A novel VPS4A variant drives lipotoxicity underlying CIMDAG syndrome

Cerebellar hypoplasia, impaired intellectual development, congenital microcephaly, dystonia, anemia, and growth retardation (CIMDAG) syndrome is caused by variants in VPS4A. We report a 5-year-old Nepalese boy with classical CIMDAG features, including developmental delay, microcephaly, dystonia, cataracts, dyserythropoietic anemia, and growth retardation. Magnetic resonance imaging showed mild cerebellar atrophy. Trio exome sequencing identified a homozygous VPS4A variant (c.863G>A; p.Arg288Gln), predicted to be deleterious. Structural analyses revealed disruption of a conserved Arginine-288 residue within the ATPases associated with diverse cellular activities domain, leading to loss of stability and increased disorder. The VPS4A-p.Arg288Gln variant showed enhanced aggregation and reduced interaction with LC3B (microtubule-associated protein 1 light chain 3 beta), impairing its localization to lipid droplets. Proband fibroblasts exhibited increased lipid accumulation, elevated free fatty acids, and higher reactive oxygen species levels, indicative of lipotoxic stress. Together, these findings demonstrate that a novel pathogenic VPS4A variant drives structural destabilization and lipotoxicity, providing mechanistic insight into lipid homeostasis perturbations in CIMDAG syndrome.