Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Abstract

BACKGROUND:

Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.

METHODS:

Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.

RESULTS:

Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5'-3' quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P<0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.

CONCLUSIONS:

Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.

• Authors: Adam S Helms, Andrea D Thompson, Amelia A Glazier, Neha Hafeez, Samat Kabani, Juliani Rodriguez, Jaime M Yob, Helen Woolcock, Francesco Mazzarotto, Neal K Lakdawala, Samuel G Wittekind, Alexandre C Pereira, Daniel L Jacoby, Steven D Colan, Euan A Ashley, Sara Saberi, James S Ware, Jodie Ingles, Christopher Semsarian, Michelle Michels, Iacopo Olivotto, Carolyn Y Ho, Sharlene M Day
• Journal: Circulation. Genomic and precision medicine (Circ Genom Precis Med) Vol. 13 Issue 5 Pg. 396-405 (10 2020) ISSN: 2574-8300 [Electronic] United States
• PMID: 32841044 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• myosin-binding protein C

Topics

• Adolescent
• Adult
• Cardiomyopathy, Hypertrophic (diagnosis, genetics)
• Carrier Proteins (genetics)
• Child
• Female
• Genotype
• Humans
• Male
• Middle Aged
• Myofibrils (metabolism, pathology)
• Phenotype
• Polymorphism, Genetic
• Registries
• Severity of Illness Index
• Spatial Analysis
• Young Adult