MYBPC3 and Dilated Cardiomyopathy

Myosin binding protein C, cardiac (MYBPC3) encodes a key sarcomeric thick-filament protein. Pathogenic variants in MYBPC3 are well known causes of hypertrophic cardiomyopathy, but accumulating data support a distinct association with dilated cardiomyopathy (DCM). DCM due to MYBPC3 presents with left ventricular dilation, systolic dysfunction, and variable onset from childhood to adulthood, typically following an autosomal dominant pattern.

Genetic studies have identified MYBPC3 rare variants in unselected DCM cohorts. In a resequencing study of 312 unrelated probands (181 familial, 131 idiopathic), 12 unique protein-altering MYBPC3 variants were found in 13 probands (4.2%) (PMID:20215591). Independent screening of 46 young DCM patients revealed a missense variant, c.2843A>C (p.Asn948Thr), absent in 88 controls (PMID:12379228). In a Vietnamese DCM cohort (n=230), a novel c.659A>G (p.Tyr220Cys) variant accounted for MYBPC3-driven disease in 2–6% of cases (PMID:34011823).

Inheritance is predominantly autosomal dominant with reduced penetrance. Segregation data remain limited, with no large multi-generation pedigrees reported for DCM-specific alleles. Several variants have recurred in unrelated probands, supporting independent pathogenicity.

Variant spectrum includes missense substitutions (e.g., c.604A>C (p.Lys202Gln), c.659A>G (p.Tyr220Cys), c.2843A>C (p.Asn948Thr)) affecting conserved domains of cMyBP-C. No recurrent founder alleles have been established outside population-specific reports.

Experimental work in a homozygous MYBPC3 mutant mouse model recapitulates DCM phenotypes with marked oxidative stress and sarcomeric disarray in both mouse and human heart samples, implicating augmented reactive oxygen species in disease progression (PMID:26508994). These data concord with haploinsufficiency as the dominant mechanism, although dominant-negative effects remain possible for select missense variants.

Integration of genetic and functional evidence supports a strong clinical validity for MYBPC3 in DCM: rare variants are identified across multiple cohorts, functional concordance is demonstrated in animal models, and variant classes include deleterious missense changes. MYBPC3 testing should be included in DCM diagnostic panels, and identification of pathogenic alleles informs cascade screening and management.

Key Take-home: MYBPC3 pathogenic variants contribute significantly to DCM risk through haploinsufficiency and oxidative stress mechanisms, warranting inclusion in genetic testing for DCM management.

References

• Biochemical and biophysical research communications • 2002 • Novel mutations in sarcomeric protein genes in dilated cardiomyopathy PMID:12379228
• Circulation: Cardiovascular Genetics • 2010 • Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy PMID:20215591
• Oxidative Medicine and Cellular Longevity • 2015 • Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation PMID:26508994
• Circulation Journal • 2021 • Genetic Determinants and Genotype-Phenotype Correlations in Vietnamese Patients With Dilated Cardiomyopathy PMID:34011823

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