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The VCP gene encodes a hexameric AAA+ ATPase essential for ubiquitin-proteasome and autophagic processes. While VCP pathogenic variants underlie inclusion body myopathy with Paget disease of bone and frontotemporal dementia and amyotrophic lateral sclerosis, a re-analysis of 745 neurodevelopmental disorder trio-exomes identified a significant burden of ultra-rare de novo variants in VCP among 567 unsolved individuals under an autosomal dominant paradigm (PMID:38965372). No individual VCP variants or familial segregation were detailed, yielding limited genetic evidence.
Current functional studies demonstrate VCP’s role in protein homeostasis and autophagosome maturation but lack neurodevelopmental models or assays linking VCP perturbations to intellectual disability or autism. No conflicting data for VCP in neurodevelopmental disorders have been reported. Collectively, evidence remains limited to gene-level burden without case validation; de novo VCP variants are a provisional candidate for neurodevelopmental disorders awaiting case series and neural modeling. Key Take-home: VCP de novo variants warrant further investigation as potential contributors to neurodevelopmental disorders in diagnostic panels.
Gene–Disease AssociationLimitedUltra-rare de novo variant burden in VCP observed in neurodevelopmental disorder cohort without individual case data or segregation ([PMID:38965372]). Genetic EvidenceLimitedBurden analysis identified VCP de novo variants in 567 unsolved NDD cases without follow-up case descriptions or segregation ([PMID:38965372]). Functional EvidenceLimitedExisting functional studies demonstrate VCP roles in ubiquitin-proteasome and autophagy pathways but no neurodevelopmental phenotype modeling. |