De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Abstract

We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore-microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.

Keywords: congenital microcephaly; intellectual disability, severe; severe global developmental delay.

Figure 1.

Photographs of patients. (A,B) Patient 1. (C,D) Patient 3. (E,F) Patient 4. (G) Patient 5 at 1 yr of age. (H,I) Patient 5 at 6 yr. Note midface hypoplasia, upslanted palpebral fissures (A), and clinodactyly (B) in Patient 1, hypertelorism in Patients 1 and 3, short philtrum and pointed chin in Patient 5, and widely spaced teeth in Patients 1, 3, and 4, and broad nasal bridge in all four patients.

Figure 2.

Variants in CHAMP1. Diagram of CHAMP1 with C2H2-type zinc finger domains (blue), SPE motifs (yellow), WK motifs (pink), and FPE motifs (green). Gene disrupting nonsense and frameshift variants identified in our patients are in green and previously identified mutations are shown in orange (Rauch et al. 2012; Hempel et al. 2015).