De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

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.

Figure 1

Facial Phenotype of Individuals with CHAMP1-Associated Disorder Facial images of individual A:II-1 at age 4 years (A), individual B:II-3 at the age of 12 months and 6 years (B), individual C:II-2 from the age of 6 till 18 years (C), individual D:II-2 at birth and at age 3 years (D), and individual E:II-2 at the age 4 and 9 years (E). Note the long face, orofacial hypotonia, epicanthic folds, upslanting palpebral fissures, short philtrum, thin and tented upper lip and everted lower lip, pointed chin, and deep-set ears.

Figure 2

Schematic Protein Structure of CHAMP1 The positions of the de novo mutations identified in this study are marked with vertical arrows and are shown in red; mutations identified in the Deciphering Developmental Disorders study are shown in black. Abbreviations are as follows: ZnF, zinc-finger domain; N, N terminus; C, C terminus.