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
Methods: From 2002From -2012, patients who received a primary prevention ICD in 12 centres were prospectively enrolled. Characteristics of patients who died within the first year following the ICD implantation were compared with those who survived >1 year and predictors of early mortality determined. Results: Among 5457 primary prevention ICD recipients, 230 (4.2%) patients died within one year following CD implantation and 5% of them received at least one appropriate ICD therapy. As compared with patients who survived >1 year (Table), causes of death were similar in the two groups. In multivariate analysis, older age, NYHA class III-IV, atrial fibrillation and lower LVEF were significantly associated with a ≤1-year survival.
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