Neurodevelopmental phenotypes in individuals with pathogenic variants in CHAMP1

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Pathogenic variants in the CHAMP1 gene are linked to a rare neurodevelopmental disorder.
• CHAMP1 encodes a kinetochore-microtubule associated protein crucial for chromosomal alignment.

Purpose of the Study:

• To characterize the clinical phenotype associated with de novo pathogenic variants in CHAMP1.
• To compare the features of newly identified cases with previously reported individuals.

Main Methods:

• Exome or gene panel sequencing to identify pathogenic CHAMP1 variants.
• Clinical data collection through caregiver interviews, behavioral surveys (Vineland), and medical record review.
• Phenotypic analysis of 14 individuals with de novo loss-of-function variants.

Main Results:

• Common phenotypes include intellectual disability, developmental delay, language impairment, microcephaly, behavioral issues (including ASD), seizures, hypotonia, and gastrointestinal/ophthalmologic problems.
• Rarely observed phenotypes include leukemia, failure to thrive, and high pain tolerance.
• Five specific de novo variants were identified in at least two individuals each.

Conclusions:

• De novo pathogenic variants in CHAMP1 result in a variable neurodevelopmental disorder.
• The identified phenotypes underscore the critical role of CHAMP1 in neurodevelopment and chromosomal stability.