Case description
A 34-year-old male with no prior medical history presented with dyspnoea and palpitations. Family history (FHx) was significant for sudden cardiac death (SCD) in his father [deceased (d.) 59 y] and two siblings (d. 47 y, d. 15 y). Electrocardiogram revealed atrial flutter, and transoesophageal echocardiogram demonstrated biatrial dilation with a reduced left ventricular (LV) ejection fraction (LVEF) of 40%–45%. Following cardioversion, LVEF improved to 50%–55%. Biventricular morphology and function were reported as normal on outside hospital cardiovascular magnetic resonance imaging (CMR).
Despite treatment with sotalol and atrial ablations at a tertiary care centre, the patient experienced recurrent atrial arrhythmias. Repeat CMR (Figure 1) revealed LV dilation and mild systolic dysfunction (LVEF 41%), alternating thinning and hypertrophy of the inferior and lateral LV walls, apical outpouching, and non-ischaemic fibrosis. Right ventricular free wall scalloping was noted with mild systolic dysfunction. Parametric mapping was negative for diffuse interstitial expansion and myocardial oedema/inflammation. Upon direct comparison to the outside CMR 5 years prior, there had been no significant change.
Figure 1.
Cardiovascular magnetic resonance imaging in a patient with overlapping phenotype cardiomyopathy. (A) Mid short axis view, T2 mapping. (B) Mid short axis view, native T1 mapping. (C) Mid short axis view, post-contrast T1 mapping. (D) Two-chamber view, cine imaging. (E) Four-chamber view, cine imaging. (F) Three-chamber view, cine imaging. (G) Two-chamber view, late gadolinium enhancement imaging. (H) Four-chamber view, late gadolinium enhancement imaging. (I) Three-chamber view, late gadolinium enhancement imaging. T1 and T2 values were normal with no evidence of diffuse interstitial expansion [Extracellular volume fraction (ECV) 25%, normal <31% based on institutionally established values] or myocardial oedema/inflammation (Panel 1). Alternating thinning (0.6 cm at the base and apex) and hypertrophy of the inferior and lateral left ventricular walls (maximum thickness 1.9 cm; arrows), along with trabeculations (asterisks) and apical outpouching (Panel 2), were noted. Right ventricular free wall scalloping was present (carets). There was patchy midmyocardial non-ischaemic fibrosis in the hypertrophied segments (arrows) as well as non-ischaemic fibrosis with a subendocardial component in the thinned segments (asterisks; Panel 3).
Given the FHx of SCD, early disease onset, and CMR findings, genetic testing was pursued and revealed that the patient is heterozygous for a likely pathogenic Filamin C (FLNC) missense variant, c.6958G>A (p.Gly2320Arg), manifesting as an overlapping phenotype cardiomyopathy (CMP) (hypertrophic, dilated, arrhythmogenic). Heart failure guideline-directed medical therapy was initiated, and the patient received an implantable cardioverter-defibrillator.
Truncating FLNC variants are most commonly associated with dilated CMP, while missense variants are more frequently linked to hypertrophic CMP.1 In this case, genetic findings favour a hypertrophic CMP genotype despite an overlapping phenotypic presentation. The c.6958G>A (p.Gly2320Arg) variant is rare based on population data from the Genome Aggregation Database. This mixed phenotype is likely influenced by additional, unmeasured genetic factors, including rare variants and common polygenic risk.2 Notably, FLNC variants have been shown to confer an increased risk of ventricular arrhythmias.3 In contrast, this case is characterized by a predominantly atrial arrhythmic presentation, underscoring the importance of comprehensive evaluation of atrial arrhythmia triggers. Even clearly visible but atypical imaging findings may not be immediately recognized as indicative of inherited cardiomyopathy. In high-risk patients, particularly those with a family history of SCD, repeat CMR and expert re-evaluation should be considered when clinical suspicion remains unresolved. Early recognition of structural heart disease and its genetic basis is crucial for risk stratification, therapeutic decision-making, and enabling surveillance of at-risk family members to prevent adverse outcomes.
Contributor Information
Angela Lee, The Ohio State University College of Medicine, 1645 Neil Ave, Columbus, OH 43210, USA.
Diana Kline, The Ohio State University College of Medicine, 1645 Neil Ave, Columbus, OH 43210, USA.
Karolina Zareba, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, 234 W 12th Ave, Columbus, OH 43210, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Columbus, OH 43210, USA.
Katarzyna Elzbieta Gil, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, 234 W 12th Ave, Columbus, OH 43210, USA.
Author contributions
Angela Lee (Conceptualization [supporting], Writing—original draft [lead]), Diana Kline (Writing—original draft [supporting], Writing—review & editing [equal]), Karolina Zareba (Writing—review & editing [supporting]), and Katarzyna Elzbieta Gil (Conceptualization, Writing—review & editing [lead])
Consent: Written informed consent for submission and publication of this case report was obtained from the patient, in line with COPE guidance.
Funding
None declared.
Data availability
Data will be made available upon request.
References
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Associated Data
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Data Availability Statement
Data will be made available upon request.