Two children with CLTC-related neurodevelopmental disorders: A case series expanding the clinical and neuroimaging phenotypes

Background The CLTC gene encodes clathrin heavy chain 1 (CHC1), a core component of the clathrin protein complex. Pathogenic variants in CLTC are associated with neurodevelopmental disorders involving multiple systems. Methods Clinical and neuroimaging data were collected from two pediatric patients with CLTC -related neurodevelopmental disorders. Whole-exome sequencing was performed, and candidate variants were validated by Sanger sequencing. Results A de novo in-frame deletion novel variant, p.(Ala1214del), was identified in Patient 1, whereas Patient 2 carried the previously reported variant, p.(Leu1217del). Both patients exhibited severe global developmental delays with no head control, epilepsy, chronic lung disease with recurrent respiratory deterioration requiring ventilatory support, and episodes of paroxysmal sympathetic hyperactivity associated with infection. Brain MRI revealed progressive white matter lesions in both cases, with intraventricular septation in Patient 1 and deep cystic white matter lesions in Patient 2. Conclusion We report the cases of two children with CLTC -related neurodevelopmental disorders caused by de novo in-frame deletion variants in exon 23. These findings highlight the phenotypic heterogeneity and expand the multisystem and neuroimaging spectra associated with pathogenic CLTC variants.