Family Screening and Disease Predictors in Gene-Elusive Dilated Cardiomyopathy.

Background

Family screening is recommended in dilated cardiomyopathy (DCM), but risk stratification of relatives of probands without pathogenic or likely pathogenic variants (gene-elusive) remains uncertain.

Objectives

This study sought to define the incidence, prognosis, and predictors of disease development in first-degree relatives of gene-elusive DCM probands.

Methods

First-degree relatives of gene-elusive DCM probands from 4 international referral centers who underwent baseline electrocardiography and echocardiography were included. The primary outcome was the development of the disease, defined as DCM or isolated left ventricular (LV) systolic dysfunction (LV ejection fraction: <50%). Major adverse cardiac events were exploratory secondary outcomes. Age-adjusted Cox models with family-clustered robust standard errors were used to identify disease predictors.

Results

Among 292 relatives (median age: 36 years, 48% male), 14 (5%) were affected at baseline. During a median follow-up of 52 months, 21 additional relatives developed disease, corresponding to an incidence rate of 17 per 1,000 person-years. Familial DCM (HR: 4.24; 95% CI: 1.38-13.1; P = 0.012), QRS duration >120 ms (HR: 7.24; 95% CI: 2.25-23.3; P < 0.001), lower LV ejection fraction (HR: 3.73; 95% CI: 2.46-5.65; P < 0.001), and LV dilatation (HR: 6.19; 95% CI: 2.27-16.9; P < 0.001) were predictors of disease development. Age at diagnosis in probands significantly correlated with age at onset in relatives (r = 0.80; 95% CI: 0.55-0.92; P < 0.001). Major adverse cardiac events occurred in 9 patients (4%).

Conclusions

First-degree relatives of gene-elusive DCM probands have a relatively low but non-negligible risk of disease development. Familial clustering, electrocardiographic or echocardiographic abnormalities, and age of disease expression in the proband may help tailor surveillance intensity.