Aug 2026· Revista Portuguesa de Cardiologia· 0 citations
Medicine
Abstract
INTRODUCTION AND
Objectives
Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in the MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to outline 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 hospitalisation for heart failure, 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 were carriers of P/LP MYH7 variants - 69% with HCM (G+/Ph+) at diagnosis and 31% P/LP MYH7 variant carriers only (G+/Ph-). Thirteen different P/LP variants were identified in the 30 families, 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=0.601) and at last follow-up (p=0.286).
Conclusions
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 potentially help tailored management strategies.
BACKGROUND
Periodic reinterpretation of variants associated with hypertrophic cardiomyopathy (HCM) is recommended in the light of evolving knowledge, but it requires considerable resources, and its clinical impact is unresolved.
OBJECTIVES
We here report the results of a systematic variant reclassification of HCM-associated variants identified at a national referral center, and the impact on clinical profiling.
METHODS
A total of 805 consecutive probands with a definite HCM diagnosis genotyped in 1998-2023 (overall 276 variants: 162 pathogenic/likely pathogenic -P/LP-, 109 variants of uncertain significance -VUS-, and 5 benign/likely benign - B/LB) underwent variant reclassification. All were analyzed for all-cause death, ventricular arrhythmia composite (sudden death, cardiac arrest, appropriate implantable cardioverter-defibrillator therapy), atrial fibrillation or cerebrovascular events, heart failure composite (NYHA class III/IV, left ventricular ejection fraction <35%, cardiac transplantation).
RESULTS
After a median follow-up of 8.8 [6.1-11.8] years, among the 276 variants, 61 (22.1%) were reclassified: 29 variants from P/LP to VUS or B/LB, 21 from VUS to P/LP, and 11 from VUS to B/LB, affecting 69 patients overall. The overall yield of genetic testing (% with P/LP) changed from 58.7 to 55.4%. At survival analysis, HRs associated with P/LP status improved after reclassification for both all-cause death and ventricular arrhythmia. No changes were observed for the other outcomes.
CONCLUSION
Systematic reclassification of genetic variants led to a refinement of variant classification accuracy due to downgrading of 5.5% of P/LP variants, although 18.3%VUS/B/LB were upgraded to P/LP. Reclassification more accurately identified risks associated with P/LP status, compared to the initial adjudication.
A. Del Franco, Valeria Setti, Federica Colio et al.· International Journal of Car...· 0 citations
BACKGROUND
Genetic mutations causing dysregulation of the RAS/mitogen-activated protein kinase pathway contribute to hypertrophic cardiomyopathy (HCM). Genotype-phenotype associations in this population remain poorly understood. This study aimed to evaluate the impact of RASopathy subtype on cardiovascular outcomes.
METHODS
We included 24 patients diagnosed with RAS signaling pathway mutations and HCM (RAS-HCM) before age 18. Data on sociodemographic, prenatal, clinical, genetic, and echocardiographic parameters were retrospectively collected from medical records spanning 2004-2024. Death, heart failure (HF), transplant (Ts), and use of implantable cardioverter defibrillator (ICD) were also evaluated.
RESULTS
Median age at HCM diagnosis was 0.42 years (IQR 7.1); median follow-up was 8.5 years. Patients were classified into Noonan syndrome (62.5%) and other RASopathies (37.5%). Pathogenic mutations were identified in PTPN11 (38%), RAF1 and BRAF (17% each), and SOS1 and RIT1 (13% each). Patients with Noonan syndrome underwent significantly more therapeutic strategies (p = 0.026). Increased end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) were linked to the development of HF (p = 0.006, p = 0.007; respectively), while increased IVSd was associated with higher mortality (p = 0.013).
CONCLUSIONS
Echocardiographic parameters (IVSd and LVPWd), and RASopathy subtype may serve as prognostic indicators in pediatric RAS-HCM patients. Further studies are warranted to elucidate the underlying molecular mechanisms.
IMPACT
Demonstrates that RASopathy subtype may influence hypertrophic cardiomyopathy (HCM) progression and clinical outcomes in pediatric patients. Identifies end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) as critical echocardiographic predictors of heart failure and cardiac mortality from early stages. Supports early genetic testing and echocardiographic monitoring to guide personalized care in pediatric RASopathies.
J. L. López-Guillén, A. Carcavilla, Jesús Díez-Sebastián et al.· Pediatric Research· 0 citations
Background: Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives: We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods: Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results: Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 {+/-} 5.0 vs. 20.0 {+/-} 4.4mm, P<0.01) and indexed LV mass (81.9 {+/-} 26.0 vs. 71.7 {+/-} 13.3g/m2, P<0.001). Of the former, MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 {+/-} 5.2 vs. 20.9 {+/-} 4.5mm, P<0.01) but lower LV ejection fraction (63.1 {+/-} 8.4 vs. 65.3 {+/-} 8.4%, P<0.001). Findings remained significant after covariate adjustment and meta-analysis. 23 (~1%) patients had >1 disease-linked variants with only 3 (~0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions: In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity.
J. H. Chan, C. Grace, K. Thomson et al.· medRxiv· 0 citations
INTRODUCTION
Hypertrophic cardiomyopathy is an inherited cardiovascular disease with heterogeneous presentation. However, the metabolic changes resulting from mutations and their relationship to the phenotype remain unclear.
OBJECTIVES
To investigate the association between TNNI3 and MYBPC3 variants and both clinical phenotype and metabolic disorders in HCM patients.
METHODS
34 newly diagnosed HCM patients, 51 healthy individuals, and 23 unaffected family members were included. Clinical information and plasma samples were collected and analyzed. Whole-exome and Sanger sequencing were used for variant identification. Non-targeted metabolomics was performed using ultra-high-performance liquid chromatography-high-resolution mass spectrometry.
RESULTS
TNNI3 and MYBPC3 variants were identified in familial HCM cases, which exhibited earlier onset and increased interventricular septum thickness. Metabolomics revealed lower L-valine and higher free fatty acid levels in HCM patients. Patients with TNNI3 variants showed dysregulation of lyso-phosphatidylcholines and lyso-phosphatidylethanolamines, along with disturbances in glutamic acid-related pathways. MYBPC3 variants were linked to dysregulation in energy metabolism. Correlation analysis highlighted associations between specific lipid metabolites and cardiac structure and function.
CONCLUSION
Significant metabolic alterations, particularly in amino acid and lipid metabolism, are prevalent in HCM. These findings enhance our understanding of HCM pathogenesis and suggest potential biomarkers and therapeutic targets for this genetic heart disease.
Hao Wu, Qiu-Yue Yu, Huimin Li et al.· BMC Cardiovascular Disorders· 0 citations
BACKGROUND
Idiopathic dilated cardiomyopathy (DCM) is a major cause of advanced heart failure and heart transplantation (HTx), yet the genetic correlates of progression to HTx and transplant-relevant arrhythmic phenotypes remain incompletely defined. We examined the genetics of idiopathic DCM in a Korean population, focusing on HTx/death and arrhythmic outcomes, to identify adverse outcome-linked genotype-phenotype associations.
METHODS
Whole-exome sequencing was performed in 202 Korean patients with idiopathic DCM including 56 HTx recipients and 146 ambulatory patients, and compared the findings with 1,093 population-based controls. Genotype-phenotype correlations were analyzed for major clinical outcomes, including HTx, death, arrhythmias, and left ventricular functional recovery.
RESULTS
Pathogenic/likely pathogenic variants were identified in 32% of patients (38% in HTx vs. 30% in ambulatory patients). TTN was the most frequently affected gene overall (12%), but LMNA variants predominated in HTx recipients (20% vs. 4%, p=0.001). LMNA carriers showed substantially higher odds of HTx/death (OR 14.65, 95% CI 3.32-139.31; FDR p<0.001), and strong association with arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation. Both missense and loss-of-function LMNA variants were associated with adverse outcomes. In contrast, TNNT2 variants were observed exclusively in ambulatory patients and identified a favourable functional-recovery phenotype, with a greater likelihood of LVEF recovery ≥10 percentage points (OR 6.03, 95% CI 1.52-28.71; FDR p=0.016).
CONCLUSIONS
LMNA variants mark a high-risk transplant-trajectory phenotype in Korean idiopathic DCM. Genetic testing may aid early identification and management of candidates for advanced HF therapies, including HTx and durable MCS.
Juhye Lee, Jinhwa Kong, Seulgi Kim et al.· The Journal of Heart and Lun...· 0 citations
As the first genetic study of hypertrophic cardiomyopathy in an Egyptian population, this work expands the global mutational spectrum, demonstrates the utility of genetic testing for risk stratification and personalised management, and underscores the need to diversify genomic datasets for equitable precision medicine.
Rana E Negm, R. Gabre, A. A. El‐Sherif et al.· Cardiology in the Young· 0 citations
