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Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies

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dc.contributor.authorOrtiz-Genga, Martín F.
dc.contributor.authorCuenca, Sofía
dc.contributor.authorDal Ferro, Matteo
dc.contributor.authorZorio, Esther
dc.contributor.authorZorio, Esther
dc.contributor.authorCliment, Vicente
dc.contributor.authorPadrón-Barthe, Laura
dc.contributor.authorDuro-Aguado, Iria
dc.contributor.authorJiménez-Jáimez, Juan
dc.contributor.authorHidalgo-Olivares, Victor M.
dc.contributor.authorGarcía-Campo, Enrique
dc.contributor.authorLanzillo, Chiara
dc.contributor.authorSuárez-Mier, M. Paz
dc.contributor.authorYonath, Hagith
dc.contributor.authorMarcos-Alonso, Sonia
dc.contributor.authorOchoa, Juan P.
dc.contributor.authorSantomé, José L.
dc.contributor.authorGarcía-Giustiniani, Diego
dc.contributor.authorRodríguez-Garrido, Jorge L.
dc.contributor.authorDomínguez, Fernando
dc.contributor.authorMerlo, Marco
dc.contributor.authorPalomino, Julián
dc.contributor.authorPeña, María L.
dc.contributor.authorTrujillo, Juan P.
dc.contributor.authorMartín-Vila, Alicia
dc.contributor.authorStolfo, Davide
dc.contributor.authorMolina, Pilar
dc.contributor.authorLara-Pezzi, Enrique
dc.contributor.authorCalvo-Iglesias, Francisco E.
dc.contributor.authorNof, Eyal
dc.contributor.authorCalò, Leonardo
dc.contributor.authorBarriales-Villa, Roberto
dc.contributor.authorGimeno Blanes, Juan Ramón
dc.contributor.authorArad, Michael
dc.contributor.authorGarcía-Pavía, Pablo
dc.contributor.authorMonserrat, Lorenzo
dc.contributor.departmentMedicina
dc.contributor.otherFacultad de Medicina
dc.date.accessioned2026-01-15T11:21:19Z
dc.date.available2026-01-15T11:21:19Z
dc.date.copyright© 2016 by the American College of Cardiology Foundation
dc.date.issued2016-11-28
dc.description.abstractBACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.
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dc.format.extent12
dc.identifier.citationJ Am Coll Cardiol 2016;68:2440–51
dc.identifier.doihttps://doi.org/10.1016/j.jacc.2016.09.927
dc.identifier.eissn1558-3597
dc.identifier.issn0735-1097
dc.identifier.urihttp://hdl.handle.net/10201/187169
dc.languageeng
dc.publisherElsevier, American College of Cardiology
dc.relationSin financiación externa a la Universidad
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0735109716364166?via%3Dihub
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectFilaminopathy
dc.subjectGenotype
dc.subjectPrognosis
dc.subjectSudden death
dc.subjectVentricular arrhythmia
dc.subjectFilamin C
dc.subject.odsNo relacionado con ningún objetivo de desarrollo sostenible
dc.titleTruncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
relation.isAuthorOfPublication4d37f6b7-66c0-4f9a-81c7-72d9bd67f2fb
relation.isAuthorOfPublication.latestForDiscovery4d37f6b7-66c0-4f9a-81c7-72d9bd67f2fb
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