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

Abstract

Background: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. Mutations in FLNC have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012 we have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. Objective(s): We aimed to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. Methods: FLNC was studied by next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. We identified a characteristic phenotype 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 analysed 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 individuals with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted in left ventricular dilatation (68%) and systolic dysfunction (46%), left ventricular myocardial fibrosis (67%), inferolateral negative T waves and low voltages on ECG (33%), ventricular arrhythmias (82%), and frequent sudden cardiac death (40 cases in 21/28 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 LOD score: 9.5). Immunohistochemical stainings of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. Conclusions: Truncating mutations in FLNC cause 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 individuals harboring truncating mutations in FLNC.