A Novel Autosomal Dominant Childhood-Onset Disorder Associated with Pathogenic Variants inVCP

Abstract

Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants inVCPare associated with adult-onset multisystem proteinopathy (MSP) that presents with myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who carry novel heterozygousVCPvariants (12de novo, 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performedin vitrofunctional studies andin silicomodelling 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 is the first description ofVCP-related neurodevelopmental disease presenting in childhood.