Severe cardiomyopathy associated with the VCP p.R155C and c.177_187del MYBPC3 gene variants

Area of Science:

• Genetics
• Cardiology
• Neurology

Background:

• Inclusion Body Myopathy, Paget's Disease of Bone, with Frontotemporal Dementia (IBMPFD) is a progressive, autosomal dominant disorder.
• IBMPFD is caused by variants in the Valosin Containing Protein (VCP) gene, affecting the ubiquitin-proteasome complex.
• Cardiomyopathy is a known, albeit typically late-stage, complication of VCP-associated IBMPFD.

Observation:

• A patient presented with acute onset of dilated cardiomyopathy.
• Genetic testing revealed concurrent pathogenic variants in both the MYBPC3 and VCP genes.
• The identified variants were MYBPC3 c.177_187del and VCP p.R155C.

Findings:

• This is the first reported case of concurrent MYBPC3 and VCP pathogenic variants.
• The combined variants led to an earlier onset and a more severe presentation of cardiomyopathy than typically observed with VCP variants alone.
• The findings suggest a potential synergistic effect of these genetic variants on cardiac function.

Implications:

• This case expands the understanding of genotype-phenotype correlations in IBMPFD and related cardiomyopathies.
• It highlights the importance of comprehensive genetic testing in patients with unexplained or rapidly progressing cardiomyopathy.
• Further research into the interaction between MYBPC3 and VCP variants may reveal novel therapeutic targets for genetic cardiomyopathies.