Key result
Genotype-negative familial HCM shows intermediate features but no difference in composite outcomes.
Why the study?
A substantial proportion of HCM patients with negative genetic testing have a positive family history, suggesting a stronger genetic component that requires phenotypic and prognostic characterization.
Do genotype-negative HCM patients with a positive family history differ in phenotype and prognosis compared to those without a family history or those who are gene-positive?
Cohort (n=654)
No
Do genotype-negative HCM patients with a positive family history differ in phenotype and prognosis compared to those without a family history or those who are gene-positive?
Genotype-negative HCM patients with a positive family history exhibit an intermediate clinical phenotype between gene-positive and genotype-negative/family history-negative patients, but share a similar overall prognosis.
BACKGROUND: A substantial proportion of hypertrophic cardiomyopathy (HCM) patients and negative genetic testing (Sarc-) have a positive family history of HCM (FH), suggesting a stronger genetic component. OBJECTIVES: The purpose of this study was to assess whether Sarc-/FH+ patients differ from Sarc-/FH- and gene-positive (Sarc+) patients in terms of phenotype and prognosis. METHODS: A total of 654 HCM patients underwent comprehensive clinical assessment and genetic testing, followed for a median of 6 years. The 3 groups (Sarc-/FH-, Sarc-/FH+, Sarc+) were compared for major arrhythmic events, heart failure, all-cause death, atrial fibrillation, and stroke. RESULTS: Of the 654 patients, 182 were Sarc-/FH- (28%), 101 were Sarc-/FH+ (15%), and 371 were Sarc+ (57%). Sarc-/FH+ were similar to Sarc+: they were younger, with higher HCM risk sudden cardiac death and lower prevalence of obstruction (age 43 [IQR: 23-53] years vs 39 [IQR: 23-52] years; P = 0.235; 19% obstructive vs 18%; P = 0.763) compared to Sarc-/FH-. However, Sarc-/FH+ were akin to Sarc-/FH- due to the lower prevalence of female sex, higher burden of cardiovascular risk factors, and less prevalent late gadolinium enhancement at cardiac magnetic resonance imaging (for female prevalence 26% vs 27%; P = 0.829; for late gadolinium enhancement in 50% vs 53%; P = 0.541), compared to Sarc+. There were no significant outcome differences, except for the incidence of stroke (2.7% for Sarc-/FH-, 1% for Sarc-/FH+, 5.9% for Sarc+, P = 0.046). CONCLUSIONS: Sarc-/FH+ represented 15% of our HCM cohort and exhibited intermediate clinical features between Sarc-/FH- and Sarc+, suggesting an interplay of monogenic/oligogenic disease with environmental factors. This population provides a unique opportunity for gene discovery and an understanding of nongenetic modifiers of HCM, deserving of dedicated investigation.
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Bonanni et al. (2025) conducted a cohort in Hypertrophic cardiomyopathy (n=654). Genotype-negative with positive family history (Sarc-/FH+) vs. Genotype-positive (Sarc+) and Genotype-negative without family history (Sarc-/FH-) was evaluated on Overall composite outcome (heart failure, major arrhythmic events, all-cause death, new-onset atrial fibrillation, or stroke) (HR 1.13, 95% CI 0.69-1.84, p=0.635). Genotype-negative patients with a positive family history of hypertrophic cardiomyopathy exhibited intermediate clinical features between Sarc-/FH- and Sarc+ patients, with no significant differences in overall composite outcomes.
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