Higher-grade pathogenic variants in obstructive hypertrophic cardiomyopathy were associated with more severe histopathological damage, earlier diagnosis, and pronounced clinical and rhythm alterations.
Cohort (n=193)
Does variant pathogenicity correlate with histopathological damage and clinical severity in patients with obstructive hypertrophic cardiomyopathy?
Higher-grade pathogenic variants in HOCM are associated with more severe histopathological changes, earlier diagnosis, and pronounced clinical alterations, highlighting a genotype-histology-phenotype interplay.
BACKGROUND: While genotype has been related to specific clinical phenotype in hypertrophic cardiomyopathy (HCM), the critical intervening role of histopathological damage remains unclear. Specifically, how graded variant pathogenicity drives the spectrum of myocardial tissue alterations, which in turn mediate the severity and precocity of clinical features is poorly defined. METHODS: A 93-cardiomyopathy-related-gene panel was used to screen 193 Chinese Obstructive Hypertrophic Cardiomyopathy (HOCM) patients. In this study, "genetic variants" were classified into four categories: Pathogenic(P), Likely Pathogenic (LP), and variants of unknown significance (VUS), an additional tier of VUS-LP. The histopathological alterations were evaluated using 172 septal tissue sections with HE and Masson trichromatic staining. Through comprehensive case review and longitudinal follow-up, we investigated the genotype-phenotype correlations, focusing on the mediating role of myocardial histology in shaping clinical presentation and outcomes. RESULTS: The median age at operation was 40.2 years, and 111 (57.5%) were men. Compared with the patients with VUS and no variants, those with LP/P and VUS-LP variants exhibited relatively severe phenotypes including earlier diagnosis age and greater asymmetric hypertrophy, and significantly worse histopathological alterations. The existence of the variant, regardless of the number, was also related to similar severe effects. Pathogenic variants and more severe histological changes were associated with an aggravated clinical phenotype, including prolonged QRS duration and elevated NT-proBNP revealing a genotype-histology-phenotype interplay in HOCM. Among patients with a family history of sudden death, the LP/P variant detection rate was 71.4% (10/14). CONCLUSIONS: Core gene panel sequencing represents an efficacious approach for genetic testing in individuals with hypertrophic cardiomyopathy (HCM). Among those at elevated risk for sudden cardiac death, there is a higher prevalence of pathogenic variants. Patients harboring higher-grade pathogenic variants demonstrate more severe pathological changes and exhibit more pronounced alterations in cardiac rhythm and clinical parameters. The consistent "fibrosis-dominant" remodeling observed in patients with variants of uncertain significance likely pathogenic (VUS-LP) indicates that histopathological severity may serve as an auxiliary phenotypic metric for the future re-evaluation of such variants. Consequently, the integration of genetic testing results with a multidisciplinary assessment of phenotypes-including clinical, pathological, and laboratory findings-is essential for guiding disease management in HCM.
Yin et al. (Wed,) conducted a cohort in Obstructive Hypertrophic Cardiomyopathy (HOCM) (n=193). Pathogenic, likely pathogenic, or VUS-LP genetic variants vs. Variants of unknown significance (VUS) or no variants was evaluated on Clinical phenotype severity and histopathological alterations. Higher-grade pathogenic variants in obstructive hypertrophic cardiomyopathy were associated with more severe histopathological damage, earlier diagnosis, and pronounced clinical and rhythm alterations.