Cerebellar Abnormalities in the Neuroimaging Spectrum of CLTC-Related Disorder

Pathogenic variants in CLTC, which encodes the clathrin heavy chain involved in vesicle-mediated trafficking in neurons, cause a rare neurodevelopmental disorder associated with variable severity of global developmental delay and intellectual disability and structural brain abnormalities. Although corpus callosum and white matter anomalies are commonly reported, the neuroimaging spectrum associated with CLTC variants has not been systematically reviewed. We report a patient with a novel de novo heterozygous missense CLTC variant presenting with brain MRI findings of pontine hypoplasia and cerebellar atrophy, abnormalities rarely described in association with this condition. Moreover, we conducted a comprehensive review of the literature, including re-evaluation of available neuroimaging, to summarize cerebral imaging findings in 30 individuals, including our case. Pontine hypoplasia and cerebellar atrophy expand the known neuroimaging phenotype of CLTC-related disorder. In addition, our review supports a potential genotype-phenotype correlation, suggesting that missense variants may be associated with a more severe phenotype.