Novel Filamin C missense mutation associated with severe restrictive cardiomyopathy overlapping with left ventricular non-compaction

Abstract Introduction Filamin C gene (FLNC) missense mutations have been previously reported in association with restrictive cardiomyopathy (RCM). The association of FLNC missense variants with non-compaction cardiomyopathy has been reported only in a single proband, but familiar or functional evidence on its causative effect is limited. Overlapping traits among cardiomyopathies related to the same genetic substrate is an emerging and a challenging scenario nowadays. Purpose To report a new pathogenic FLNC missense variant in association with a particular form of restrictive/non-compaction overlapping cardiomyopathy. Methods The probands fulfill the diagnostic criteria for RCM based on current guidelines. Genetic testing in the probands was performed by NGS, using a broad gene panel (containing over 240 genes). Clinical and genetic cascade screening were expanded to first-degree relatives when it was possible. All mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, echocardiography, cardiac magnetic resonance (MRI), 24h Holter monitoring, and ergometry. None of them had major systemic illnesses nor clinical symptoms of muscular involvement. Results The p.Gly2011Arg variant in the FLNC gene was the only relevant variant in the three probands. This variant is virtually absent in the general population (gnomAD). The variant showed a de novo presentation in the first family and segregated with the phenotype in the four studied relatives from the second family (three affected carriers and one unaffected non-carrier). In the third case no familial information was available. This variant affects an ultraconserved residue and is located in a relevant sub-region of Filamin-C, which is necessary for its interaction with other Z-disc proteins. Detailed clinical information is available on all carriers (n=5, 1 male). The average age at diagnosis is 17 years [1–36]. An abnormal ECG was the earliest clinical manifestation (left ventricular hypertrophy by voltage criteria and extensive repolarization abnormalities). Significant hypertrabeculations, mainly at the anterolateral wall and basal anteroseptal segments, was present in all affected carriers. Interestingly, none of them showed an abnormal late-gadolinium enhancement pattern on MRI. The four carriers who were older than 35 years were found to have severe restrictive pattern on echocardiography (functional parameters and secondary features such as bi-atrial dilation), all four suffered from limiting dyspnea, and two are under pre-transplant workup (A-II-1 and B-III-1). One of them had a cardioembolic event (femoral acute ischemia, A-II-1). One relative has recently died from advanced heart failure (B-II-2). Conclusion This is the first description on this overlapping (restrictive/non-compaction cardiomyopathy) and aggressive phenotype associated with a missense FLNC variant. This description widens the clinical spectrum related to FLNC missense mutations. Pedigrees and clinical characterization Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Health in Code