and interpreted the mouse in situ hybridization analysis. I.E.S. and S.F.B. contributed to the project concept and coordinated families. E.H. and G.R.S. coordinated families. P.A.F. and M.R.S. coordinated the X-chromosome gene sequencing and analysis. J.C.M. and J.G. coordinated and supervised the project in concept and design, supervised molecular studies, managed collaborations and significantly edited successive drafts. All authors contributed to the discussion of the results and the preparation of successive manuscript drafts with the opportunity to comment critically and constructively.

Corresponding authors

Correspondence to Leanne M Dibbens or Jozef Gécz.

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