Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency

Abstract

CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

Fig. 1

Genetic findings in the study participants. a Mutations in CHAMP1 aligned on the protein, mapped to NM_001164144.1. Blue text represents frameshift variants and green text represents nonsense variants. Orange bars represent zinc finger domains. b Deletions of the CHAMP1 gene. Alternating black and gray bars indicate chromosome bands, black bars represent the coordinates of participant deletions. OMIM genes are listed below participant deletions, green text indicates the gene can be disease causing

Fig. 2

Vineland-3 Domains in participants. The horizontal lines represent the minimum and maximum score within a group, the ends of the box represent the upper and lower quartiles, and the line within the box represents the median. The dark purple represents the deletion group, and the light blue represents the mutation group. Outliers are represented with black scatter points, the two outliers with low Communication and Socialization scores are from two independent participants. Asterix represent significance. *p ≤ 0.05, **p < 0.01, ***p ≤ 0.001, ****p ≤ 0.0001

Fig. 3

Distribution of Vineland-3 Standard Scores in participants. The light blue bars/line represent the mutation group, the dark purple bars/line represent the deletion group, and the black line represents the general population (M = 100, SD = 15)