| Author |
Ockeloen, Charlotte W. Lichtenbelt, Klaske D. Alhaddad, Bader Pfundt, Rolph Becker, Jessica Van Gassen, Koen L. I. Lessel, Davor Wieczorek, Dagmar Engels, Hartmut Fuchs, Sigrid Johannsen, Jessika Denecke, Jonas Strom, Tim M. Kubisch, Christian Zink, Alexander M. Haack, Tobias B. Herkert, Johanna C. Wohlleber, Eva Hempel, Maja Cremer, Kirsten Kleefstra, Tjitske |
| Description |
Country affiliation: Germany Author Affiliation: Hempel M ( Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.); Cremer K ( Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.); Ockeloen CW ( Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.); Lichtenbelt KD ( Department of Medical Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.); Herkert JC ( Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.); Denecke J ( Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany.); Haack TB ( Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany); Zink AM ( Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.); Becker J ( Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.); Wohlleber E ( Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.); Johannsen J ( Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany.); Alhaddad B ( Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.); Pfundt R ( Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.); Fuchs S ( Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.); Wieczorek D ( Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.); Strom TM ( Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany); van Gassen KL ( Department of Medical Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.); Kleefstra T ( Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.); Kubisch C ( Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.); Engels H ( Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address: hartmut.engels@uni-bonn.de.); Lessel D ( Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: d.lessel@uke.de.) |
| Abstract |
CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability. |
