FLNC (Filamin-C)
Details
FLNC encodes filamin-C (γ-filamin), a striated muscle-specific actin crosslinking protein that links the costamere to the Z-disc and participates in signal transduction with integrins. Truncating FLNC variants cause a high-risk form of arrhythmogenic cardiomyopathy with predominantly left ventricular involvement, frequent sudden cardiac death, and — in many patients — co-existing myofibrillar myopathy.
Key Facts
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Protein role: Filamin-C links the costamere to the Z-disc via interactions with sarcolemmal proteins (γ/δ-sarcoglycans of the dystrophin glycoprotein complex, β1A-integrin) and Z-disc proteins (myotilin, FATZ). It is a major structural element of the extramyofibrillar cytoskeleton. (sources/acm-hrs-2019)
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Disease-causing variant type: Predominantly truncating variants (no odds ratio data available; recognized by cohort studies). An autosomal dominant nonsense variant (p.Trp2710*) in the last exon causes filamin-C aggregation within skeletal muscle → myofibrillar myopathy. (sources/acm-hrs-2019)
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Clinical phenotype: FLNC ACM presents as ALVC or biventricular cardiomyopathy; SCD and ICD-treated arrhythmias are frequent. In 12 patients with SCD in a Spanish cohort (54 FLNC variant carriers identified from 28 unrelated index patients), the mean LVEF was 39.6±12%. (sources/acm-hrs-2019)
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ECG in FLNC disease: Minor repolarization changes only (not an early marker of disease — in contrast to ARVC/desmosomal variants where ECG changes appear early). (sources/acm-hrs-2019)
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ICD recommendation:
- COR IIa, LOE C-LD: ICD is reasonable in FLNC ACM with LVEF <45%. (sources/acm-hrs-2019)
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Extracardiac features: Also causes myofibrillar myopathy (skeletal muscle involvement); must be considered in any patient presenting with cardiomyopathy + myopathy.
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Exercise restriction: Data are insufficient to make specific exercise recommendations for FLNC ACM; guidelines currently address exercise restriction specifically for ARVC. (sources/acm-hrs-2019)
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VA meta-analysis (DCM, n=11,451): Truncating FLNC mutations investigated in three cohort studies; 82% of participants experienced premature SCD or sustained VA. FLNC is one of three gene variants (with LMNA and PLN) highlighted as key non-pooled arrhythmic risk predictors in DCM. Mechanism: FLNC truncating variants cause DCM/ACM overlap phenotype with LV dysfunction via disrupted Z-disc anchoring and costamere-sarcomere interaction. (sources/VA-DCM-Sammani-2020)
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VUS burden in early-onset AF: FLNC was among the most common VUS genes (81 VUSs) in 1293 patients with early-onset AF who underwent WGS. Because FLNC is associated with potentially fatal ventricular arrhythmias (VT/SCD), detection of a FLNC VUS is an example where genetic counseling with anticipatory guidance is especially important to address patient anxiety. (sources/eoaf-jama-2021)
Contradictions / Open Questions
- 82% SCD/VA rate — small cohort, potential ascertainment bias: The finding that 82% of FLNC truncating variant carriers experienced premature SCD or sustained VA derives from a small number of cohort studies with a total of 12 SCD cases from 54 carriers (a Spanish cohort). This extreme event rate almost certainly reflects referral and survival bias — index cases presented with arrhythmias and family members were screened after events. Population-level penetrance is likely substantially lower. (sources/VA-DCM-Sammani-2020, sources/acm-hrs-2019)
- No exercise restriction guidance specific to FLNC: Guidelines acknowledge insufficient data for specific exercise recommendations in FLNC ACM, in contrast to the explicit Class I exercise restriction in ARVC. Yet FLNC patients experience exercise-induced arrhythmias and carry high arrhythmic risk. The absence of guidance leaves clinicians and patients without evidence-based direction on physical activity. (sources/acm-hrs-2019)
- FLNC VUS in AF panels — management uncertainty: FLNC harbored 81 VUSs in the early-onset AF cohort, making it the second highest VUS-burden gene. Because FLNC is associated with potentially fatal ventricular arrhythmias rather than AF, a FLNC VUS in an AF patient raises concerns disproportionate to its clinical actionability — a genetic counseling dilemma with no guideline resolution. (sources/eoaf-jama-2021)
Connections
- Related to entities/ALVC
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to concepts/Sudden-Cardiac-Death
- Related to concepts/Early-Onset-Atrial-Fibrillation
- Related to concepts/VA-Risk-Stratification-DCM
- Related to entities/DCM