FLNC mutations in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations

Introduction Mutations in FLNC encoding filamin C have been firstly reported to cause dominant myofibrillar and distal myopathy. More recently, dominant pathogenic variants in FLNC have also been linked to the development of isolated cardiac phenotypes. Objective Only few publications on cohorts with FLNC pathogenic variants are published and the pathophysiology of FLNC-related cardiomyopathy is poorly understood. The aim of this retrospective study is to establish the prevalence of mutation in the FLNC gene in the different subtypes of cardiomyopathies and search for genotype-phenotype associations. Methods DNAs from a cohort of 1150 unrelated index-patients with an isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 52 cardiomyopathy disease-causing genes. Results A FLNC pathogenic mutation was identified in 28 patients corresponding to a prevalence ranging from 1 to 8% depending on the cardiomyopathy subtypes. Truncating mutations were always identified in patients with dilated cardiomyopathy, while mis-sense or in-frame mutations were found in other phenotypes. In the cohort, nine patients (32%) were implanted with an automatic defibrillator. In 7 families (25%), history of sudden cardiac death (SCD) before 50 years was reported. A personal or family history of SCD was significantly higher in patients with truncating variants than in patients carrying missense variants (P = 0.01). Acute heart failure was observed in 7 patients (25%). Four patients died of cardiac cause including 3 from SCD and 1 from heart failure. Conclusion This work highlights the role of FLNCin studied cardiomyopathy subtypes. A correlation between the type of the mutation and the cardiomyopathy subtype was observed as well as with SCD risk. These new data should be taken into consideration for patient's management and primary prevention of sudden cardiac death.