ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium

• Published in: Revista española de cardiología (English ed.) 2023-05, Vol.76 (5), p.301-311
• Main Authors: Bermúdez-Jiménez, Francisco José, Carriel, Víctor, Santos-Mateo, Juan José, Fernández, Adrián, García-Hernández, Soledad, Ramos, Karina Analía, Piqueras-Flores, Jesús, Cabrera-Romero, Eva, Barriales-Villa, Roberto, de la Higuera Romero, Luis, Alcalá López, Juan Emilio, Gimeno Blanes, Juan Ramón, Sánchez-Porras, David, Campos, Fernando, Alaminos, Miguel, Oyonarte-Ramírez, José Manuel, Álvarez, Miguel, Tercedor, Luis, Brodehl, Andreas, Jiménez-Jáimez, Juan
• Format: Article
• Language: English
• Subjects: Cardiomiopatía Hipertrófica; Cardiomiopatía restrictiva; Cardiomyopathies; Cardiomyopathies - diagnosis; Cardiomyopathies - genetics; Cardiomyopathy; Cardiomyopathy, Hypertrophic - diagnosis; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Restrictive - genetics; Filamin C; Filamina C; Filaminas; Filamins; Filamins - genetics; Heart Failure; Humans; Hypertrophic; Miocardio en dientes de sierra; Miocardiopatía; Mutation; Mutation, Missense; Myocardium; Phenotype; Restrictive; Saw-tooth myocardium
• ISSN: 1885-5857; 1885-5857
• DOI: 10.1016/j.rec.2022.08.002

Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling. Recientemente se han descrito mutaciones missense en la filamina C (FLNC) como causa de miocardiopatía. Los conocimientos sobre la patogenicidad y la correlación genotipo-fenotipo son escasos. Nuestro objetivo es describir un fenotipo cardiaco distintivo relacionado con mutaciones missense en el dominio ROD2 de FLNC (FLNC-mRod2). Incluimos 21 familias independientes con fenotipo de miocardiopatía hipertrófica (MCH)/miocardiopatía restrictiva (MCR) portadoras de variantes missense en FLNC-mRod2. Se estudió clínicamente a los portadores, además de hacer un cribado en cascada. Se analizó histológicamente el tejido miocárdico de tres corazones explantados y se