Family screening for hypertrophic cardiomyopathy: Initial cardiologic assessment, and long-term follow-up of genotype-positive phenotype-negative individuals

Aims: (i) Investigate the prevalence of hypertrophic cardiomyopathy (HCM) in individuals with pathogenic/likely pathogenic (P/LP) gene variants detected through family cascade testing in relatives, and (ii) evaluate phenotypic progression in genotype-positive phenotype-negative (G+/P-) individuals during follow-up.

Results: From 2000 to 2023, 273 individuals underwent cardiologic evaluation following P/LP variant detection through family screening. Upon initial evaluation, HCM was diagnosed in 128 (47 %) individuals. Comparing with 145 G+/P- individuals, HCM patients were older (48 vs 38 years, p < 0.001) and more likely male (57 % vs 34 %, p < 0.001). During follow-up (median 11 years), 14 (11 %) of the HCM patients died (two from sudden cardiac death), four (3 %) underwent myectomy, 15 (12 %) developed atrial fibrillation and 17 (13 %) required implantable cardioverter-defibrillator implantation (15 primary prevention, 88 %). HCM-related adverse outcomes correlated with younger diagnosis age. During follow-up (median 8 years) of 118 (out of 145) G+/P- subjects with at least one year of follow-up, seven (6 %) individuals (71 % female, diagnosed age 39-77, after median follow-up 6 years) developed HCM (mean maximal wall thickness increasing from 10.2 mm to 13.3 mm). In this G+/P- cohort, significant echocardiographic changes from baseline to last visit were negligible. Over half (56 %) had <1 mm change of maximal wall thickness. No adverse cardiac outcomes occurred.

Conclusion: The initial evaluation was high-yield, with HCM being diagnosed in 47 % of G+ individuals, more frequently in older males. Over a median 8-year follow-up, 6 % of G+/P- individuals developed mild HCM, with no adverse cardiac outcomes. These data support initial screening in all first degree relatives, but (very) low-frequency cardiologic evaluations for G+/P- individuals thereafter.