Childhood-Onset Filamin c Related Cardiomyopathy: Genotype-Phenotype Correlation and Outcome.
TL;DR
A retrospective cohort study of children with CMP features and a (likely) pathogenic FLNC variant, identified via literature search or in the Belgian Pediatric Cardiology Registry, to evaluate cardiovascular outcomes and genotype-phenotype correlations finds the need for early genetic screening, risk stratification, and personalized follow-up to improve outcome.
Abstract
Filamin C (FLNC) contributes to 1%-8% of adult-onset cardiomyopathy (CMP), with a high prevalence of end-stage heart failure and sudden cardiac death, particularly for FLNC truncating variants (FLNCtv), rendering it one of the high-risk CMP genes. Outcome data and genotype-phenotype correlation in children are scarce. We conducted a retrospective cohort study of children (< 18 years) with CMP features and a (likely) pathogenic FLNC variant, identified via literature search or in the Belgian Pediatric Cardiology Registry (BePCaR), to evaluate cardiovascular outcomes and genotype-phenotype correlations. Seventy-four individuals (56.8% male, median age 4.5 years) from 57 families were included. Restrictive CMP was the most prevalent phenotype. Half of the patients experienced major adverse cardiovascular events, including heart transplantation (20.3%) and death (13.5%). Hypertrophic CMP was exclusively associated with ROD2 domain variants. Mortality was significantly higher in FLNCtv carriers versus non-truncating carriers (26.9% vs. 6.3%, p = 0.019), and multivariate analysis identified FLNCtv as an independent predictor of adverse outcome (OR = 6.4, 95% CI: [1.36, 29.80]). Extracardiac manifestations occurred in 32.4%, predominantly in RCM patients, with myopathy-associated variants clustering in exons 21 and 41. Pathogenic FLNC variants associate with early-onset CMP and poor prognosis, underscoring the need for early genetic screening, risk stratification, and personalized follow-up to improve outcome.