Are variants of uncertain significance clinically equivalent to genotype-negative status in hypertrophic cardiomyopathy? A single-center analysis

Background

The clinical relevance of variants of uncertain significance (VUS) in hypertrophic cardiomyopathy (HCM) remains unclear, despite growing interest with the advent of genotype-guided therapies.

Purpose

To assess whether carriers of VUS differ phenotypically and prognostically from genotype-negative HCM patients (pts).

Methods

A single-center retrospective study including HCM pts followed at a dedicated cardiomyopathies consultation. HCM phenocopies and pts without genetic testing were excluded. Data were obtained from medical records review. Pts were categorized as VUS carriers or genotype-negative (GN).

Results

Among 134 HCM pts, 75 were included: 35 (46.7%) with VUS and 40 (53.3%) GN. Most VUS were in sarcomeric genes (60%) – mainly in β-myosin heavy chain - MYH7 (20%); 23% carried ≥ 2 concomitant VUS.

Baseline characteristics were similar in VUS and GN pts, namely male sex predominance (57.3%; p=0.333), age of diagnosis (57 ± 18 years, p=0.953) and initial assessment due to routine cardiovascular (CV) screening (52%; p=0.686). The majority had no family history of HCM or sudden cardiac death (p=0.377 and p=0.679, respectively). 72% had an asymmetrical septal hypertrophy phenotype (p=0.075), with obstructive physiology in 36% (p= 0.247).

At mean follow-up of 8 ± 6 years (p=0.342), functional status, cardiac biomarkers, imaging features and medical therapy were similar.

Most were in class I of New York Heart Association (p=0.491), with preserved left ventricle (LV) ejection fraction (57± 9%; p=0.415) but impaired left ventricle (LV) global longitudinal strain (-14 ± 5%; p=0.997).

Maximal LV wall thickness was 17±4 mm (p=0.827) and 31% had systolic anterior motion of mitral valve anterior leaflet (p=0.894), with LV outflow tract obstruction in 29.3% (p=0.384). 71% (p=0.553) and 11.1% (p= 0.858) were under beta-blocker and cardiac myosin inhibitors therapies, respectively.

Myocardial fibrosis was present in 77% (p=0.738), predominantly intramyocardial, with extensive (≥ 15%) late-gadolinium enhancement (LGE) in nearly half (p=0.380).

Clinical outcomes also did not differ – 24% developed atrial fibrillation (AF; p=0.448) in 7 ± 6 years from initial diagnosis (p=0.794), implantable cardioverter defibrillator (ICD) implantation occurred in 16% (p=0.312) and 33% experienced at least one adverse CV event (p=0.413), with similar survival across VUS and GN pts – figure 1. Urgent visits due to AF with rapid ventricular response (8%; p= 0.403) and ischemic events (8%; p=0.597) were the most frequent contributors.

Conclusion

In our real-world HCM cohort, VUS carriers showed comparable phenotypic expression and clinical outcomes to GN pts. These findings support current guidelines, without evidence for VUS-specific management beyond periodic variant re-evaluation. Further studies, including the integration of polygenic risk scores, are needed to better clarify the role of VUS in HCM.For image description, please refer to the figure legend and surrounding text.