REPORT De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment Maja Hempel, 1,10 Kirsten Cremer, 2,10 Charlotte W. Ockeloen, 3,10 Klaske D. Lichtenbelt, 4,10 Johanna C. Herkert, 5,10 Jonas Denecke, 6 Tobias B. Haack, 7,8 Alexander M. Zink, 2 Jessica Becker, 2 Eva Wohlleber, 2 Jessika Johannsen, 6 Bader Alhaddad, 8 Rolph Pfundt, 3 Sigrid Fuchs, 1 Dagmar Wieczorek, 9 Tim M. Strom, 7,8 Koen L.I. van Gassen, 4 Tjitske Kleefstra, 3 Christian Kubisch, 1 Hartmut Engels, 2,11, * and Davor Lessel 1,11, * 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 delete- rious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor devel- opmental 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. Intellectual disability (ID) is defined as substantial impair- ment of cognitive and adaptive functions with an onset in childhood and has an estimated prevalence of 1.5%– 2.0%. 1 The rapid development of new technologies, including next-generation sequencing, has allowed for the elucidation of a large number of previously undiag- nosed Mendelian disorders during recent years. This holds especially true for children with seemingly sporadic, non- syndromic or mild dysmorphic forms of intellectual disability and/or global developmental delay (ID/GDD) who could not be analyzed systematically on a genome- wide level before the advent of chromosomal microarrays and whole-exome or genome sequencing. Indeed, recent studies have identified pathogenic de novo mutations in a rapidly growing number of individuals with ID/GDD and thus have established the power of proband-parent trio whole-exome sequencing in particular. 2–4 Here, we report five unrelated individuals, three males and two females, with ID/GDD, severe speech impairment, and similar (though subtle) facial dysmorphisms (Table 1; Figure 1). In all five individuals, trio whole-exome sequencing identified causative de novo frameshift or nonsense mutations in CHAMP1 (chromosome align- ment-maintaining phosphoprotein 1; also called CAMP, ZNF828, or C13orf8). CHAMP1 (GenBank: NM_032436.2; MIM: 616327) encodes a zinc-finger protein, which is involved in the maintenance of kinetochore-microtubule attachment during mitosis and the regulation of accurate chromosome segregation, 5 both known to be crucial for cortical and mental development. 6 All biological samples and images were obtained after written informed consent was given by the parents of the affected individuals. The study was performed in accordance with the Declaration of Helsinki protocols and approved by the ethics commit- tees of the respective institutions. The first proband (individual II-1 of family A) is the first child of healthy unrelated parents of European descent. He was born after an uneventful pregnancy at 40 weeks of gestation with normal birth weight and length and a borderline occipitofrontal head circumference (OFC) of 33 cm (À2 SD). Feeding difficulties, vomiting, and weight loss characterized the early postnatal period. Develop- mental delay, muscular hypotonia, and strabismus first became evident at the age of 3 months. Hyperopia was diagnosed at the age of 9 months. All milestones of motor development were delayed; he was rolling over at 12 months, sitting at 12 months, crawling at 30 months, and walking at 4 years. At the age of four years, he dis- played severe developmental delay with microcephaly (OFC À2.2 SD) and truncal and orofacial hypotonia. His gait was slightly ataxic, and he displayed stereotypic move- ments including frequent hand fluttering and jactitation. His behavior was very friendly and open-minded. In addi- tion to joint hypermobility and an umbilical hernia, mild 1 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; 2 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; 3 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; 4 Department of Medical Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands; 5 Department of Genetics, University Medical Center Gronin- gen, University of Groningen, 9700 RB Groningen, the Netherlands; 6 Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany; 7 Institute of Human Genetics, Helmholtz Zentrum Mu ¨nchen, 85764 Neuherberg, Germany; 8 Institute of Human Genetics, Technische Univer- sita ¨t Mu ¨nchen, 81675 Munich, Germany; 9 Institut fu ¨r Humangenetik, Universita ¨tsklinikum Essen, Universita ¨t Duisburg-Essen, 45122 Essen, Germany 10 These authors contributed equally to this work 11 These authors contributed equally to this work *Correspondence: hartmut.engels@uni-bonn.de (H.E.), d.lessel@uke.de (D.L.) http://dx.doi.org/10.1016/j.ajhg.2015.08.003. Ó2015 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 97, 493–500, September 3, 2015 493