FLNC -Related Cardiomyopathies in an Admixed Population: Expanding the Genotype-Phenotype Spectrum and Clinical Correlates

Q: What is the clinical evidence from this study?

Study design: Observational. Population: FLNC-Related Cardiomyopathies (n=97). Intervention: FLNC variants. Primary outcome: Arrhythmic, heart failure, and composite outcomes.

Q: What does this research mean for the field?

In admixed populations, FLNC truncating variants predominantly cause arrhythmogenic and dilated cardiomyopathy, whereas missense variants associate with hypertrophic and restrictive cardiomyopathy, confirming that genotype-phenotype relationships are consistent across diverse genetic ancestries. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

Natália Olivetti; Luciana Sacilotto; Julia de Barros Negri Ferreira; Silas Ramos Furquim; Márya Duarte Pagotti; Bruno Moreira dos Santos; Marjorie Mizuta; P. Senra; Giovanna Napolitano Pereira Ribeiro; Kelvin Henrique Vilalva; Fernanda Almeida Andrade; Mariana Lombardi Peres de Carvalho; Emanuelle Ferreira Marques; José Salvatore Leister Patané; Lucas Vieira Lacerda Pires; Angélica Nakagawa Lima; Alexandre C. Pereira; Francisco Darrieux; Maurício Scanavacca; Fábio Danziato Fernandes; José Eduardo Krieger

doi:10.1161/circgen.126.005733

Why the study?

Available genotype-phenotype data for FLNC-related cardiomyopathies are predominantly from European and North American populations, with limited data from admixed populations.

Key Points

To examine the genotype-phenotype spectrum, ancestral background, and clinical outcomes associated with FLNC gene variants in an admixed population undergoing genetic evaluation for cardiomyopathy.
Screened exome sequencing data from 2,654 unrelated probands with suspected inherited cardiomyopathy and performed cascade genetic testing in relatives.
Evaluated clinical, electrocardiographic, cardiovascular imaging, genetic ancestry, and longitudinal follow-up data across 97 FLNC variant carriers.
Identified 97 carriers (72 with cardiomyopathy, 25 phenotype-negative), observing truncating variants clustered in arrhythmogenic and dilated cardiomyopathies, while missense variants concentrated in hypertrophic and restrictive forms.
Detected 12 novel pathogenic or likely pathogenic variants not previously cataloged in gnomAD or ClinVar, with genetic ancestry showing no significant interaction with variant type or cardiac phenotype.
Identified nonsustained ventricular tachycardia, low QRS voltage, and late gadolinium enhancement on cardiac MRI as significant exploratory predictors of adverse heart failure and arrhythmic outcomes.

Study Design

Type

Observational (n=97)

Structured PICO

P

Population

97 carriers of FLNC variants (58 probands, 39 relatives) identified from a cohort of 2,654 probands undergoing exome sequencing for suspected inherited cardiomyopathy.

O

Outcome

Genotype-phenotype associations and exploratory outcomes (arrhythmic, heart failure, and composite outcomes)

FLNC truncating variants are associated with arrhythmogenic and dilated cardiomyopathies, while missense variants are linked to hypertrophic and restrictive cardiomyopathies, expanding the known genotype-phenotype spectrum in admixed populations.

Limitations

Validation in larger, independent cohorts is required

Implication

May inform FLNC variant interpretation in admixed populations; extends prior European/North American associations but remains hypothesis-generating.

Abstract

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Discussion

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Cite This Study

Olivetti et al. (2026) conducted an observational in FLNC-Related Cardiomyopathies (n=97). FLNC variants was evaluated on Arrhythmic, heart failure, and composite outcomes.

synapsesocial.com/papers/6ac1abb2cc6172083c928b2c https://doi.org/10.1161/circgen.126.005733

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FLNC -Related Cardiomyopathies in an Admixed Population: Expanding the Genotype-Phenotype Spectrum and Clinical Correlates

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

FLNC -Related Cardiomyopathies in an Admixed Population: Expanding the Genotype-Phenotype Spectrum and Clinical Correlates

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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