Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Valosin-containing protein (VCP) gene mutations are linked to multisystem proteinopathy 1 (MSP1), a rare autosomal dominant disorder.
• MSP1 encompasses a spectrum of conditions including inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).
• Clinical heterogeneity and novel genetic variants contribute to diagnostic challenges in MSP1.

Purpose of the Study:

• To report clinical and genetic findings in five patients with novel VCP gene variants.
• To expand the understanding of the VCP gene's role in MSP1 pathogenesis.
• To emphasize the importance of considering MSP1 in the differential diagnosis of related neurological and bone disorders.

Main Methods:

• Clinical evaluation of five patients presenting with MSP1-related symptoms.
• Genetic analysis to identify mutations in the VCP gene.
• Correlation of identified VCP variants with clinical manifestations.

Main Results:

• Identification of three novel heterozygous pathogenic VCP variants: c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F).
• Association of these novel variants with cardinal MSP1 manifestations, including myopathy, PDB, and FTD.
• Demonstration of significant clinical heterogeneity among patients with VCP variants.

Conclusions:

• The VCP gene harbors a spectrum of heterozygous pathogenic variants associated with MSP1.
• High clinical heterogeneity underscores the complexity of MSP1 diagnosis.
• Increased awareness and early consideration of MSP1 are crucial for timely diagnosis and improved management of affected individuals.