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Filamin C (FLNC) encodes a large actin‐crosslinking protein critical for sarcomeric integrity in striated muscle. Heterozygous truncating and splice‐site variants in FLNC have emerged as a significant cause of autosomal dominant dilated cardiomyopathy (DCM), characterized by left ventricular dilatation, dysfunction, and a high risk of ventricular arrhythmias and sudden cardiac death. FLNC‐related DCM often presents in adulthood with progressive heart failure and may lack overt skeletal muscle involvement, distinguishing it from FLNC‐associated myofibrillar myopathies.
Genetic evidence supporting a strong gene–disease relationship includes over 145 unrelated carriers of FLNC variants in pooled cohorts, with 12 of 270 gene‐elusive arrhythmogenic cardiomyopathy probands harboring FLNC variants and 13 affected relatives confirmed to carry the same mutations (PMID:34601126). Segregation of novel splice‐site mutations (e.g., c.2389+1G>A) across multiple affected family members further substantiates pathogenicity (PMID:29551499). FLNC truncating variants (stopgain, frameshift, splice) predominate in DCM, while missense changes are less frequent but may disrupt dimerization or actin binding.
The spectrum of pathogenic FLNC alleles in DCM includes canonical loss‐of‐function variants such as c.5897C>A (p.Ser1966Ter), which co‐segregate with disease and lead to protein haploinsufficiency and sarcomeric disarray (PMID:28008423). Deep intronic alterations and rare structural variants in FLNC contribute to a minority of cases, but truncating variants account for up to 8.7% of DCM patients undergoing heart transplantation (PMID:37461109). Recurrent splice mutations have been documented in ethnically diverse cohorts, without clear founder effects.
Functional studies demonstrate that FLNC loss‐of‐function underlies DCM pathogenesis. Morpholino knockdown of filamin C orthologs in zebrafish elicits sarcomeric disorganization and impaired cardiac contractility, supporting haploinsufficiency (PMID:28008423). Patient‐derived iPSC‐cardiomyocytes with FLNC truncations exhibit arrhythmias and contractile dysfunction, which can be rescued by targeting downstream platelet‐derived growth factor receptor alpha (PDGFRA) signaling (PMID:35196083). Disruption of FLNC–actin binding in knock‐in mice leads to embryonic lethality or adult‐onset DCM depending on timing, confirming the essential role of FLNC–actin interactions in myocardial integrity (PMID:37492967).
No credible refuting evidence has emerged; instead, multiple independent studies across familial and sporadic cohorts converge on a haploinsufficiency model. While rare biallelic presentations with congenital DCM have been reported, the majority of FLNC‐DCM follows autosomal dominant transmission with variable expressivity and incomplete penetrance.
In summary, robust genetic and experimental data classify the FLNC–DCM association as Strong. Genetic testing for FLNC truncating variants informs diagnosis, guides family screening, and stratifies risk for arrhythmias and sudden death. Early identification of FLNC mutation carriers enables timely therapeutic interventions, including implantable cardioverter‐defibrillator placement.
Gene–Disease AssociationStrong
Genetic EvidenceStrongTruncating and splice variants in >145 probands across multiple families; reached ClinGen genetic cap Functional EvidenceModerateZebrafish, iPSC and mouse models recapitulate DCM phenotype; PDGFRA rescue experiments |