%0 Journal Article
%T Variable clinical expression of a novel FLNC truncating variant in a large family.
%A Tomer O
%A Horowitz-Cederboim S
%A Rivkin D
%A Meiner V
%A Gollob MH
%A Zwas DR
%A Durst R
%A Shauer A
%J Int J Cardiol
%V 401
%N 0
%D 2024 Apr 15
%M 38360096
%F 4.039
%R 10.1016/j.ijcard.2024.131849
%X <B>BACKGROUND: </B>Variants in Filamin-C (FLNC) have been associated with various hereditary cardiomyopathies. Recent literature reports a prevalence of sudden cardiac death (SCD) of 13-25% among carriers of truncating-variants, with mean age of 42±15 years for first SCD event. This study reports two familial cases of SCD and the results of cascade screening of their large family.<BR><B>METHODS: </B>Molecular-autopsy of the SCD victims revealed a novel truncating-variant in the FLNC gene (chr 7:128496880 [hg19]; NM_001458.5; c.7467_7474del; p.(Ser2490fs)). We screened thirty-two family members following genetic counseling, and variant carriers underwent a comprehensive workup followed by consultation with a cardiologist with expertise in the genetics of cardiac diseases.<BR><B>RESULTS: </B>Seventeen variant carriers were identified: ages between 9 and 85 (mean 47±26). Fifteen underwent clinical evaluation. To date, none of the identified carriers has had major adverse events. In evaluated patients, ECG showed right-axis deviation in 60% (n = 9). Holter recorded frequent premature ventricular contractions (PVCs) (991±2030 per 24 h) in 33% (n = 5) with 4 patients having polymorphic PVC morphology. Three carriers had echocardiographic evidence of mild left-ventricular (LV) systolic dysfunction and another with mild LV dilatation. Cardiac magnetic-resonance (CMR) exhibited late‑gadolinium-enhancement in 10 out of 11 exams, mainly in the mid-myocardium and sub-epicardium, frequently involving the septum and the inferior-lateral wall.<BR><B>CONCLUSIONS: </B>This large FLNC truncating variant carrier family exhibits high cardiomyopathy penetrance, best diagnosed by CMR, with variable clinical expressions. These findings present a challenge in SCD prevention management and underscoring the imperative for better risk stratification measures.