Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Hypertrophic cardiomyopathy (HCM) (n=963). Intervention: Pathogenic MYH7 missense variants within the myosin interacting-heads motif (IHM) BH-FH molecular interface vs. Pathogenic MYH7 missense variants located elsewhere in the myosin heavy chain (MHC) head outside the interface. Primary outcome: Age at clinical HCM diagnosis (primary diagnosis or left ventricular thickness >= 13 mm) (HR 1.92, p=5.0e-9).

Q: What does this research mean for the field?

Pathogenic MYH7 variants within the blocked-head to free-head (BH-FH) thick filament molecular interface cause hypertrophic cardiomyopathy diagnosis approximately 12 years earlier and significantly increase the risk of adverse cardiac outcomes compared to non-interface variants. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Debabrata Dutta; Yuri Kim; Carolyn Y. Ho; Jonathan G. Seidman; Christine E. Seidman; Roger Craig; Raúl Padrón

doi:10.1073/pnas.2529234123

June 29, 2026Proceedings of the National Academy of Sciences

Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy

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Key result

MYH7 interface variants linked to ~92% higher rate of HCM diagnosis vs non-interface variants.

HR 1.92
P 5.0e-9
n=963

Why the study?

HCM variants in thick filament protein genes cause cardiac hypertrophy, but their structural consequences across the human cardiac thick filament interactome remained to be defined.

Do pathogenic missense variants located within molecular interfaces of the cardiac thick filament lead to earlier disease onset and increased adverse clinical outcomes compared to variants outside of interfaces in patients with hypertrophic cardiomyopathy?

Study Design

Type

Observational (n=963)

Multicenter

Yes

Structured PICO

Do pathogenic missense variants located within molecular interfaces of the cardiac thick filament lead to earlier disease onset and increased adverse clinical outcomes compared to variants outside of interfaces in patients with hypertrophic cardiomyopathy?

P

Population

963 patients with hypertrophic cardiomyopathy and pathogenic missense variants in MYH7 (n=890) or MYBPC3 (n=73) from the Sarcomeric Human Cardiomyopathy Registry (SHaRe), alongside structural mapping of 233 pathogenic and 21 benign ClinVar variants.

E

Exposure

Pathogenic missense variants located within molecular interfaces of the cardiac thick filament (specifically MYH7 BH-FH interface, n=123 patients; and BH-S2 interface, n=172 patients)

C

Comparator

Pathogenic missense variants located outside of those molecular interfaces in the myosin heavy chain (MHC) head (n=433 and n=431 patients, respectively), across the entire MHC protein, or within the myosin tail (n=556 patients); 21 benign missense variants served as structural controls.

O

Outcome

Mean age at clinical manifestation/primary diagnosis of HCM (defined as left ventricular wall thickness ≥ 13 mm in adults or z-score based on body mass index for children) and age-specific disease burden including LV outflow tract obstruction (≥ 50 mmHg), atrial fibrillation, ventricular arrhythmic composite (first occurrence of sudden cardiac death, resuscitated cardiac arrest, or appropriate ICD therapy), heart failure composite (first occurrence of cardiac transplantation, LVAD implantation, LVEF < 35%, or NYHA class III/IV symptoms), stroke, and death.hard clinical

Main Result

Hazard Ratio: 1.92

p-value: p=5.0e-9

Mapping HCM variants onto the native human cardiac thick filament cryo-EM structure demonstrates that pathogenic missense variants cluster in protein-protein interfaces (whereas benign variants do not), and patients with MYH7 interface variants experience significantly earlier disease onset and worse clinical outcomes, enabling improved genetic risk stratification.

Limitations

The 6 Å-resolution cryo-EM map lacks amino acid side-chain densities, limiting structural conclusions to qualitative assessments of residue locations.
Not all longitudinal clinical information was available for every patient in the SHaRe registry.
Statistical power requirements (>= 40 variants per region) limited clinical outcome comparisons to MYH7 variants.
Vast numbers of rare and prevalent TTN missense variants in all genomes confound accurate clinical classification of titin variants.
The 6 Å-resolution cryo-EM map (PDB 8G4L) lacks amino acid side-chain densities, limiting structural assessment to qualitative conclusions based on amino acid location.
Clinical outcome analyses required ≥ 40 variants within an interface or region for statistical power, which limited clinical correlation analyses strictly to MYH7 variants.
Not all clinical endpoint information was available for every patient in the SHaRe registry.
Vast numbers of rare and prevalent TTN missense variants in genomes may confound accurate clinical classification of TTN variants.

Implication

May support refined HCM risk stratification for MYH7 carriers; extends structural interface mapping to outcomes but leaves prospective validation open.

Abstract

Hypertrophic cardiomyopathy (HCM) variants in genes encoding the myosin heavy chain (MHC) ( MYH7 ), myosin light chains ( MYL2 and MYL3 ), and cardiac myosin binding protein-C (cMyBP-C, MYBPC3 ) lead to cardiac hypertrophy, with abnormal contractility, relaxation, and energy consumption. Here, we defined the structural consequences of pathogenic and benign missense variants in these genes by mapping 233 variants ( MYH7 , n = 175; MYBPC3 , n = 41; MYL2 , n = 12; MYL3 , n = 5) onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 30 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the MHC, essential and regulatory light chains, and cMyBP-C. None of the 21 variants classified as benign were within interfaces. We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients.

Discussion

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Cite This Study

Dutta et al. (2026) conducted an observational in Hypertrophic cardiomyopathy (HCM) (n=963). Pathogenic MYH7 missense variants within the myosin interacting-heads motif (IHM) BH-FH molecular interface vs. Pathogenic MYH7 missense variants located elsewhere in the myosin heavy chain (MHC) head outside the interface was evaluated on Age at clinical HCM diagnosis (primary diagnosis or left ventricular thickness >= 13 mm) (HR 1.92, p=5.0e-9). Pathogenic MYH7 variants within the BH-FH molecular interface caused HCM diagnosis ~12 years earlier (HR 1.92, p=5.0e-9) and increased heart failure risk (HR 2.64) vs non-interface head variants.

synapsesocial.com/papers/6a44ae015cd2549c8bc435f2 https://doi.org/10.1073/pnas.2529234123

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Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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