Phenotypic impact of sarcomeric versus non-sarcomeric genetic variants in hypertrophic cardiomyopathy: a real-world analysis

Introduction

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disease, most commonly caused by sarcomeric gene variants, although non-sarcomeric pathogenic variants are increasingly recognized. Whether these distinct genetic substrates translate into different phenotypic expressions in real-world HCM populations remains incompletely understood.

Purpose

To compare phenotypic expression between sarcomeric and non-sarcomeric pathogenic or likely pathogenic (P/LP) variants in a real-world HCM population.

Methods

We conducted a retrospective singer-centre analysis including HCM pts followed at cardiomyopathy’s clinic from a tertiary hospital. Presumed HCM phenocopies were excluded. Data was collected from electronic medical records.

Results

Among 165 HCM pts, 59 (35.8%) genotype-positive pts were included – 48 (81.4%) with sarcomeric variants and 11 (18.6%) with non-sarcomeric variants. In sarcomeric pts, thick-filament protein mutations accounted for most P/LP variants (n=33, 55.9%).

Mostly male (n=30, 51%; p= 0.786), with age diagnosis 42 ± 20 years (p=0.376), without family history of HCM (n=26, 44.4%; p= 0.778) or sudden cardiac death at young age (n=50, 84.7%; p=1). A modest association regarding to the context of HCM diagnosis (Crámer’s V = 0.352) was observed, with sarcomeric pts were more frequently diagnosed during routine evaluation (n=19, 39.6%), while non-sarcomeric were firstly diagnosed due to familial screening (n=5, 45.5%), p=0.043. Both groups had similar prevalence of cardiovascular risk factors.

Regarding to imaging parameters, no major differences were also found, with asymmetrical interventricular hypertrophy as a predominant phenotype (n=50, 84.7%; p=0.275) and evidence of extensive fibrosis (late gadolinium enhancement ≥ 15% in 31%, p= 0.410). Almost one-third was diagnosed with atrial fibrillation, (n=18, 30.5%; p=0.284), with similar time to onset after HCM diagnosis 13 ± 18 years (p=0.084).

At median follow up time of 8 (IQR 10) years, 16.9% were proposed for implantable cardioverter-defibrillator and 23.7% experienced adverse cardiovascular events (p=0.432), similar overall.

Conclusion

In this real-world HCM cohort, sarcomeric and non-sarcomeric P/LP variants were associated with largely overlapping clinical, imaging, and outcome profiles. Apart from differences in the context of diagnosis, phenotypic expression and adverse cardiovascular events were comparable, highlighting the need for individualized risk stratification beyond genetic categorization alone.