Circulation. Genomic and precision medicine · 2026
FLNC-Related Cardiomyopathies in an Admixed Population: Expanding the Genotype-Phenotype Spectrum and Clinical Correlates.
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Olivetti Natalia Quintella Sangiorgi, Sacilotto Luciana, Ferreira Julia de Barros Negri, Furquim Silas, Pagotti Márya, Santos Bruno Moreira, Mizuta Marjorie, Senra Paula de Mendonça, Napolitano Giovanna, Vilalva Kelvin, Andrade Fernanda, Carvalho Mariana Lombardi Peres de, Marques Emanuelle Leonília, Patane Jose Salvatore Leister, Pires Lucas Vieira Lacerda, Lima Angelica Nakagawa, Pereira Alexandre C, Darrieux Francisco da Costa, Scanavacca Mauricio, Fernandes Fábio, Krieger Jose E
Аннотация
BACKGROUND: Pathogenic and likely pathogenic variants in filamin C (FLNC) cause a broad spectrum of cardiomyopathies. However, available genotype-phenotype data are derived predominantly from European and North American populations, with limited representation of admixed populations.
METHODS: We characterized carriers of pathogenic/likely pathogenic FLNC variants identified among 2654 unrelated probands undergoing exome sequencing for suspected inherited cardiomyopathy and their relatives identified through cascade screening. Clinical, electrocardiographic, imaging, genetic, and longitudinal data were analyzed according to cardiomyopathy phenotype and variant class. Genetic ancestry was evaluated. Associations with arrhythmic, heart failure, and composite outcomes were examined in exploratory analyses.
RESULTS: The cohort included 97 carriers (58 probands, 39 relatives), of whom 72 had cardiomyopathy and 25 were phenotype-negative at evaluation. Truncating variants predominated among patients with arrhythmogenic cardiomyopathy and dilated cardiomyopathy, whereas missense variants were concentrated among those with hypertrophic cardiomyopathy and restrictive cardiomyopathy. Arrhythmogenic cardiomyopathy and dilated cardiomyopathy were characterized by a greater burden of ventricular arrhythmias, low QRS voltage, systolic dysfunction, and myocardial fibrosis, whereas hypertrophic cardiomyopathy and restrictive cardiomyopathy showed greater wall thickness and more atrial arrhythmias. Twelve pathogenic/likely pathogenic variants absent from gnomAD and ClinVar were identified. Ancestry analysis confirmed heterogeneous genetic backgrounds but detected no ancestry-related differences in variant class or phenotype. In exploratory outcome analyses, nonsustained ventricular tachycardia, low QRS voltage, and late gadolinium enhancement were associated with outcomes.
CONCLUSIONS: This deeply phenotyped Brazilian cohort expands the FLNC variant spectrum and supports broad genotype-phenotype associations across an admixed population. Exploratory findings suggest that markers of ventricular arrhythmia and myocardial fibrosis may complement left ventricular ejection fraction in future risk-stratification strategies, although validation in larger, independent cohorts is required.
METHODS: We characterized carriers of pathogenic/likely pathogenic FLNC variants identified among 2654 unrelated probands undergoing exome sequencing for suspected inherited cardiomyopathy and their relatives identified through cascade screening. Clinical, electrocardiographic, imaging, genetic, and longitudinal data were analyzed according to cardiomyopathy phenotype and variant class. Genetic ancestry was evaluated. Associations with arrhythmic, heart failure, and composite outcomes were examined in exploratory analyses.
RESULTS: The cohort included 97 carriers (58 probands, 39 relatives), of whom 72 had cardiomyopathy and 25 were phenotype-negative at evaluation. Truncating variants predominated among patients with arrhythmogenic cardiomyopathy and dilated cardiomyopathy, whereas missense variants were concentrated among those with hypertrophic cardiomyopathy and restrictive cardiomyopathy. Arrhythmogenic cardiomyopathy and dilated cardiomyopathy were characterized by a greater burden of ventricular arrhythmias, low QRS voltage, systolic dysfunction, and myocardial fibrosis, whereas hypertrophic cardiomyopathy and restrictive cardiomyopathy showed greater wall thickness and more atrial arrhythmias. Twelve pathogenic/likely pathogenic variants absent from gnomAD and ClinVar were identified. Ancestry analysis confirmed heterogeneous genetic backgrounds but detected no ancestry-related differences in variant class or phenotype. In exploratory outcome analyses, nonsustained ventricular tachycardia, low QRS voltage, and late gadolinium enhancement were associated with outcomes.
CONCLUSIONS: This deeply phenotyped Brazilian cohort expands the FLNC variant spectrum and supports broad genotype-phenotype associations across an admixed population. Exploratory findings suggest that markers of ventricular arrhythmia and myocardial fibrosis may complement left ventricular ejection fraction in future risk-stratification strategies, although validation in larger, independent cohorts is required.