An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Valosin-containing protein (VCP) is an AAA+ ATPase crucial for ubiquitin-dependent cellular functions.
• Pathogenic VCP variants are linked to adult-onset multisystem proteinopathy (MSP), affecting muscles, bones, cognition, and motor neurons.

Purpose of the Study:

• To identify and characterize novel VCP variants associated with a childhood-onset neurodevelopmental disorder.
• To investigate the functional impact of these variants on VCP protein activity and cellular processes.

Main Methods:

• GeneMatcher was used to identify individuals with VCP variants.
• Trio exome sequencing and multigene panels were employed for variant identification.
• In vitro functional assays and in silico modeling assessed variant impact on VCP ATPase activity and protein function.

Main Results:

• Thirteen unrelated individuals with heterozygous VCP variants (12 de novo, 1 inherited) were identified.
• Variants included missense, in-frame deletions, frameshift, and splicing alterations.
• Functional studies revealed decreased or hyperactivated ATPase activity, and predicted haploinsufficiency, indicating loss-of-function mechanisms.

Conclusions:

• This study expands the known disease spectrum of VCP to include childhood-onset neurodevelopmental disorders.
• The findings highlight VCP as a significant gene in pediatric neurodevelopmental conditions.
• The identified variants provide insights into VCP-related disorders and potential therapeutic targets.