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Pontocerebellar hypoplasia type 2E (PCH2E) is an autosomal recessive neurodevelopmental disorder characterized by prenatal onset microcephaly, profound developmental delay and epilepsy. Biallelic loss-of-function variants in VPS53, encoding a subunit of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes, have been reported in a single neonate presenting with classic PCH2E features plus hearing impairment and liver disease, expanding the phenotypic spectrum (PMID:39842660). No additional affected relatives or segregation data are available, and variant details remain limited to this case.
Early functional studies in a VPS50-related disorder, which shares EARP components with VPS53, demonstrated severe reduction of VPS53 protein levels in patient fibroblasts, supporting a loss-of-function mechanism for VPS53 variants (PMID:38876772). No animal models or rescue experiments have been described for VPS53-associated PCH2E. Further cohorts and mechanistic studies are needed to corroborate pathogenicity and define genotype–phenotype correlations.
Key take-home: VPS53‐related PCH2E is a rare autosomal recessive disorder with limited published cases, expanded to include hepatic and auditory involvement, warranting vigilance for extraneurological features in diagnosis.
Gene–Disease AssociationLimitedSingle published proband with biallelic VPS53 variants in PCH2E, no segregation data, limited variant characterization Genetic EvidenceLimitedOne patient report of biallelic VPS53 loss-of-function variants expanding phenotypic spectrum ([PMID:39842660]) Functional EvidenceLimitedPatient fibroblast data in EARP complex deficiency show reduced VPS53 protein, supporting haploinsufficiency mechanism ([PMID:38876772]) |