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Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Nature Genetics volume 49, pages 511514 (2017) | Download Citation

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

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Acknowledgements

We thank the studied families and the Lefroy family for their participation in and support of this study. We thank the DNA and cell bank of the ICM (Paris, France) for DNA extraction, Sinead Eyre (QBI) for study coordination and M. Kean (RCH) and M. Seal (MCRI) for assistance with MRI protocols and scanning. This work was funded in part by National Health and Medical Research Council (NHMRC) Australia Project grants (GNT1059666, GNT631466, GNT1064174, GNT1048849, GNT1104455 and GNT1064174), the Agence Nationale de la Recherche (ANR Blanc CILAXCAL, ANR Blanc HARTaGeNe), Assistance Publique des Hôpitaux de Paris (APHP), the 'Programme Hospitalier de Recherche Clinique' (PHRC) ACCREM, and the 'Investissements d'Avenir' programs ANR-10-IAIHU-06 (IHU-A-ICM), ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02. A.P.L.M. and L.R.M. are supported by an Australian Postgraduate Award, T.J.E. is supported by a University of Queensland Research Scholarship, and A.P. is supported by a QBI PhD scholarship. S.H. and A.Q. are respectively supported by a master's and a doctoral grant from the Fondation pour la Recherche Médicale (FRM). M.B. is supported by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (GNT1054618). E.H.S. is supported by a grant from the NIH (2R01NS058721), and R.J.L. is supported by a Melbourne Children's Clinician Scientist Fellowship. L.J.R. is supported by an NMHRC Principal Research Fellowship, and P.J.L. is supported by an NHMRC Career Development Fellowship (GNT1032364). C.D. and C.N. are supported as members of the Bio-Psy Labex. This work was supported in part by the Victorian Government's Operational Infrastructure Support Program and Australian Government NHMRC IRIISS.

Author information

Author notes

    • Ashley P L Marsh
    • , Delphine Heron
    •  & Timothy J Edwards

    These authors contributed equally to this work.

    • Linda J Richards
    • , Paul J Lockhart
    •  & Christel Depienne

    These authors jointly directed this work.

Affiliations

  1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Ashley P L Marsh
    • , Greta Gillies
    • , Kate Pope
    • , Sarah E M Stephenson
    • , Martin B Delatycki
    • , David J Amor
    •  & Paul J Lockhart
  2. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.

    • Ashley P L Marsh
    • , Simone A Mandelstam
    • , Sarah E M Stephenson
    • , Martin B Delatycki
    • , David J Amor
    • , Richard J Leventer
    •  & Paul J Lockhart
  3. AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.

    • Delphine Heron
    • , Caroline Nava
    • , Anne Faudet
    • , Solveig Heide
    • , Boris Keren
    • , Fabien Lesne
    • , Cyril Mignot
    • , Alexis Brice
    •  & Christel Depienne
  4. Groupe de Recherche Clinique (GRC) `Déficience Intellectuelle et Autisme' UPMC, Paris, France.

    • Delphine Heron
    • , Solveig Heide
    •  & Cyril Mignot
  5. Centre de Référence `Déficiences Intellectuelles de Causes Rares', Paris, France.

    • Delphine Heron
    • , Cyril Mignot
    •  & Thierry Billette de Villemeur
  6. Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia.

    • Timothy J Edwards
    • , Jens Bunt
    • , Ilan Gobius
    • , Laura R Morcom
    • , Annalisa Paolino
    •  & Linda J Richards
  7. School of Medicine, University of Queensland, Herston, Brisbane, Australia.

    • Timothy J Edwards
  8. IGBMC, Université de Strasbourg, CNRS, INSERM, UMR7104 U964, Strasbourg, France.

    • Angélique Quartier
    • , Jean-Louis Mandel
    • , Amélie Piton
    •  & Christel Depienne
  9. Drug Delivery, Disposition and Dynamics (D4), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

    • Charles Galea
  10. INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.

    • Caroline Nava
    • , Agnès Rastetter
    • , Boris Keren
    • , Aurélie Méneret
    • , Oriane Trouillard
    • , Quentin Welniarz
    • , Alexis Brice
    • , Emmanuel Roze
    •  & Christel Depienne
  11. AP-HP, Hôpital Trousseau, Service de Neuropédiatrie, Paris, France.

    • Marie-Laure Moutard
    •  & Thierry Billette de Villemeur
  12. UPMC, GRC ConCer-LD, Sorbonne Université, Paris, France.

    • Marie-Laure Moutard
    •  & Thierry Billette de Villemeur
  13. Centre de Référence `Neurogénétique', Paris, France.

    • Marie-Laure Moutard
  14. Developmental Imaging and Child Neuropsychology Research Groups, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Vicki Anderson
    • , Alissandra McIlroy
    • , Megan Spencer-Smith
    •  & Amanda Wood
  15. Génétique Médicale, CHU Paris Nord, Hôpital Jean Verdier, Bondy, France.

    • Pierre Bitoun
  16. AP-HP GHUEP, Hôpital Armand Trousseau, Service de Radiologie, Paris, France.

    • Catherine Garel
  17. iCONICS Facility, ICM, Paris, France.

    • Justine Guegan
  18. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • Vesna Lukic
  19. Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.

    • Simone A Mandelstam
  20. Department of Radiology, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Simone A Mandelstam
  21. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • George McGillivray
  22. AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Paris, France.

    • Aurélie Méneret
    •  & Emmanuel Roze
  23. Service de Génétique Clinique, Centre de Référence CLAD-Ouest, CHU Rennes, Rennes, France.

    • Sylvie Odent
  24. UMR 6290 CNRS, IGDR Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.

    • Sylvie Odent
  25. AP-HP, Groupe Hospitalier Saint-Louis -La Riboisière -Fernand Vidal, Laboratoire de Génétique, Paris, France.

    • Florence Riant
  26. Neuropsychology Research Unit, School of Psychology, University of Queensland, Brisbane, Australia.

    • Gail A Robinson
  27. School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, Victoria, Australia.

    • Megan Spencer-Smith
  28. Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada.

    • Myriam Srour
  29. Department of Neurology and Neurosurgery, McGill University Health Center, Montreal, Quebec, Canada.

    • Myriam Srour
    •  & Guy Rouleau
  30. Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • Rick Tankard
    •  & Melanie Bahlo
  31. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.

    • Rick Tankard
    •  & Melanie Bahlo
  32. Institut de Biologie Paris Seine, Neuroscience Paris Seine, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.

    • Quentin Welniarz
  33. School of Life and Health Sciences, Aston University, Birmingham, UK.

    • Amanda Wood
  34. Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.

    • Guy Rouleau
  35. INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris-Descartes University, Sorbonne Paris Cité and Imagine Institute, Paris, France.

    • Tania Attié-Bitach
  36. AP-HP, Hôpital Necker-Enfants Malades, Département de Génétique, Paris, France.

    • Tania Attié-Bitach
  37. Victorian Clinical Genetics Services, Parkville, Victoria, Australia.

    • Martin B Delatycki
  38. Laboratoires de Génétique, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

    • Jean-Louis Mandel
    • , Amélie Piton
    •  & Christel Depienne
  39. INSERM U1141, Paris, France.

    • Thierry Billette de Villemeur
  40. Department of Neurology, UCSF Benioff Children's Hospital, San Francisco, California, USA.

    • Elliott H Sherr
  41. Neuroscience Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Richard J Leventer
  42. Department of Neurology, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Leventer
  43. University of Queensland, School of Biomedical Sciences, St. Lucia, Brisbane, Australia.

    • Linda J Richards

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Contributions

A.P.L.M., D.H., T.J.E., C. Galea, E.H.S., R.J.L., L.J.R., P.J.L. and C.D. contributed to formulation of theory and prediction. A.P.L.M., D.H., T.J.E., C.N., S.E.M.S., J.-L.M., A. Piton, L.J.R., P.J.L. and C.D. contributed to experimental conception and design.A.P.L.M., D.H., T.J.E., C. Galea, A.Q., C.N., A.R., M.-L.M., V.A., P.B., J.B., A.F., C. Garel, G.G., I.G., J.G., S.H., B.K., F.L., V.L., S.A.M., G.M., A. McIlroy, A. Meneret, C.M., L.R.M., S.O., A. Paolino, K.P., F.R., G.A.R., M.S.-S., M.S., S.E.M.S., R.T., O.T., Q.W., A.W., E.R., A. Piton, M.B., T.B.d.V., E.H.S., R.J.L., L.J.R., P.J.L. and C.D. contributed to acquisition, analysis and/or interpretation of data. A.P.L.M., T.J.E., P.J.L. and C.D. contributed to drafting the article. A.P.L.M., D.H., T.J.E., A.Q., C. Galea, C.N., M.-L.M., V.A., S.A.M., G.M., A.M., G.A.R., A.B., G.R., T.A.-B., M.B.D., J.-L.M., D.J.A., E.R., A. Piton, M.B., T.B.d.V., E.H.S., R.J.L., L.J.R., P.J.L. and C.D. contributed to critically revising the article for important intellectual content.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Linda J Richards or Paul J Lockhart or Christel Depienne.

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DOI

https://doi.org/10.1038/ng.3794

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