Family Screening in Hypertrophic Cardiomyopathy: Identification of Relatives With Low Yield From Systematic Follow-Up

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease, and clinical and genetic family screening is recommended by guidelines.

Objectives: This study sought to investigate the diagnostic yield of screening relatives of HCM patients and identify predictive factors for HCM development during long-term follow-up in relatives from gene-elusive families.

Methods: This was a retrospective cohort study of families screened at clinics for inherited cardiomyopathies in Eastern Denmark, from 2006 to 2023.

Results: We included 1,230 relatives (55% female; age: 42 ± 17 years) from 531 families. The combined clinical and genetic yield at baseline was 26% (n = 321). After 7 years (mean) of follow-up (6,762 person-years), 43 (4%) additional relatives developed HCM. The strongest predictors of developing HCM were carrying a likely pathogenic/pathogenic variant (HR: 4.58; 95% CI: 2.50-8.40; P < 0.001) and larger left ventricular maximum wall thickness (MWT) (HR: 2.21 per mm; 95% CI: 1.76-2.77 per mm; P < 0.001). In gene-elusive families, we found that an MWT of ≥10 mm represented the optimal classification threshold for developing HCM (area under the curve: 0.80), with only 2 (0.4%) relatives from gene-elusive families with an MWT of <10 mm developing HCM during follow-up.

Conclusions: In HCM, the diagnostic yield of a single screening visit was 1 in 4, and the additional yield during 7 years of follow-up was 4%. Gene carriers and relatives from gene-elusive families with a baseline MWT of ≥10 mm were at the highest risk of developing HCM during follow-up. These findings may inform future recommendations on the management of relatives of HCM patients.

Keywords: family screening; genetics; hypertrophic cardiomyopathy.