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1000 Titel
  • X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
1000 Autor/in
  1. Hu, H. |
  2. Haas, S. A. |
  3. Chelly, J. |
  4. Van Esch, H. |
  5. Raynaud, M. |
  6. de Brouwer, A. P. M. |
  7. Weinert, S. |
  8. Froyen, G. |
  9. Frints, S. G. M. |
  10. Laumonnier, F. |
  11. Zemojtel, T. |
  12. Love, M. I. |
  13. Richard, H. |
  14. Emde, A.-K. |
  15. Bienek, M. |
  16. Jensen, C. |
  17. Hambrock, M. |
  18. Fischer, U. |
  19. Langnick, C. |
  20. Feldkamp, M. |
  21. Wissink-Lindhout, W. |
  22. Lebrun, N. |
  23. Castelnau, L. |
  24. Rucci, J. |
  25. Montjean, R. |
  26. Dorseuil, O. |
  27. Billuart, P. |
  28. Stuhlmann, T. |
  29. Shaw, M. |
  30. Corbett, M. A. |
  31. Gardner, A. |
  32. Willis-Owen, S. |
  33. Tan, C. |
  34. Friend, K. L. |
  35. Belet, S. |
  36. Van Roozendaal, K. E. P. |
  37. Jimenez-Pocquet, M. |
  38. Moizard, M.-P. |
  39. Ronce, N. |
  40. Sun, R. |
  41. O'Keeffe, S. |
  42. Chenna, R. |
  43. van Bömmel, A. |
  44. Göke, J. |
  45. Hackett, A. |
  46. Field, M. |
  47. Christie, L. |
  48. Boyle, J. |
  49. Haan, E. |
  50. Nelson, J. |
  51. Turner, G. |
  52. Baynam, G. |
  53. Gillessen-Kaesbach, G. |
  54. Müller, U. |
  55. Steinberger, D. |
  56. Budny, B. |
  57. Badura-Stronka, M. |
  58. Latos-Bieleńska, A. |
  59. Ousager, L. B. |
  60. Wieacker, P. |
  61. Criado, G. Rodríguez |
  62. Bondeson, M.-L. |
  63. Annerén, G. |
  64. Dufke, A. |
  65. Cohen, M. |
  66. Maldergem, L. Van |
  67. Vincent-Delorme, C. |
  68. Echenne, B. |
  69. Simon-Bouy, B. |
  70. Kleefstra, T. |
  71. Willemsen, M. |
  72. Fryns, J.-P. |
  73. Devriendt, K. |
  74. Ullmann, R. |
  75. Vingron, M. |
  76. Wrogemann, K. |
  77. Wienker, T. F. |
  78. Tzschach, A. |
  79. Van Bokhoven, H. |
  80. Gecz, J. |
  81. Jentsch, T. J. |
  82. Chen, W. |
  83. Ropers, H.-H. |
  84. Kalscheuer, V. M. |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-02-03
1000 Erschienen in
1000 Quellenangabe
  • 21:133–148
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • https://dx.doi.org/10.1038/mp.2014.193 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414091/ |
1000 Ergänzendes Material
  • https://www.nature.com/mp/journal/v21/n1/suppinfo/mp2014193s1.html?url=/mp/journal/v21/n1/full/mp2014193a.html |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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1000 Label
1000 Förderer
  1. German Ministry of Education and Research (BMBF) |
  2. European Union |
  3. Max Planck Society |
  4. NWO |
  5. Dutch Brain Foundation |
  6. WCH Foundation |
  7. Australian NHMRC |
  8. Fondation pour la Recherche Médicale (FRM) |
1000 Fördernummer
  1. -
  2. 241995
  3. -
  4. 91666017
  5. 2009(2)-81
  6. -
  7. -
  8. DEQ2000326477
1000 Förderprogramm
  1. -
  2. EU FP7 project: GENCODYS
  3. Max Planck Innovation Funds
  4. VENI grant
  5. -
  6. -
  7. -
  8. Equipe FRM 2013
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer German Ministry of Education and Research (BMBF) |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer European Union |
    1000 Förderprogramm EU FP7 project: GENCODYS
    1000 Fördernummer 241995
  3. 1000 joinedFunding-child
    1000 Förderer Max Planck Society |
    1000 Förderprogramm Max Planck Innovation Funds
    1000 Fördernummer -
  4. 1000 joinedFunding-child
    1000 Förderer NWO |
    1000 Förderprogramm VENI grant
    1000 Fördernummer 91666017
  5. 1000 joinedFunding-child
    1000 Förderer Dutch Brain Foundation |
    1000 Förderprogramm -
    1000 Fördernummer 2009(2)-81
  6. 1000 joinedFunding-child
    1000 Förderer WCH Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
  7. 1000 joinedFunding-child
    1000 Förderer Australian NHMRC |
    1000 Förderprogramm -
    1000 Fördernummer -
  8. 1000 joinedFunding-child
    1000 Förderer Fondation pour la Recherche Médicale (FRM) |
    1000 Förderprogramm Equipe FRM 2013
    1000 Fördernummer DEQ2000326477
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6405299.rdf
1000 Erstellt am 2017-11-06T18:01:03.370+0100
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