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An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.
- Source :
-
American Journal of Human Genetics . Nov2023, Vol. 110 Issue 11, p1959-1975. 17p. - Publication Year :
- 2023
-
Abstract
- Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP -related disease to include neurodevelopmental disease presenting in childhood. Valosin-containing protein (VCP) is an ATPase that assists in cellular recycling pathways. Pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), affecting the brain, muscle, and bone. This article describes 13 individuals with VCP variants associated with childhood-onset neurodevelopmental disorder, possibly mediated by a loss-of-function mechanism. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00029297
- Volume :
- 110
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- American Journal of Human Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 173317241
- Full Text :
- https://doi.org/10.1016/j.ajhg.2023.10.007