{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:03:08Z","timestamp":1789635788879,"version":"4.0.0"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Variants in the filamin C (FLNC) gene are increasingly recognized as causes of cardiac and skeletal muscle disease. Cardiomyopathy-associated FLNC variants span dilated cardiomyopathy (DCM), nondilated left ventricular cardiomyopathy (NDLVC), arrhythmogenic cardiomyopathy (ACM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM), but their clinical interpretation depends strongly on variant class and evidence of pathogenicity. FLNC truncating variants (FLNCtv), including nonsense, frameshift, and canonical splice-site variants, usually cause haploinsufficiency through nonsense-mediated decay and are predominantly associated with DCM\/NDLVC and left-dominant ACM. These phenotypes frequently show subepicardial or circumferential ring-like fibrosis and clinically important ventricular arrhythmias that may occur despite only mild left ventricular dysfunction. On the other hand, selected pathogenic missense variants, particularly within the actin-binding domain or ROD2 immunoglobulin-like repeats 18\u201321, may promote protein misfolding and aggregation and have been associated with HCM or RCM, including the distinctive saw-tooth myocardial phenotype. However, most reported FLNC missense variants remain variants of uncertain significance and must not be considered disease-causing on the basis of location alone. This narrative review summarizes FLNC molecular biology, genotype-phenotype relationships, imaging features, arrhythmic risk, and implications for clinical management. It also discusses the limited evidence linking FLNCtv to arrhythmogenic mitral valve prolapse with mitral annular disjunction. Accurate variant classification and phenotype integration are essential for diagnosis and for individualized prevention of sudden cardiac death (SCD).<\/jats:p>","DOI":"10.3390\/genes17091136","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:17Z","timestamp":1789632197000},"page":"1136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Multifaceted Role of the FLNC Gene in Hereditary Cardiomyopathies and Prognosis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9170-4668","authenticated-orcid":false,"given":"Maria","family":"D\u2019Apolito","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ranaldi","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Gaudiano","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Bruna","family":"Maffione","sequence":"additional","affiliation":[{"name":"Human Anatomy, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Santacroce","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-5062","authenticated-orcid":false,"given":"Massimo","family":"Iacoviello","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Polyclinic University Hospital, Viale L. Pinto 1, 71100 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5627-9221","authenticated-orcid":false,"given":"Maurizio","family":"Margaglione","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/35052082","article-title":"Filamins as integrators of cell mechanics and signalling","volume":"2","author":"Stossel","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4161\/cam.5.2.14401","article-title":"The filamins: Organizers of cell structure and function","volume":"5","author":"Nakamura","year":"2011","journal-title":"Cell Adhes. Migr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mao, Z., and Nakamura, F. (2020). Structure and Function of Filamin C in the Muscle Z-Disc. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082696"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCRESAHA.120.317076","article-title":"Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation","volume":"129","author":"Agarwal","year":"2021","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0167-4889(01)00072-6","article-title":"Structural and functional aspects of filamins","volume":"1538","author":"Sonnenberg","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","first-page":"20250008","article-title":"The Multiple Faces of Cardiomyopathy Due to Filamin C Gene Variants (FLNC)","volume":"5","author":"Nunes","year":"2025","journal-title":"ABC Heart Fail. Cardiomyop."},{"key":"ref_7","first-page":"101027","article-title":"A child with dilated cardiomyopathy and homozygous splice site variant in FLNC gene","volume":"38","author":"Alsubhi","year":"2023","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_8","first-page":"20240059","article-title":"Filamin C and Cardiomyopathies: Linking Genetic Variants to Their Phenotypic Impact","volume":"5","author":"Olivetti","year":"2025","journal-title":"ABC Heart Fail. Cardiomyop."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/humu.24004","article-title":"A mutation update for the FLNC gene in myopathies and cardiomyopathies","volume":"41","author":"Verdonschot","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.jacc.2016.09.927","article-title":"Truncating FLNC Mutations Are Associated with High-Risk Dilated and Arrhythmogenic Cardiomyopathies","volume":"68","author":"Cuenca","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-biophys-050511-102252","article-title":"Filamins in Mechanosensing and Signaling","volume":"41","author":"Razinia","year":"2012","journal-title":"Annu. Rev. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jacbts.2016.05.004","article-title":"FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy","volume":"1","author":"Begay","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_13","first-page":"326","article-title":"Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: A comprehensive genotype-imaging phenotype study","volume":"21","author":"Augusto","year":"2020","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Baban, A., Alesi, V., Magliozzi, M., Parlapiano, G., Genovese, S., Cicenia, M., Loddo, S., Lodato, V., Di Chiara, L., and Fattori, F. (2022). Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9100332"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1016\/j.hrthm.2023.08.003","article-title":"Phenotypic variability of filamin C\u2013related cardiomyopathy: Insights from a novel Dutch founder variant","volume":"20","author":"Schoonvelde","year":"2023","journal-title":"Heart Rhythm"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/cge.13715","article-title":"Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese","volume":"97","author":"Lee","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ijcard.2020.08.052","article-title":"A founder mutation in FLNC is likely a major cause of idiopathic dilated cardiomyopathy in Ashkenazi Jews","volume":"323","author":"Liebman","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ijcard.2020.04.005","article-title":"Reduction in Filamin C transcript is associated with arrhythmogenic cardiomyopathy in Ashkenazi Jews","volume":"317","author":"Oz","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s40246-024-00683-9","article-title":"Novel FLNC variants in pediatric cardiomyopathy: An insight into disease mechanisms","volume":"18","author":"Dong","year":"2024","journal-title":"Hum. Genom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiomyopathies","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100200","DOI":"10.1016\/j.shj.2023.100200","article-title":"The Genetic Evaluation of Dilated Cardiomyopathy","volume":"7","author":"Bui","year":"2023","journal-title":"Struct. Heart"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ciarambino, T., Menna, G., Sansone, G., and Giordano, M. (2021). Cardiomyopathies: An Overview. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147722"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated Cardiomyopathy: Genetic Determinants and Mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5326","DOI":"10.1038\/ncomms6326","article-title":"Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy","volume":"5","author":"Coto","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.jacep.2017.12.003","article-title":"Filamin C Truncation Mutations Are Associated with Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell\u2013Cell Adhesion Structures","volume":"4","author":"Begay","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Filamin C Registry Consortium, Gigli, M., Stolfo, D., Barbati, G., Graw, S., Chen, S.N., Merlo, M., Medo, K., Gregorio, C., and Dal Ferro, M. (2025). Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants. JAMA Cardiol., 10, 359\u2013369.","DOI":"10.1001\/jamacardio.2024.5543"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e230165","DOI":"10.1148\/ryct.230165","article-title":"Filamin C\u2013Associated Cardiomyopathy on Cardiac MR Images","volume":"5","author":"Weller","year":"2023","journal-title":"Radiol. Cardiothorac. Imaging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.hrthm.2021.09.029","article-title":"Filamin-C Variant-Associated Cardiomyopathy: A Pooled Analysis of Individual Patient Data to Evaluate the Clinical Profile and Risk of Sudden Cardiac Death","volume":"19","author":"Celeghin","year":"2022","journal-title":"Heart Rhythm"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1001\/jamacardio.2021.1106","article-title":"Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C with Frequent Ventricular Arrhythmia and End-stage Heart Failure","volume":"6","author":"Akhtar","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1001\/jamacardio.2020.6500","article-title":"Assessing the role of rare genetic variation in patients with heart failure","volume":"6","author":"Povysil","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e003645","DOI":"10.1161\/CIRCGEN.121.003645","article-title":"Loss-of-Function FLNC Variants Are Associated with Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population","volume":"15","author":"Carruth","year":"2022","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCGENETICS.114.001003","article-title":"Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia\/Cardiomyopathy Patients and Family Members","volume":"8","author":"Groeneweg","year":"2015","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1161\/CIRCRESAHA.117.309345","article-title":"Arrhythmogenic Cardiomyopathy","volume":"121","author":"Corrado","year":"2017","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1161\/01.CIR.94.5.983","article-title":"Arrhythmogenic right ventricular cardiomyopathy: Dysplasia, dystrophy or myocarditis?","volume":"94","author":"Basso","year":"1996","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13023-016-0407-1","article-title":"Arrhythmogenic cardiomyopathy","volume":"11","author":"Pilichou","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.ajhg.2008.01.010","article-title":"Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene","volume":"82","author":"Merner","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1093\/eurjhf\/hfs119","article-title":"Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy","volume":"14","author":"Asimaki","year":"2012","journal-title":"Eur. J. Heart Fail."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1016\/j.hrthm.2009.07.041","article-title":"Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene","volume":"6","author":"Asimaki","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e301","DOI":"10.1016\/j.hrthm.2019.05.007","article-title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy","volume":"16","author":"Towbin","year":"2019","journal-title":"Heart Rhythm"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/CIRCRESAHA.121.318346","article-title":"Molecular Genetic Basis of Hypertrophic Cardiomyopathy","volume":"128","author":"Marian","year":"2021","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e001584","DOI":"10.1161\/CIRCGENETICS.116.001584","article-title":"Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients","volume":"10","author":"Lorca","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/cge.13594","article-title":"FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations","volume":"96","author":"Ader","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/mgg3.488","article-title":"Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy","volume":"6","author":"Cui","year":"2018","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1093\/brain\/aws200","article-title":"Pathophysiology of protein aggregation and extended phenotyping in filaminopathy","volume":"135","author":"Kley","year":"2012","journal-title":"Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1161\/CIRCGEN.122.004054","article-title":"Clinical Outcomes and Genetic Analyses of Restrictive Cardiomyopathy in Children","volume":"16","author":"Ishida","year":"2023","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vio, R., Angelini, A., Basso, C., Cipriani, A., Zorzi, A., Melacini, P., Thiene, G., Rampazzo, A., Corrado, D., and Calore, C. (2021). Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies. J. Clin. Med., 10.","DOI":"10.3390\/jcm10091954"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39276","DOI":"10.1038\/srep39276","article-title":"Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics","volume":"7","author":"Rindler","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kostareva, A., Kiselev, A., Gudkova, A., Frishman, G., Ruepp, A., Frishman, D., Smolina, N., Tarnovskaya, S., Nilsson, D., and Zlotina, A. (2016). Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163362"},{"key":"ref_49","first-page":"e002388","article-title":"Missense Mutations in the FLNC Gene Causing Familial Restrictive Cardiomyopathy","volume":"12","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/humu.22942","article-title":"Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy","volume":"37","author":"Brodehl","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e001780","DOI":"10.1161\/CIRCGENETICS.117.001780","article-title":"Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy","volume":"10","author":"Tucker","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_52","first-page":"301","article-title":"ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive\/hypertrophic cardiomyopathy and saw-tooth myocardium","volume":"76","author":"Carriel","year":"2023","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.mayocp.2018.11.028","article-title":"A Novel Truncating Variant in FLNC-Encoded Filamin C May Serve as a Proarrhythmic Genetic Substrate for Arrhythmogenic Bileaflet Mitral Valve Prolapse Syndrome","volume":"94","author":"Bains","year":"2019","journal-title":"Mayo Clin. Proc."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1136\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:22:08Z","timestamp":1789633328000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091136"],"URL":"https:\/\/doi.org\/10.3390\/genes17091136","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}