RARE DISEASE
Rare familial disorder with hypertrophic cardiomyopathy
Rare familial disorder with hypertrophic cardiomyopathy
Rare familial disorder with hypertrophic cardiomyopathy
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Drug discovery
3
drugs
With orphan designations
Overview
Familial Hypertrophic Cardiomyopathy (HCM) is an autosomal-dominant genetic disorder caused by mutations in sarcomere proteins (e.g., MYH7, MYBPC3). It manifests as asymmetric left ventricular hypertrophy, myocardial disarray, and fibrosis [1][5][9]. Clinical features include arrhythmias, heart failure, and sudden cardiac death [1][5][9]. Diagnosis relies on echocardiography, cardiac MRI, and genetic testing [9][12][15]. Management targets symptom relief, obstruction reduction, and sudden death risk stratification [2][7][15].
Therapies
First-line: β-blockers, non-dihydropyridine calcium channel blockers, or disopyramide for obstruction [2][7][15].
Septal reduction (myectomy/alcohol ablation) for refractory symptoms [2][7][11].
Implantable cardioverter-defibrillators (ICDs) for high sudden death risk; anticoagulation for atrial fibrillation [2][11][15].
Emerging therapies: Cardiac myosin inhibitors (e.g., mavacamten) [2][15].
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
263 drug discovery papers about Rare familial disorder with hypertrophic cardiomyopathy, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
263 drug discovery papers about Rare familial disorder with hypertrophic cardiomyopathy, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-25 | A new insight of hypertrophic cardiomyopathy: integrated analysis of differentially expressed genes, expression quantitative trait loci, and mendelian randomization.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) has a genetic basis, with pathogenic variants identified in the majority of familial cases and unclear mechanism. This study aimed to identify the genetic contributors underlying HCM pathogenesis and to identify novel genetic targets of HCM via integrated analysis of microarray datasets. METHODS: Three independent HCM datasets were used for comprehensive analysis by using R software. Differentially expressed genes (DEGs) between HCM and control, expression quantitative trait loci (eQTL) analysis, and Two-Sample Mendelian Randomization (TSMR) analyses were performed to identify the novel genes. CIBERSORT was utilized for immune cell infiltration analysis. Finally, the identified genes were verified, and their targeted drugs were explored. RESULTS: TSMR analysis revealed that four significantly HCM co-expressed genes, TNNT1, KCNK17, GADD45B, and CXCL6, were enriched in essential biological processes and pathways, including macrophage activation and neural system regulation. TNNT1 and CXCL6 genes were validated as the novel genes, enhancing the reliability of our findings. The candidate compounds with predicted binding affinity (Atorvastatin, Zearalenone, Cotinine, and S-1,2-Dichlorovinyl-N-acetylcysteine) were predicted and molecular docking was performed to evaluate the binding ability of the drug to the protein. CONCLUSIONS: This study reveals a new molecular insight in the pathogenesis of HCM, highlighting TNNT1 and CXCL6 as candidate targets in specific molecular pathways for the interference of HCM.
2026-04-15 | Myosin Inhibitors in Hypertrophic Obstructive Cardiomyopathy: Experience with Mavacamten in a National Referral Center
Background: Hypertrophic cardiomyopathy (HCM) is defined by left ventricular wall thickening not attributable to other causes, with an estimated prevalence of 1 in 200-500 individuals.HCM is classified as obstructive (HOCM) when the left ventricular outflow tract (LVOT) gradient exceeds 30 mmHg. 1 Symptom presence correlates with worse prognosis. 2First-line treatment includes beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide to reduce LVOT obstruction and managing arrhythmias, atrial fibrillation, or embolic risk.Despite medical therapy, up to 50% of patients remain symptomatic and/or exhibit significant LVOT obstruction. 3Septal reduction therapies such as surgical myectomy or alcohol septal ablation are in those cases requiredprocedures carrying risks even in experienced centers. 4cently, European cardiomyopathies guidelines incorporated myosin ATPase inhibitors, such as mavacamten, as a novel alternative therapy.Objective: To describe the initial experience of a national referral centre for familial cardiomyopathies using mavacamten in the treatment of HOCM. Methods:A retrospective, single-centre study was conducted including patients with HOCM treated with mavacamten.Clinical and demographic data were collected at baseline and during follow-up, including left ventricular ejection fraction (LVEF), peak LVOT gradient, NT-proBNP, highsensitivity troponin T, NYHA functional class, and 6-minute walk test.Adherence and tolerance to therapy were assessed.Follow-up occurred at 4, 8, and 12 weeks, with extended data at 18 and 24 weeks for some patients.Results: 8 patients were included.All started mavacamten at 5 mg/day.None required dose reduction due to LVEF deterioration, and the drug was well tolerated without significant adverse effects.All patients experienced marked clinical and functional improvement, with a reduction in LVOT gradients and NT-proBNP levels.Notably, all reached NYHA class I-II, and none required invasive septal reduction therapy (see table ).The cohort was clinically and genetically heterogeneous, supporting the efficacy of the new treatment. Conclusion:This case series demonstrates that mavacamten is a safe and effective non-invasive treatment option for symptomatic HOCM patients in a real-world setting.The observed improvements in clinical status, biomarkers, and echocardiographic parameters align with findings from clinical trials.Mavacamten may reduce the need for invasive septal reduction in appropriately selected patients.
2026-03-01 | PO54 Phenotype and outcome of Hypertrophic Cardiomyopathy patients with MYH7 Variants: a longitudinal Cohort Study
Abstract Introduction and Aim Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to delineate the clinical features and long-term cardiovascular outcome of patients with MYH7-related HCM, and to look for clinical and prognostic implications of specific variants. Methods A retrospective longitudinal analysis was conducted on 30 unrelated HCM families with pathogenic/likely pathogenic (P/LP) MYH7 mutations. A composite endpoint encompassing heart failure hospitalisation, cardiovascular admissions, or all-cause mortality was evaluated. Kaplan–Meier survival analysis was used to compare outcomes across prevalent variants and genetic profiles. Results Among 118 individuals (30 probands, 88 relatives), 77 carried P/LP MYH7 variants — 69% with HCM (G+/Ph+) at diagnosis and 31% just carriers (G+/Ph-). Thirteen P/LP variants were identified, with four (p.Ile263Thr, p.Ala797Thr, p.Glu1356Lys, p.Arg663His) accounting for two-thirds of cases. HCM patients had a mean age at diagnosis of 40.4±18.1 years and 49% were male. Baseline maximal wall thickness (MWT) was 18.6±0.8 mm, left atrial diameter (LAD) was 41.3±9.4 mm, and 23% exhibited resting left ventricular outflow tract obstruction (LVOTO); 68% had abnormal ECGs, but only one patient had atrial fibrillation (AF). Probands showed significantly larger LAD than relatives (p=0.004). A history of premature familial sudden cardiac death (SCD) was reported in 43% families. During a median follow-up of 9.5 years (IQR 3.4-24.7, range 0.2-46.8 years), 35% of patients reached the composite endpoint, including 16 deaths (1 SCD) and 6 heart failure (HF) - related hospitalisations; 30% of patients developed AF, 17% received an ICD for primary prevention of SCD and 17% had a pacemaker implantation. Older age at diagnosis (p<0.01) and increased LAD (p=0.048) predicted poorer outcomes. The composite endpoint was similar between probands and relatives with HCM (p=0.08) and across the main variants (p=0.06). Overall penetrance was 70%, with only one carrier progressing to mild HCM. ESC HCM Risk-SCD scores were similar across variants, both at baseline (p=0.60) and at last follow-up (p=0.29). Conclusion Most patients with MYH7-related HCM presented with a benign phenotype over the long term. Nonetheless, the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may help tailored management strategies.
2026-04-25 | A new insight of hypertrophic cardiomyopathy: integrated analysis of differentially expressed genes, expression quantitative trait loci, and mendelian randomization.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) has a genetic basis, with pathogenic variants identified in the majority of familial cases and unclear mechanism. This study aimed to identify the genetic contributors underlying HCM pathogenesis and to identify novel genetic targets of HCM via integrated analysis of microarray datasets. METHODS: Three independent HCM datasets were used for comprehensive analysis by using R software. Differentially expressed genes (DEGs) between HCM and control, expression quantitative trait loci (eQTL) analysis, and Two-Sample Mendelian Randomization (TSMR) analyses were performed to identify the novel genes. CIBERSORT was utilized for immune cell infiltration analysis. Finally, the identified genes were verified, and their targeted drugs were explored. RESULTS: TSMR analysis revealed that four significantly HCM co-expressed genes, TNNT1, KCNK17, GADD45B, and CXCL6, were enriched in essential biological processes and pathways, including macrophage activation and neural system regulation. TNNT1 and CXCL6 genes were validated as the novel genes, enhancing the reliability of our findings. The candidate compounds with predicted binding affinity (Atorvastatin, Zearalenone, Cotinine, and S-1,2-Dichlorovinyl-N-acetylcysteine) were predicted and molecular docking was performed to evaluate the binding ability of the drug to the protein. CONCLUSIONS: This study reveals a new molecular insight in the pathogenesis of HCM, highlighting TNNT1 and CXCL6 as candidate targets in specific molecular pathways for the interference of HCM.
2026-04-15 | Myosin Inhibitors in Hypertrophic Obstructive Cardiomyopathy: Experience with Mavacamten in a National Referral Center
Background: Hypertrophic cardiomyopathy (HCM) is defined by left ventricular wall thickening not attributable to other causes, with an estimated prevalence of 1 in 200-500 individuals.HCM is classified as obstructive (HOCM) when the left ventricular outflow tract (LVOT) gradient exceeds 30 mmHg. 1 Symptom presence correlates with worse prognosis. 2First-line treatment includes beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide to reduce LVOT obstruction and managing arrhythmias, atrial fibrillation, or embolic risk.Despite medical therapy, up to 50% of patients remain symptomatic and/or exhibit significant LVOT obstruction. 3Septal reduction therapies such as surgical myectomy or alcohol septal ablation are in those cases requiredprocedures carrying risks even in experienced centers. 4cently, European cardiomyopathies guidelines incorporated myosin ATPase inhibitors, such as mavacamten, as a novel alternative therapy.Objective: To describe the initial experience of a national referral centre for familial cardiomyopathies using mavacamten in the treatment of HOCM. Methods:A retrospective, single-centre study was conducted including patients with HOCM treated with mavacamten.Clinical and demographic data were collected at baseline and during follow-up, including left ventricular ejection fraction (LVEF), peak LVOT gradient, NT-proBNP, highsensitivity troponin T, NYHA functional class, and 6-minute walk test.Adherence and tolerance to therapy were assessed.Follow-up occurred at 4, 8, and 12 weeks, with extended data at 18 and 24 weeks for some patients.Results: 8 patients were included.All started mavacamten at 5 mg/day.None required dose reduction due to LVEF deterioration, and the drug was well tolerated without significant adverse effects.All patients experienced marked clinical and functional improvement, with a reduction in LVOT gradients and NT-proBNP levels.Notably, all reached NYHA class I-II, and none required invasive septal reduction therapy (see table ).The cohort was clinically and genetically heterogeneous, supporting the efficacy of the new treatment. Conclusion:This case series demonstrates that mavacamten is a safe and effective non-invasive treatment option for symptomatic HOCM patients in a real-world setting.The observed improvements in clinical status, biomarkers, and echocardiographic parameters align with findings from clinical trials.Mavacamten may reduce the need for invasive septal reduction in appropriately selected patients.
2026-03-01 | PO54 Phenotype and outcome of Hypertrophic Cardiomyopathy patients with MYH7 Variants: a longitudinal Cohort Study
Abstract Introduction and Aim Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to delineate the clinical features and long-term cardiovascular outcome of patients with MYH7-related HCM, and to look for clinical and prognostic implications of specific variants. Methods A retrospective longitudinal analysis was conducted on 30 unrelated HCM families with pathogenic/likely pathogenic (P/LP) MYH7 mutations. A composite endpoint encompassing heart failure hospitalisation, cardiovascular admissions, or all-cause mortality was evaluated. Kaplan–Meier survival analysis was used to compare outcomes across prevalent variants and genetic profiles. Results Among 118 individuals (30 probands, 88 relatives), 77 carried P/LP MYH7 variants — 69% with HCM (G+/Ph+) at diagnosis and 31% just carriers (G+/Ph-). Thirteen P/LP variants were identified, with four (p.Ile263Thr, p.Ala797Thr, p.Glu1356Lys, p.Arg663His) accounting for two-thirds of cases. HCM patients had a mean age at diagnosis of 40.4±18.1 years and 49% were male. Baseline maximal wall thickness (MWT) was 18.6±0.8 mm, left atrial diameter (LAD) was 41.3±9.4 mm, and 23% exhibited resting left ventricular outflow tract obstruction (LVOTO); 68% had abnormal ECGs, but only one patient had atrial fibrillation (AF). Probands showed significantly larger LAD than relatives (p=0.004). A history of premature familial sudden cardiac death (SCD) was reported in 43% families. During a median follow-up of 9.5 years (IQR 3.4-24.7, range 0.2-46.8 years), 35% of patients reached the composite endpoint, including 16 deaths (1 SCD) and 6 heart failure (HF) - related hospitalisations; 30% of patients developed AF, 17% received an ICD for primary prevention of SCD and 17% had a pacemaker implantation. Older age at diagnosis (p<0.01) and increased LAD (p=0.048) predicted poorer outcomes. The composite endpoint was similar between probands and relatives with HCM (p=0.08) and across the main variants (p=0.06). Overall penetrance was 70%, with only one carrier progressing to mild HCM. ESC HCM Risk-SCD scores were similar across variants, both at baseline (p=0.60) and at last follow-up (p=0.29). Conclusion Most patients with MYH7-related HCM presented with a benign phenotype over the long term. Nonetheless, the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may help tailored management strategies.
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Drug Discovery Landscape
3 orphan drug designations for Rare familial disorder with hypertrophic cardiomyopathy.
3 orphan drug designations for Rare familial disorder with hypertrophic cardiomyopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
non-replicating AAV-based gene therapy vector with a single stranded DNA genome engineered to carry an expression cassette encoding for human cardiac myosin binding protein-C (cMyBP-C; hMYBPC3 transgene) | gene therapies | FDA | 2023-09-26 | — | BioMarin Pharmaceutical Inc. |
Adeno-associated virus serotype 9 containing human MYBPC3 gene | gene therapies | EMA | 2022-04-13 | — | Yes Pharmaceutical Development Services GmbH |
a native AAV9 capsid with a genomic cassette containing a cardiomyocyte-specific promoter and the wild-type human MYBPC3 gene | gene therapies | FDA | 2021-05-12 | — | Tenaya Therapeutics |
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