Aug 2026· International Journal of Cardiology· pp.
134718
· 0 citations· 20 references
Medicine
TL;DR
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.
Abstract
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.
Background: Genetic testing is a Class I recommendation for patients with hypertrophic cardiomyopathy (HCM). As knowledge and frameworks continue to evolve, genetic variant classifications may change with new evidence over time. Classifications rely on evidence sought from publicly available case data, improved classification rules, and gene-disease validity. We evaluated the frequency and reasons for variant reclassification from a large multi-center international HCM registry (Sarcomeric Human Cardiomyopathy Registry; SHaRe). Methods: Participants were clinically evaluated at specialised HCM centres. Genetic variants were sought from the genetic test report, with classifications based on either the initial report, an updated report or some underwent further SHaRe adjudication. All variants were computationally reannotated and reevaluated. Variants underwent expedited curation if no new evidence was present. The remainder underwent full manual curation using accepted criteria and classified as pathogenic/likely pathogenic (P/LP), variant of uncertain significance (VUS) and benign/likely benign (B/LB). Results: Of 12,187 HCM patients, 8,054 (66%) had genetic testing between 1989-2020, and 4,923 (61%) had a variant identified in one of 29 HCM genes (1606 unique variants). Expedited curation was performed for 704 (44%) variants and 902 (56%) underwent manual curation. There were 1275 (79%) variants that retained their classification: 146 B/LB, 660 VUS, and 468 P/LP. While 276 (17%) variants (n=672 patients) were reclassified (n=276), including 73 upgrades: 61 from VUS to P/LP (199 patients), and 12 from B/LB to VUS. There were 203 downgrades: 108 from P/LP to VUS (n=196 patients), and 95 from P/LP or VUS to B/LB. VUS were additionally subclassified: 90 VUS-High, 129 VUS-Mid, 115 VUS-Low. Sub-classification of VUS resulted in less uncertainty, with 369 (40.6%) variants reclassified as VUS-Low or B/LB, indicating a very strong probability of not being HCM associated. Conclusions: Clinically meaningful reclassification occurred in 10% of variants identified in HCM probands. Most VUS were unlikely to be causal, and sub-classification has potential to reduce their burden on clinicians and families. Periodic reevaluation is essential for accurate clinical interpretation.
S. Hespe, G. Powell, L. Catto et al.· medRxiv· 0 citations
Most patients with MYH7-related HCM presented with a benign phenotype over the long term, and 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.
Catarina Gregório, M. Vilela, Ana Beatriz Garcia et al.· Revista Portuguesa de Cardio...· 0 citations
clinical monitoring. Patients with sarcomeric variants generally have worse prognosis than those without, including earlier disease onset and higher rates of sudden cardiac death, heart failure and arrhythmias. 3 Historically, HCM was regarded as a monogenic disorder caused by pathogenic variants in sarcomeric genes. While MYH7 and MYBPC3 continue to account for the majority of genetically confirmed cases, contemporary research has revealed a more complex and heterogeneous genetic architecture. Recent gene re-evaluations and variant reclassifications have highlighted the role of non-sarcomeric genes, including FHOD3 , ALPK3 , CSRP3 and TRIM63 , as contributors to HCM phenotypes. 3 Common genetic variants play a substantial role in HCM susceptibility and disease expression, with genome-wide association studies identifying 70 susceptibility loci associated with HCM risk. Polygenic risk scores derived from these common variants significantly modify disease penetrance, severity and outcomes, particularly in pathogenic variant carriers where penetrance differs. 3 These findings have important implications for clinical practice; they reinforce the concept of HCM as a spectrum of diseases rather than a single genetic entity, setting the stage for more individualised approaches to diagnosis, counselling and management.
Clara Saldarriaga· Cardiac failure review· 0 citations
Background In dilated (DCM) and arrhythmogenic cardiomyopathies (ACM), monogenic variants in causative genes are key prognostic factors. In the general population, the clinical role of these variants remains debated. Objectives This study aimed to determine the association between rare, predicted deleterious variants (PDrV) in DCM- and ACM-associated genes and disease-related outcomes in the general population. Methods Using United Kingdom Biobank whole-exome sequencing data, we identified PDrVs in 25 DCM/ACM-validated genes. We assessed disease penetrance in carriers and their risk for two primary outcomes—sudden cardiac death/malignant ventricular arrhythmias (SCD/MVA) and heart failure death/heart transplant (HF/HT)—using cause-specific Cox models accounting for competing risks. Results Among 469,671 participants, 54.2% were females and the median age at baseline was 53.5 (IQR: 10.3). During a median follow-up of 14 years (IQR: 2), 5786 SCD/MVA and 4611 HF/HT events occurred. A PDrV was found in 12,973 (2.8%) individuals. Despite low penetrance for DCM (1.0%), PDrV impacted on both outcomes. Compared to noncarriers, PDrV carriers had a higher risk of SCD/MVA (HR: 1.28; 95% CI: 1.11-1.48). In participants free from DCM or other heart diseases at recruitment, SCD/MVA risk was solely associated with ACM genes (HR: 1.34; 95% CI: 1.07-1.69). Carriers also exhibited a higher risk of HF/HT (HR: 1.32; 95% CI: 1.08-1.62), which was not confirmed in subgroup without other heart diseases. Conclusions PDrV carriers have a higher risk of severe cardiac events, even without a clinical overt disease phenotype at baseline evaluation. Moreover, PDrV in arrhythmic genes significantly influence SCD/MVA risk, regardless of phenotypic diagnosis of DCM.
I. Gandin, A. Vergani, M. Massi et al.· JACC: Advances· 0 citations
BACKGROUND
Dilated cardiomyopathy (DCM) exhibits substantial genotypic heterogeneity, paralleled by diverse cardiac magnetic resonance (CMR) phenotypes and clinical presentations. However, the specific genotype-phenotype associations underlying this heterogeneity remain incompletely clear.
METHODS
Ninety DCM patients were prospectively enrolled and stratified into three subtypes: high-risk arrhythmogenic variant carriers (HRAv, n = 30), TTN truncating variant carriers (TTNtv, n = 30), and genotype-negative patients (GN, n = 30). High-risk arrhythmogenic variants were identified as DSP, FLNC, LMNA, and PLN variants. Comprehensive CMR parameter comparisons and logistic regression analyses were performed to identify the associations between genotypes and CMR features.
RESULTS
Among 90 participants (mean age, 46 years; 54 men), no significant differences were observed in ventricular volumes, systolic functions or LV strain among subtypes. HRAv patients presented with a higher prevalence of LGE (83%) compared with TTNtv (13%) and GN (40%) (p < 0.001), with typical linear midwall, ring-like, and subepicardial patterns. Global native T1 mapping(1379 vs. 1329 vs. 1335 ms, p = 0.037), T2 mapping (46.3 vs. 44.1 vs. 42.8 ms, p < 0.001), and extracellular volume (ECV)(35.8 vs. 31.3 vs. 30.5%, p < 0.001) were significantly elevated in HRAv compared with TTNtv and GN. In Firth penalized logistic regression models, higher global T2 (odds ratio[OR] = 1.22, 95%CI: 1.06-1.43, p = 0.004), higher global ECV(OR = 1.45, 95%CI: 1.17-1.86, p < 0.001), and LGE presence(OR = 9.22, 95%CI: 3.26-29.81, p < 0.001) were independently associated with HRAv status when separately added to the baseline model.
CONCLUSION
Compared with TTNtv and genotype-negative DCM, HRAv is characterized by a distinct CMR tissue phenotype marked by more extensive myocardial injury and fibrosis, despite similar ventricular remodeling and systolic impairment. These findings suggest that CMR tissue characterization may help identify genotype-associated phenotypic differences in DCM.
Zhi-Gang Zhang, Yang-Jie Li, Yuan-Wei Xu et al.· International Journal of Car...· 0 citations
Background Genetic testing (GT) is established in ambulatory cardiomyopathy (CM), but its utility after heart transplantation (HTx) recipients remains poorly characterized. Objectives This study aimed to evaluate the clinical utility of GT in adult HTx recipients with CM, focusing on etiologic reclassification, family cascade screening, and the genetic architecture of end-stage disease. Methods GenbaseHTx is a nationwide, multicenter retrospective study of adult HTx recipients transplanted for CM across 12 Spanish centers (2010-2023). GT results were centrally adjudicated using American College of Medical Genetics and Genomics criteria. Outcomes included prevalence of pathogenic/likely pathogenic variants, etiologic reclassification after GT, and cascade screening activation. Results Among 657 HTx recipients, a pathogenic/likely pathogenic variant was identified in 53% (351/657). GT led to etiologic reclassification in 35% (231/657) (42% when performed post-HTx −106/253-). Family screening (performed in 69% of families −224/328-) identified affected relatives in 22% (19/90) of genotype-negative and 42% (49/107) of genotype-positive cases. Notably, a genetic etiology was identified in 36% (15/42) of CM initially attributed to acquired or “second-hit” causes. In dilated cardiomyopathy, the genetic architecture of transplanted patients differed from ambulatory cohorts, with lower TTN variant prevalence and enrichment of arrhythmogenic genes. Conclusions GT remains clinically actionable after HTx, enabling etiologic reclassification and driving cascade screening. These findings support systematic GT in HTx recipients with CM, including those with prior environmental triggers or second-hit etiologies, and regardless of time from transplantation.
C. Moliner-Abós, D. C. Cabrera Argana, David Belmar Cliville et al.· JACC: Advances· 2 citations
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