Hypertrophic Cardiomyopathy 26

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Classifications

Harrison's Part

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Inheritance

1

Autosomal Dominant HP:0000006

CMH26 families transmit a single heterozygous non-truncating FLNC variant in an autosomal dominant pattern. Penetrance is reduced and expressivity variable: most reported FLNC-HCM variants segregate incompletely, and de novo variants account for a meaningful share of probands — in the ROD2 missense series only 6 of 21 families showed even moderate genotype-phenotype segregation and the remainder were de novo, while 2 of 12 variants in the ECG-defined hypertrophic/restrictive cohort were apparently de novo.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:28356264 SUPPORT Human Clinical

"Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation."

Establishes dominant transmission with reduced penetrance as the inheritance pattern in the largest dedicated FLNC-HCM screening cohort.

PMID:26666891 SUPPORT Human Clinical

"we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM"

Dominant segregation of non-truncating FLNC variants in the restrictive pole of the same hypertrophic-restrictive continuum modelled by this entry (MONDO records restrictive cardiomyopathy 5 as a synonym of CMH26).

PMID:35952944 SUPPORT Human Clinical

"A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants."

Quantifies both the incomplete segregation and the de novo fraction in the ROD2 missense series. PARTIAL because it qualifies rather than establishes dominant transmission.

+ 1 more reference

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Mechanistic Hypotheses

3

Non-truncating filamin C aggregation / Z-disc proteotoxicity model

flnc_nontruncating_aggregation_model CANONICAL

Evidence balance 4 support

The default model for the hypertrophic pole of FLNC disease holds that missense and other non-truncating variants yield a filamin C protein that is still expressed but misfolds, accumulates as large cytoplasmic aggregates, and destabilizes the Z-disc. Sarcomeric organization degrades, the myocardium becomes stiff and hypertrophies, and the patient develops a hypertrophic-restrictive phenotype. This is explicitly the opposite arm of the FLNC mechanism dichotomy from the haploinsufficiency that follows truncation.

Pathograph links

Filamin C Z-Disc Cross-Linking Defect -> Mutant Filamin C Aggregation and Proteostatic Burden DIRECT Variant-class-specific arm: only non-truncating variants generate a misfolded, aggregation-prone filamin C protein.

Show evidence (4 references)

PMID:34535832 SUPPORT Other

"Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation."

States the two-mechanism dichotomy directly and assigns protein aggregation to the non-truncating variant class that causes the hypertrophic phenotype. Evidence source is OTHER because this is a review.

PMID:25351925 SUPPORT Human Clinical

"Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle"

The human arm of the founding CMH26 study: sarcomeric disorganization in the myocardium of FLNC-mutated hypertrophic cardiomyopathy patients.

PMID:25351925 SUPPORT In Vitro

"functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates"

The functional arm of the same study: the HCM-associated FLNC variants form filamin C aggregates when expressed. Split from the preceding item because the two halves of the source sentence report different evidence types.

+ 1 more reference

Convergent proteotoxic / lysosomal-autophagic mechanism across FLNC variant classes

flnc_convergent_proteotoxicity ALTERNATIVE

Evidence balance 3 support

An isogenic CRISPR hiPSC-cardiomyocyte series complicates the clean dichotomy. An in-frame deletion that preserves filamin C expression but causes aggregation — the engineered analogue of the hypertrophic variant class — and a haploinsufficient line modelling the dilated class both converged on increased lysosome content, enhanced autophagic flux, and accumulation of filamin C binding partners and Z-disc proteins, while sarcomere formation and contractile function were preserved in both heterozygous states. This argues that the proximal cardiomyocyte lesion in the hypertrophic arm is proteostatic rather than contractile, and that the two variant classes may share a downstream degradative bottleneck even though their clinical phenotypes diverge.

Pathograph links

Mutant Filamin C Aggregation and Proteostatic Burden -> Z-Disc and Sarcomere Disarray INDIRECT UNKNOWN INTERMEDIATES The step from proteostatic burden to structural disarray is inferred rather than demonstrated: in heterozygous human iPSC-cardiomyocytes the lysosomal/autophagic phenotype appeared while sarcomere assembly and function were still preserved, so the intermediates that eventually convert proteostatic stress into myocardial disarray are unknown.

Show evidence (3 references)

DOI:10.1161/CIRCRESAHA.120.317076 SUPPORT In Vitro

"Although sarcomere formation and function were unaffected in FLNC +/ − and FLNC +/Δ7aa hiPSC-CMs, these heterozygous variants caused increases in lysosome content"

The load-bearing observation for this hypothesis: in the patient-realistic heterozygous states, sarcomere assembly and contractile function were preserved while the proteostatic phenotype appeared, in both the aggregate-forming and the haploinsufficient line.

DOI:10.1161/CIRCRESAHA.120.317076 SUPPORT In Vitro

"these heterozygous variants caused increases in lysosome content, enhancement of autophagic flux, and accumulation of FLNC-binding partners and Z-disc proteins."

The shared lysosomal/autophagic response of the aggregate-forming and the haploinsufficient heterozygous lines is the basis for this convergence hypothesis.

DOI:10.1161/CIRCRESAHA.120.317076 SUPPORT In Vitro

"which did not affect FLNC expression but caused aggregate formation, similar to FLNC variants associated with hypertrophic cardiomyopathy."

Establishes that the engineered in-frame deletion is an explicit model of the hypertrophic (aggregate-forming) FLNC variant class, which is what makes this experiment relevant to CMH26 rather than only to the dilated arm.

ROD2-domain signaling / matrix-remodeling arm without demonstrable aggregation

flnc_rod2_nonaggregating_signaling_model EMERGING

Evidence balance 2 support

A competing or superimposed arm proposes that at least some non-truncating FLNC variants — specifically those clustered in the ROD2 domain, a protein-interaction and signaling region — produce the hypertrophic-restrictive phenotype without forming detectable cytoplasmic aggregates, acting instead through altered filamin C distribution among cardiomyocytes and differential extracellular matrix remodeling. In the largest ROD2-specific series the transfected cell models failed to show aggregation, which is difficult to reconcile with a purely proteotoxic model and leaves the proximal mechanism for this variant subset unresolved.

Pathograph links

Filamin C Z-Disc Cross-Linking Defect -> Altered Extracellular Matrix Remodeling INDIRECT UNKNOWN INTERMEDIATES ROD2-domain arm: matrix remodeling and redistributed filamin C are observed histologically without demonstrable aggregation, and the intermediates are unknown.

Show evidence (2 references)

PMID:35952944 SUPPORT In Vitro

"HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC."

Cell-model result that directly withholds support from the aggregation model for ROD2 missense variants, motivating a separate, non-proteotoxic hypothesis arm for this subset.

PMID:35952944 SUPPORT Human Clinical

"Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology."

Names the histological correlates — matrix remodeling and altered filamin C distribution — that this arm proposes in place of aggregate deposition.

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Discussions and Knowledge Gaps

3

Is FLNC a genuine hypertrophic cardiomyopathy gene, or is the reported FLNC-HCM association largely an artefact of rare missense variation being common in the general population?

CONTROVERSY OPEN flnc_missense_hcm_pathogenicity_contested

Attached to

pathophysiology#Filamin C Z-Disc Cross-Linking Defect genetic#FLNC Non-Truncating Pathogenic Variants

The evidence is genuinely split. In favour: FLNC missense variants segregate with HCM in multiple families, produce filamin C aggregates in patient myocardium and in cells, and in a 3,289-case sarcomere-negative HCM cohort the etiologic fraction reaches 0.98 within the ECG-defined subgroup. Against: a 540-patient HCM cohort found FLNC variants at a rate statistically indistinguishable from controls with poor pedigree segregation and no excess mortality; even the supportive 448-patient screen downgraded 14 of 20 candidate variants to uncertain or likely benign; and the burden analysis puts the etiologic fraction across all HCM cases at only 0.45. Decisively, the ClinGen Hereditary Cardiovascular Disease GCEP did not simply fail to curate FLNC-HCM: it re-curated FLNC as one of three genes selected for HCM-like phenotypes presenting as isolated left ventricular hypertrophy, restricted the curation to non-loss-of-function variants (explicitly separating them from the loss-of-function arrhythmogenic entity), retained a Definitive classification (8.1 genetic + 6 experimental = 14.1 points) — but assigned it to the disease entity myofibrillar myopathy, with left ventricular hypertrophy and restrictive cardiomyopathy listed as associated features rather than as a standalone hypertrophic entity. So the expert-panel position is that the non-truncating FLNC cardiac phenotype is the cardiac expression of filaminopathy/MFM, not a separate CMH. The emerging resolution is that FLNC-related hypertrophic disease is real but narrower than the raw carrier rates imply, is best identified phenotype-first (restrictive features plus the characteristic repolarization ECG) rather than genotype-first, and is arguably better nosologically placed on the filaminopathy spectrum than in the CMH numbered series.

Proposed experiments

Prospective ROD2-restricted segregation and functional study

exp_cmh26_rod2_segregation_functional

Recruit families carrying ROD2-domain FLNC missense variants — the subset with the strongest clustering signal — and collect prospective cascade segregation data alongside a standardized functional battery (aggregation assay, filamin C distribution, lysosomal/autophagic readouts) in patient-derived cardiomyocytes. Powering segregation and function together on one variant class is the most direct route to converting the current variants of uncertain significance into interpretable calls.

ClinGen gene-disease validity curation of FLNC for the hypertrophic phenotype

exp_cmh26_clingen_hcm_validity_curation

Formal ClinGen Hereditary Cardiovascular Disease GCEP curation of the FLNC-hypertrophic cardiomyopathy relationship, matching the existing Definitive assertions for FLNC-myofibrillar myopathy and FLNC-dilated cardiomyopathy. An expert-panel classification, restricted to non-truncating alleles, would settle whether CMH26 should be reported clinically and would give this entry a citable validity anchor.

Show evidence (4 references)

PMID:30411535 SUPPORT Human Clinical

"FLNC mutations were common in both HCM patients and healthy population. The pathogenicity of FLNC mutations detected in HCM patients and its association with the clinical outcomes should be cautiously interpreted."

The sceptical position in this controversy, stated by its authors.

PMID:41672210 SUPPORT Human Clinical

"Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99)."

The proposed resolution: low explanatory power overall, very high within a phenotypically defined subgroup.

PMID:39132495 SUPPORT Other

"FLNC was curated for non -loss of function variants only, after pre-curation supported these variant types as distinct from the arrhythmogenic cardiomyopathy disease entity associated with loss of function FLNC variants."

The ClinGen expert panel independently adopts the same variant-class split this entry is built on, and did so as an explicit pre-curation decision. Evidence source is OTHER because this is an expert-panel curation report.

+ 1 more reference

Should CMH26 be modelled as a hypertrophic cardiomyopathy, given that MONDO lists restrictive cardiomyopathy 5 among its exact synonyms and every large series describes a hypertrophic-restrictive overlap rather than pure hypertrophy?

INTERPRETATION OPEN cmh26_hypertrophic_vs_restrictive_boundary

Attached to

pathophysiology#Impaired Diastolic Relaxation and Myocardial Stiffening

MONDO:0014883 is asserted as a subtype of familial hypertrophic cardiomyopathy and carries CMH26 and cardiomyopathy, familial restrictive 5 as exact synonyms of the same node, reflecting the OMIM 617047 entry. The literature supports the merge: the ROD2 series describes an HCM-RCM overlap, the 2026 family study describes hypertrophic and restrictive features together, and the original FLNC restrictive families carry the same class of non-truncating allele. This entry follows MONDO in treating the hypertrophic node as primary while curating restrictive physiology as a first-class phenotype rather than splitting a second entity. If MONDO later separates the restrictive node, this entry should be re-scoped rather than duplicated.

Show evidence (1 reference)

PMID:35952944 SUPPORT Human Clinical

"FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling."

Documents the overlap that motivates treating hypertrophic and restrictive presentations as one entity here.

Do the available Flnc animal models say anything about CMH26, given that every published mouse model is a loss-of-function model and therefore reproduces the truncating dilated arm rather than the non-truncating hypertrophic one?

HUMAN MODEL MISMATCH OPEN flnc_animal_models_do_not_model_the_hypertrophic_arm

Attached to

pathophysiology#Mutant Filamin C Aggregation and Proteostatic Burden pathophysiology#Filamin C Z-Disc Cross-Linking Defect

Mouse Flnc genetics has been done exclusively by deletion. Global and cardiomyocyte-specific Flnc knockouts die in utero from ruptured ventricular myocardium, and an inducible adult cardiac-specific knockout produces rapid onset dilated cardiomyopathy with reduced systolic force and Z-disk misalignment. Both are loss-of-function, i.e. the haploinsufficiency mechanism that in humans causes the dilated and arrhythmogenic phenotypes, and neither reproduces hypertrophy, restrictive physiology, or filamin C aggregation. No knock-in of a human CMH26 missense allele has been reported. The consequence is that the aggregation and proteostasis nodes of this entry rest on human myocardium, human iPSC-cardiomyocytes and transfected cell lines, with no in vivo corroboration at all — and that mouse Flnc data must not be imported into this entry as if it modelled the hypertrophic arm.

Proposed experiments

Knock-in mouse carrying a human CMH26 ROD2 missense allele

exp_cmh26_missense_knockin_mouse

Generate a knock-in mouse bearing a segregating human ROD2-domain FLNC missense allele (rather than a null allele) and phenotype it for wall thickness, diastolic function, trabeculation, filamin C aggregation, and lysosomal/autophagic markers. This is the missing in vivo test of whether the non-truncating allele class is sufficient to produce the hypertrophic and restrictive phenotype in a mammal.

Engineered heart tissue from CMH26 patient iPSC-cardiomyocytes

exp_cmh26_engineered_heart_tissue_diastolic

Build three-dimensional engineered heart tissue from patient-derived CMH26 iPSC-cardiomyocytes and measure passive tension and relaxation kinetics alongside aggregate and lysosomal readouts, to test whether aggregation is sufficient to produce the stiffness that defines the clinical phenotype without invoking an animal model.

Show evidence (2 references)

PMID:35055055 SUPPORT Model Organism

"To determine how FLNC regulates systolic force transmission and DCM remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO) model to produce a rapid onset of DCM in adult mice."

The best-characterized adult mouse Flnc model is a knockout and produces dilated, not hypertrophic, cardiomyopathy — establishing the mismatch this discussion records.

PMID:36706168 SUPPORT Model Organism

"we demonstrated Flnc global (FlncgKO) and cardiomyocyte-specific knockout (FlnccKO) mice died in utero from severely ruptured ventricular myocardium"

The complete-loss mouse phenotype is embryonic myocardial rupture, a developmental structural failure with no counterpart in adult-onset human CMH26, reinforcing that mouse Flnc deletion does not model this entity.

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Pathophysiology

8

Filamin C Z-Disc Cross-Linking Defect

FLNC encodes filamin C, the striated-muscle filamin. It is an actin-cross-linking dimer built from an N-terminal actin-binding domain plus 24 immunoglobulin-like repeats, with calpain-sensitive hinges, dimerization through repeat 24, and Z-disc targeting via a unique 82-residue insertion in repeat 20; at the Z-disc it cross-links thin filaments from adjacent sarcomeres and links the sarcomere to the sarcolemma. The primary lesion in CMH26 is a qualitative perturbation of this cross-linking protein by a non-truncating (usually missense) variant — not a thick- or thin-filament contractile lesion, and not simple loss of one allele. Reported HCM-associated variants are predominantly missense and cluster in the ROD2 region.

Non-truncating filamin C aggregation / Z-disc proteotoxicity model ROD2-domain signaling / matrix-remodeling arm without demonstrable aggregation

Cardiomyocyte CL:0000746

FLNC hgnc:3756

Actin crosslink formation GO:0051764 ⚠ ABNORMAL

actin filament binding GO:0051015 ⚠ ABNORMAL structural constituent of muscle GO:0008307 ⚠ ABNORMAL

Z disc GO:0030018

Myocardium UBERON:0002349

Downstream

Mutant Filamin C Aggregation and Proteostatic Burden Variant-class-specific arm: only non-truncating variants generate a misfolded, aggregation-prone filamin C protein.

Z-Disc and Sarcomere Disarray

Altered Extracellular Matrix Remodeling ROD2-domain arm: matrix remodeling and redistributed filamin C are observed histologically without demonstrable aggregation, and the intermediates are unknown.

Show evidence (6 references)

PMID:32295012 SUPPORT Other

"FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres."

Establishes the Z-disc localization and Z-disc-forming role of filamin C that this trigger node perturbs. Evidence source is OTHER because this is a structural review.

PMID:32295012 SUPPORT Other

"FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2)."

Gives the domain architecture that determines where HCM-associated missense variants fall.

PMID:32295012 SUPPORT Other

"The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit."

Sources the repeat-24 dimerization step whose failure is the proximal molecular event in the aggregation arm.

+ 3 more references

Mutant Filamin C Aggregation and Proteostatic Burden

Non-truncating FLNC variants yield a protein that is expressed but misfolding-prone. In patient myocardium and in cells transfected with the HCM- and RCM-associated variants, mutant filamin C accumulates as large cytoplasmic inclusions rather than distributing normally to the Z-disc. The aggregate load sequesters filamin C away from its Z-disc function and imposes a protein-quality burden on the cardiomyocyte. This node is the mechanistic signature that separates the hypertrophic/restrictive FLNC phenotypes from the truncating dilated/arrhythmogenic phenotypes, in which myocardial immunohistochemistry shows no abnormal filamin C aggregates.

Convergent proteotoxic / lysosomal-autophagic mechanism across FLNC variant classes

Cardiomyocyte CL:0000746

Protein refolding GO:0042026 ⚠ ABNORMAL Protein homooligomerization (filamin C dimerization) GO:0051260 ↓ DECREASED Autophagy GO:0006914 ↑ INCREASED

Inclusion body GO:0016234 Lysosome GO:0005764

Downstream

Z-Disc and Sarcomere Disarray The step from proteostatic burden to structural disarray is inferred rather than demonstrated: in heterozygous human iPSC-cardiomyocytes the lysosomal/autophagic phenotype appeared while sarcomere assembly and function were still preserved, so the intermediates that eventually convert proteostatic stress into myocardial disarray are unknown.

Show evidence (5 references)

PMID:25351925 SUPPORT In Vitro

"functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates"

Direct functional demonstration that the HCM-associated FLNC variants generate filamin C aggregates.

PMID:26666891 SUPPORT Human Clinical

"Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry."

Confirms filamin C-specific aggregates in human myocardium carrying non-truncating FLNC variants at the restrictive pole of this hypertrophic-restrictive entity.

PMID:27908349 SUPPORT Human Clinical

"Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations."

The negative control for this node from the opposite variant class: truncating FLNC carriers, who develop dilated/arrhythmogenic rather than hypertrophic disease, do not show the aggregates. Anchors aggregation as specific to the non-truncating class.

+ 2 more references

Z-Disc and Sarcomere Disarray

Loss of competent filamin C cross-linking at the Z-disc, compounded by aggregate sequestration of the protein, degrades sarcomeric organization. Endomyocardial and explant tissue from FLNC-mutated hypertrophic patients shows marked sarcomeric abnormalities, the cardiomyocyte-level lesion that the myocardium then compensates for by hypertrophy and matrix deposition.

Cardiomyocyte CL:0000746

Sarcomere organization GO:0045214 ⚠ ABNORMAL

Z disc GO:0030018

Myocardium UBERON:0002349

Downstream

Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling

Impaired Diastolic Relaxation and Myocardial Stiffening

Show evidence (2 references)

PMID:25351925 SUPPORT Human Clinical

"Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle"

Documents sarcomeric disorganization in the myocardium of FLNC-mutated hypertrophic cardiomyopathy patients.

PMID:34535832 SUPPORT Other

"Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance."

Supplies the normal function — sarcomere stability maintenance — whose loss produces this node. Evidence source is OTHER because this is a review.

Altered Extracellular Matrix Remodeling

Myocardium from carriers of ROD2-domain FLNC missense variants shows differential extracellular matrix remodeling on histology, alongside altered distribution of filamin C among cardiomyocytes. The direction and mechanical consequence of that remodeling were not measured; it is placed upstream of the diastolic node as the plausible tissue-level correlate of the restrictive component in this variant subset, where aggregation is not demonstrable, but the link is an inference rather than a reported result.

Cardiomyocyte CL:0000746

Myocardium UBERON:0002349

Downstream

Impaired Diastolic Relaxation and Myocardial Stiffening

Show evidence (1 reference)

PMID:35952944 SUPPORT Human Clinical

"Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology."

Direct histological evidence of matrix remodeling in ROD2 missense carriers with the HCM-RCM overlap phenotype.

Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling

The myocardium responds to the Z-disc lesion with cardiomyocyte hypertrophy and geometric remodeling, giving the defining left ventricular hypertrophy of CMH26. Unlike sarcomeric hypertrophic cardiomyopathy driven by hypercontractile thick-filament mutations, the FLNC-hypertrophic ventricle remodels toward a small, thick-walled, poorly compliant cavity with lower rather than higher contractility.

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Myocardium UBERON:0002349

Downstream

Impaired Diastolic Relaxation and Myocardial Stiffening

Electrical Instability and Arrhythmogenesis

Show evidence (2 references)

PMID:41672210 SUPPORT Human Clinical

"FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype."

Characterizes the FLNC hypertrophic remodeling pattern — small cavity, reduced contractility — as distinct from the hypercontractile sarcomeric HCM pattern.

PMID:25351925 SUPPORT Human Clinical

"Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families."

Establishes that the hypertrophic phenotype, not a dilated one, is what segregates with these FLNC variants across multiple families.

Impaired Diastolic Relaxation and Myocardial Stiffening

The stiffened, hypertrophied ventricle fills poorly. Severe diastolic dysfunction — rather than systolic failure of a dilated chamber — is the dominant hemodynamic abnormality in FLNC hypertrophic disease and is what pushes the phenotype toward the restrictive end of the continuum, with advanced heart failure at relatively young ages.

Myocardium UBERON:0002349

Downstream

Heart Failure and Sudden Cardiac Death

Show evidence (2 references)

PMID:35952944 SUPPORT Human Clinical

"During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths"

Quantifies diastolic dysfunction as the dominant functional lesion in the ROD2 missense HCM-RCM cohort, with transplant and heart-failure death as outcomes.

PMID:26666891 SUPPORT Human Clinical

"Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases."

Independent family-based evidence that non-truncating FLNC variants cause heart failure through diastolic rather than systolic failure.

Electrical Instability and Arrhythmogenesis

A distinctive repolarization ECG pattern marks the genetically explained subgroup, and the founding CMH26 series reported an excess of sudden cardiac death among FLNC-mutated patients. The magnitude of that arrhythmic risk is contested — a later 540-patient HCM cohort found no excess all-cause or cardiac mortality among FLNC variant carriers — and whether the arrhythmic substrate resembles that of the truncating dilated/arrhythmogenic FLNC phenotype is not established.

Myocardium UBERON:0002349

Downstream

Heart Failure and Sudden Cardiac Death

Show evidence (2 references)

PMID:25351925 SUPPORT Human Clinical

"Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death."

Establishes excess sudden cardiac death in the founding FLNC hypertrophic cardiomyopathy cohort.

PMID:41672210 SUPPORT Human Clinical

"Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197)."

Documents an FLNC-specific repolarization abnormality, the electrical correlate of this node, at 37 percent versus 1 percent in non-FLNC HCM.

Heart Failure and Sudden Cardiac Death

The terminal common outcome of CMH26: advanced heart failure requiring transplantation, heart-failure death, or cardiac arrest. In the ECG-defined FLNC hypertrophic/restrictive group, at least one such event had occurred in the majority of families.

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group"

Quantifies the hard-outcome burden in FLNC hypertrophic/restrictive families.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 5

Hypertrophic Cardiomyopathy HP:0001639

Show evidence (2 references)

PMID:25351925 SUPPORT Human Clinical

"Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families."

Segregation of FLNC variants with hypertrophic cardiomyopathy in eight independent families.

PMID:28356264 SUPPORT Human Clinical

"We provide a compelling evidence of the involvement of FLNC in the development of HCM."

Independent large-cohort confirmation of the FLNC-hypertrophic cardiomyopathy association.

Left Ventricular Hypertrophy HP:0001712

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype."

Describes the FLNC hypertrophic remodeling geometry (small cavity, low contractility) that accompanies the wall thickening.

Left Ventricular Diastolic Dysfunction VERY_FREQUENT HP:0025168

Show evidence (2 references)

PMID:35952944 SUPPORT Human Clinical

"During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths"

Reports diastolic dysfunction in 16 of 20 assessed individuals (80%), supporting both the association and the VERY_FREQUENT frequency band (80-100%).

PMID:26666891 SUPPORT Human Clinical

"Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases."

Independent confirmation that severe diastolic dysfunction is the heart-failure mechanism in non-truncating FLNC disease.

Congestive Heart Failure HP:0001635

Show evidence (2 references)

PMID:41672210 SUPPORT Human Clinical

"Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group"

Documents heart-failure death and transplantation as outcomes in FLNC hypertrophic/restrictive families.

PMID:35952944 SUPPORT Human Clinical

"During a median follow-up of 6.49 years, they presented with advanced heart failure"

Independent cohort reporting progression to advanced heart failure.

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:25351925 SUPPORT Human Clinical

"Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death."

Direct statement of increased sudden cardiac death incidence in FLNC hypertrophic cardiomyopathy patients.

PMID:30411535 REFUTE Human Clinical

"FLNC mutations did not increase the risk for either all-cause mortality (HR 0.746, 95% CI 0.222-2.295, p = 0.575) or cardiac mortality (HR 0.615, 95% CI 0.153-1.947, p = 0.354) in HCM patients during a follow-up of 4.7 ± 3.2 years."

A large single-center HCM cohort that found no excess mortality among FLNC variant carriers, directly contradicting the sudden-death excess reported in the founding series. Recorded as REFUTE so the conflict is explicit rather than averaged away.

Other 4

Restrictive Cardiomyopathy HP:0001723

Show evidence (2 references)

PMID:41672210 SUPPORT Human Clinical

"Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities."

States the combined hypertrophic-and-restrictive character of the non-truncating FLNC phenotype.

PMID:35952944 SUPPORT Human Clinical

"FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling."

Independent series reporting the same restrictive-hypertrophic overlap for ROD2-domain missense variants.

Distinctive Repolarization ECG Pattern FREQUENT Abnormal EKG HP:0003115

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197)."

Supports both the phenotype and the FREQUENT band (37%, i.e. within 30-79%), and establishes its discriminating value against non-FLNC HCM.

Left Ventricular Hypertrabeculation Increased density of left ventricular trabeculae HP:0031194

Show evidence (1 reference)

PMID:35952944 SUPPORT Human Clinical

"showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance)."

Reports hypertrabeculation with saw-tooth appearance as part of the FLNC-mRod2 cardiac phenotype. The source describes increased trabeculation only and never uses the word "noncompaction", so the binding is to increased trabecular density rather than to left ventricular noncompaction, whose defining thin compacted layer would contradict the thick-walled hypertrophic phenotype modelled here; the preferred_term preserves the source wording.

Extracardiac Musculoskeletal Abnormalities Abnormality of the musculoskeletal system HP:0033127

Show evidence (2 references)

PMID:41672210 SUPPORT Human Clinical

"musculoskeletal abnormalities were present in 4 families (33%)"

Reports extracardiac musculoskeletal involvement in 4 of 12 (33%) FLNC hypertrophic/restrictive families. No frequency band is asserted because the reported proportion is family-level, not the per-individual frequency the FrequencyEnum bands describe.

PMID:35952944 REFUTE Human Clinical

"absence of cardiac conduction disturbances or skeletal myopathy"

Directly contradicts extracardiac muscle involvement as a general feature: the 21-family ROD2 missense cohort had no clinical skeletal myopathy. Recorded as REFUTE so the inconsistency between cohorts is explicit, and so this phenotype is never read as equating CMH26 with FLNC myofibrillar myopathy.

🧬

Genetic Associations

1

FLNC Non-Truncating Pathogenic Variants (Non-truncating (predominantly missense) pathogenic variants)

Gene: FLNC hgnc:3756 relationship_type: CAUSATIVE

Autosomal Dominant

Show evidence (9 references)

PMID:34535832 SUPPORT Other

"Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy."

The core genotype-phenotype rule for this entry, stated explicitly: non-truncating variants map to the hypertrophic and restrictive phenotypes, truncating variants to the dilated and arrhythmogenic ones. Evidence source is OTHER because this is a review.

PMID:27908349 SUPPORT Human Clinical

"Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy."

The strongest single piece of evidence for the variant-class split: in a 2,877-patient screen, truncating FLNC variants did not occur at all among 1,078 hypertrophic cardiomyopathy patients.

PMID:27908349 SUPPORT Human Clinical

"Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death."

Names the phenotype that the truncating class does cause, which is the entity this one must not be conflated with.

+ 6 more references

Variants (4)

FLNC p.A1539T

Gene: FLNC hgnc:3756

The founding CMH26 missense variant, identified by whole-exome sequencing and segregating with familial hypertrophic cardiomyopathy in the index family reported by Valdes-Mas and colleagues.

Show evidence (1 reference)

PMID:25351925 SUPPORT Human Clinical

"Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family."

Names the variant and reports its segregation with familial hypertrophic cardiomyopathy in the index family.

FLNC p.S1624L

Gene: FLNC hgnc:3756

ROD-region missense variant segregating with autosomal dominant restrictive cardiomyopathy; myocardial immunohistochemistry showed filamin C-specific cytoplasmic inclusions, and the same variant produced cytoplasmic aggregates in transfected myoblasts.

Show evidence (1 reference)

PMID:26666891 SUPPORT Human Clinical

"Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry."

Ties this specific allele to filamin C-positive myocardial inclusions, the aggregation signature of the non-truncating variant class.

FLNC p.I2160F

Gene: FLNC hgnc:3756

Second missense variant reported with autosomal dominant restrictive cardiomyopathy in the same study, in a family whose myocardium likewise showed cytoplasmic protein inclusions.

Show evidence (1 reference)

PMID:26666891 SUPPORT Human Clinical

"we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM"

Reports p.I2160F as the second segregating non-truncating allele in this two-family series.

FLNC ROD2-domain missense variants

Gene: FLNC hgnc:3756

A class rather than a single allele: rare missense variants clustered in the ROD2 domain, recruited across 21 families, that produce an HCM-RCM overlap with saw-tooth hypertrabeculation, severe diastolic dysfunction, and no demonstrable cytoplasmic aggregation in cell models.

Show evidence (2 references)

PMID:32112656 SUPPORT Other

"Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain."

Establishes ROD2-clustered missense variation as the characteristic CMH26 genotype class. Evidence source is OTHER because this is a mutation-update review.

PMID:35952944 SUPPORT Human Clinical

"We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2)."

Defines the ROD2 missense cohort whose phenotype this variant class entry describes.

💊

Medical Actions

5

Implantable Cardioverter Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Device therapy for primary or secondary prevention of sudden cardiac death. The founding CMH26 series reported excess sudden cardiac death among FLNC-mutated hypertrophic patients, and cardiac arrest is among the recorded hard outcomes in contemporary FLNC hypertrophic/restrictive families, so arrhythmic risk stratification is part of routine care. Note that the evidence base for arrhythmic risk in the non-truncating hypertrophic class is weaker and more contested than for FLNC truncating dilated/arrhythmogenic disease, where prompt defibrillator implantation is explicitly recommended; one large HCM cohort found no excess mortality in FLNC carriers.

Mechanism Target:

INHIBITS Electrical Instability and Arrhythmogenesis — A defibrillator does not modify the Z-disc lesion; it terminates the malignant ventricular arrhythmia that the remodeled myocardium generates.

Show evidence (2 references)

PMID:25351925 SUPPORT Human Clinical

"Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death."

Establishes the arrhythmic risk that motivates defibrillator consideration. PARTIAL because the paper reports risk, not device outcomes.

PMID:27908349 SUPPORT Human Clinical

"Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC."

The explicit device recommendation in the FLNC literature is for the truncating class, not this one. Recorded as PARTIAL and cited here precisely to mark that the recommendation does not transfer automatically to non-truncating hypertrophic carriers.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Definitive therapy for end-stage disease. Restrictive physiology with severe diastolic dysfunction drives young carriers to advanced heart failure, and transplantation is a recorded outcome in both the ROD2 missense cohort and the original FLNC restrictive families.

Mechanism Target:

INHIBITS Heart Failure and Sudden Cardiac Death — Replaces the failing organ; it is a rescue rather than a mechanism-directed therapy.

Show evidence (2 references)

PMID:26666891 SUPPORT Human Clinical

"Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases."

Documents transplantation as the treatment reached by patients with non-truncating FLNC cardiomyopathy.

PMID:35952944 SUPPORT Human Clinical

"During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths"

Three transplants among 20 assessed ROD2 missense carriers over a median 6.5 years.

Symptom-Directed Heart Failure and Antianginal Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: beta-blocker NCIT:C29576 non-dihydropyridine calcium channel blocker NCIT:C333

There is no FLNC-specific disease-modifying therapy, so pharmacological management is the generic hypertrophic-cardiomyopathy regimen: beta-blockers (or non-dihydropyridine calcium channel blockers when beta-blockade is not tolerated) to slow the heart rate, lengthen diastolic filling time and relieve angina and dyspnoea, with diuresis added cautiously once restrictive physiology and congestion dominate. Because the FLNC ventricle is small and stiff with impaired filling rather than obstructed by hypercontractility, the therapeutic goal here is filling time and congestion control rather than relief of outflow obstruction.

Mechanism Target:

INHIBITS Impaired Diastolic Relaxation and Myocardial Stiffening — Rate control lengthens diastole and partially offsets impaired filling; it does not modify the Z-disc or aggregation lesion upstream.

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype."

Establishes the haemodynamic problem this therapy is aimed at — small cavity, impaired filling, reduced contractility. PARTIAL because the paper characterizes the phenotype and does not report treatment outcomes; no FLNC-specific pharmacotherapy trial exists.

Cardiac Myosin Inhibition (mechanistically questionable in this entity)

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten (cardiac myosin inhibitor)

Cardiac myosin inhibitors such as mavacamten are a mechanism-directed therapy for hypertrophic cardiomyopathy — they reduce actin-myosin cross-bridge formation and so relieve the hypercontractility and outflow obstruction of sarcomeric HCM. That rationale does not transfer cleanly to CMH26. The FLNC-related hypertrophic/restrictive phenotype is explicitly described as occurring without hypercontractility, with lower contractility and a small cavity, so reducing contractility further is mechanistically questionable here. This entry records the treatment specifically to mark the caveat: no trial of a myosin inhibitor in genotyped FLNC carriers has been reported, and the phenotype argues against extrapolating the sarcomeric-HCM indication.

Show evidence (2 references)

PMID:41672210 REFUTE Human Clinical

"Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities."

Recorded as REFUTE because the absence of hypercontractility removes the mechanistic premise of cardiac myosin inhibition in this entity; the evidence argues against the treatment rather than for it.

DOI:10.1161/CIRCRESAHA.120.317076 SUPPORT In Vitro

"Although sarcomere formation and function were unaffected in FLNC +/ − and FLNC +/Δ7aa hiPSC-CMs, these heterozygous variants caused increases in lysosome content"

Cell-level corroboration that the heterozygous FLNC lesion is proteostatic rather than contractile, which is the same reason a contractility-lowering drug is a poor mechanistic fit. PARTIAL because it is an in vitro model, not a treatment study.

Cascade Genetic Screening and Longitudinal Surveillance of Relatives

Category: Screening Action: cascade genetic testing of relatives Ontology label: Genetic Testing NCIT:C15709

Because penetrance is reduced and expressivity variable, first-degree relatives of a carrier are offered predictive genetic testing followed by periodic ECG and echocardiography. The ECG is particularly valuable here given the FLNC-specific repolarization pattern. Cascade screening is also the means by which segregation data accumulate — the evidence most needed to resolve the pathogenicity of individual FLNC missense variants.

Show evidence (2 references)

PMID:35952944 SUPPORT Human Clinical

"Carriers underwent advanced cardiac imaging and genetic cascade screening."

Documents cascade screening plus imaging as the family-management approach used in the reference FLNC hypertrophic/restrictive cohort.

PMID:28356264 SUPPORT Human Clinical

"Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation."

Reduced penetrance and sparse segregation data are exactly why longitudinal family surveillance rather than one-off testing is required.

🔬

Diagnosis

5

Echocardiography

First-line imaging. Establishes the hypertrophic phenotype (wall thickness), the characteristically small left ventricular cavity, and the restrictive filling pattern with severe diastolic dysfunction that distinguishes FLNC hypertrophic disease from hypercontractile sarcomeric HCM. Also the surveillance modality for genotype-positive relatives.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype."

These are the echocardiographic parameters (cavity size, contractility, diastolic function) that characterize the FLNC phenotype.

Electrocardiography

A 12-lead ECG is disproportionately informative in this entity: the distinctive repolarization pattern is present in about a third of FLNC variant carriers with HCM/RCM but in only 1% of non-FLNC HCM patients, and the ECG-positive subgroup is the one in which rare FLNC missense variants are almost fully explanatory. It therefore functions as a phenotype-first triage step for FLNC variant interpretation.

electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99)."

Quantifies the diagnostic value of the ECG phenotype for FLNC variant interpretation.

Cardiac Magnetic Resonance Imaging

Advanced imaging is part of the standard workup of FLNC variant carriers, characterizing wall thickness, cavity size, trabecular morphology (the saw-tooth hypertrabeculation of the ROD2 phenotype), and myocardial tissue characterization. No FLNC-specific late-gadolinium-enhancement signature has been established for the hypertrophic arm, so this is used as in other hypertrophic cardiomyopathies rather than as a gene-specific test.

cardiac magnetic resonance imaging NCIT:C137915

Show evidence (1 reference)

PMID:35952944 SUPPORT Human Clinical

"Carriers underwent advanced cardiac imaging and genetic cascade screening."

Documents advanced cardiac imaging as part of the standard evaluation of FLNC variant carriers. PARTIAL because the abstract does not name the modality or report a gene-specific imaging finding.

Genetic Testing

Multi-gene cardiomyopathy panel or exome sequencing including FLNC. Three interpretive rules are specific to this gene: the variant class must be recorded (non-truncating for CMH26, truncating for the dilated/arrhythmogenic entity); missense variants require segregation or functional support before being called pathogenic, since FLNC missense variation is common in unaffected populations; and calls in exons 46-48 must be checked against the highly homologous downstream FLNC pseudogene, which is a short-read mis-mapping hazard in exactly the ROD2-adjacent region where this entity's variants cluster.

genetic testing NCIT:C15709

Show evidence (3 references)

PMID:28356264 SUPPORT Human Clinical

"A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes."

Establishes the panel-based testing approach in which FLNC is sequenced alongside the classic sarcomere genes.

PMID:30411535 SUPPORT Human Clinical

"Pedigree analysis showed that mutations were not well segregated with HCM."

Supports the requirement for segregation evidence before calling an FLNC missense variant causal in a hypertrophic cardiomyopathy patient.

PMID:39132495 SUPPORT Other

"FLNC has a pseudogene located 53.6kb downstream from the functional FLNC gene, and exons 46, 47, and 48 are 98% homologous in the functional and pseudogene."

Documents the technical hazard specific to sequencing this gene: near-identical pseudogene sequence over exons 46-48 makes short-read alignment ambiguous there, so variant calls in those exons need orthogonal confirmation before being reported. Sourced to the ClinGen HCVD-GCEP reappraisal, an expert-panel document rather than a primary study, hence OTHER.

Endomyocardial or Explant Histopathology

Not routine, but mechanistically decisive when tissue is available: filamin C-specific cytoplasmic inclusions identify the non-truncating aggregation mechanism, whereas their absence is characteristic of truncating FLNC disease. ROD2-domain missense carriers may instead show differential extracellular matrix remodeling without aggregates.

Show evidence (1 reference)

PMID:26666891 SUPPORT Human Clinical

"Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry."

Demonstrates the diagnostic histopathological signature of non-truncating FLNC disease.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No population-based prevalence estimate exists for the FLNC-specific form of hypertrophic cardiomyopathy. Occurrence is reported only as the yield of FLNC variants within sequenced HCM cohorts, and even that yield is disputed (see the case_fractions on the genetic entry and the discussion on contested missense pathogenicity). Rare-variant burden analysis in a large sarcomere-negative HCM cohort put the etiologic fraction of rare FLNC missense variants across all HCM cases at only 0.45, rising to 0.98 in the subgroup with the characteristic repolarization ECG.

Show evidence (1 reference)

PMID:41672210 SUPPORT Human Clinical

"Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99)."

Quantifies how much of the HCM case load rare FLNC missense variants actually explain, and shows the explanatory fraction is concentrated in an ECG-defined subgroup. PARTIAL because an etiologic fraction is not a population prevalence.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 26:

Sarcomeric hypertrophic cardiomyopathy (MYH7, MYBPC3 and other thick/thin filament genes) MONDO:0005045

Overlapping Features The dominant cause of familial HCM and the main alternative when left ventricular hypertrophy is found. Sarcomeric HCM arises from hypercontractile thick- and thin-filament lesions, whereas CMH26 is a Z-disc/protein-quality disease whose ventricle is not hypercontractile.

Distinguishing Features

A pathogenic variant in a definitive sarcomere gene (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1) explains the phenotype.
FLNC carriers show smaller cavity size, lower contractility, more severe diastolic dysfunction, and a restrictive tendency rather than hypercontractility.
The FLNC-specific repolarization ECG occurs in only about 1% of non-FLNC HCM patients.

Show evidence (2 references)

PMID:41672210 SUPPORT Human Clinical

"Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities."

States that the FLNC hypertrophic phenotype is discrete from generic HCM, including the absence of hypercontractility.

PMID:25351925 SUPPORT Human Clinical

"Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown."

Situates FLNC among the non-sarcomeric explanations sought for genotype-negative HCM.

FLNC truncating dilated and left-dominant arrhythmogenic cardiomyopathy MONDO:0005021

Overlapping Features The same gene, the opposite variant class and a different disease. Truncating FLNC variants cause a high-risk overlapping dilated/left-dominant arrhythmogenic phenotype with ventricular dilation, systolic dysfunction, myocardial fibrosis, a heavy ventricular-arrhythmia burden and frequent premature sudden death — and are absent from hypertrophic cohorts. dismech covers the arrhythmogenic and dilated poles of this in Arrhythmogenic_Right_Ventricular_Cardiomyopathy, DSP_Cardiomyopathy and Dilated_Cardiomyopathy; this entry deliberately does not duplicate them.

Distinguishing Features

The FLNC allele is truncating (nonsense, frameshift, splice-loss) rather than missense.
Left ventricular dilation with systolic dysfunction, not a small stiff hypertrophied cavity.
Myocardial immunohistochemistry shows no abnormal filamin C aggregates.
Inferolateral negative T waves and low QRS voltages, with early prophylactic defibrillator implantation recommended.

Show evidence (2 references)

PMID:27908349 SUPPORT Human Clinical

"Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death."

Defines the alternative FLNC entity that must be distinguished from CMH26.

PMID:27908349 SUPPORT Human Clinical

"Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy."

The distinguishing genotype fact: truncating alleles do not appear in hypertrophic cardiomyopathy.

FLNC myofibrillar myopathy (filaminopathy, MFM5) MONDO:0018943

Overlapping Features The skeletal-muscle FLNC disease. Adult-onset, slowly progressive muscle weakness with intracellular protein aggregates, classically caused by variants in the dimerization domain. Cardiac FLNC series repeatedly note the absence of clinical skeletal myopathy, so overt limb-girdle weakness points away from CMH26. dismech covers this in Myofibrillar_Myopathy.

Distinguishing Features

Progressive proximal skeletal-muscle weakness dominates the presentation.
Muscle biopsy shows myofibrillar disorganization with protein aggregates.
Cardiac involvement, when present, is secondary rather than the presenting problem.

Show evidence (2 references)

PMID:37174721 SUPPORT Human Clinical

"A subtype of MFM is caused by heterozygous mutations in the filamin C (FLNC) gene, exhibiting progressive muscle weakness, muscle structural alterations and intracellular protein accumulations."

Defines the skeletal-muscle FLNC phenotype that constitutes this differential.

PMID:33557094 SUPPORT Other

"Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy."

Records the historical relationship between the myopathic and cardiac FLNC phenotypes. Evidence source is OTHER because this is a review.

Familial restrictive cardiomyopathy from other causes Not Yet Curated MONDO:0016340

Overlapping Features Sarcomere-gene and other familial restrictive cardiomyopathies present with the same stiff, non-dilated ventricle and severe diastolic dysfunction. Because MONDO records restrictive cardiomyopathy 5 as a synonym of CMH26, the boundary between the hypertrophic and restrictive labels for a given FLNC family is partly nosological rather than biological.

Distinguishing Features

Restrictive physiology without significant wall thickening favors a non-FLNC restrictive cardiomyopathy.
Identification of a non-truncating FLNC variant with filamin C-positive myocardial inclusions favors this entity.

Show evidence (1 reference)

PMID:26666891 SUPPORT Human Clinical

"Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies."

Names the sarcomeric familial restrictive cardiomyopathies that form this differential and notes their shared genetic architecture with FLNC disease.

🧫

Experimental Models

3

Transfected cell models expressing mutant filamin C CELL_LINE

Heterologous and myogenic cell lines transfected with plasmids carrying individual FLNC missense variants, read out by confocal microscopy for filamin C distribution and aggregate formation. This is the workhorse assay that separates the two mechanistic arms of this entry: the founding CMH26 variants and the restrictive p.S1624L allele produce large cytoplasmic aggregates, whereas ROD2-domain variants did not. Note the assay is not single-species — the ROD2 experiments used human HT1080 fibrosarcoma cells alongside the rat H9c2 cardiomyoblast line — so the organism binding below reflects only the human component.

Organism

human NCBITaxon:9606

Cell source

Human HT1080 cells and myoblast lines (plus the rat H9c2 line) transfected with FLNC missense constructs

Publication

PMID:35952944

Show evidence (2 references)

PMID:35952944 SUPPORT In Vitro

"Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy."

Describes the model system and readout.

PMID:26666891 SUPPORT In Vitro

"Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity."

The positive result from the same class of assay, for an aggregation-competent non-truncating variant.

Isogenic CRISPR FLNC hiPSC-cardiomyocyte series IPSC_DERIVED_MODEL

Human induced pluripotent stem cell-derived cardiomyocytes CRISPR-edited to a matched allelic series: wild type, FLNC null, FLNC haploinsufficient (modelling the truncating/dilated arm), and a heterozygous in-frame deletion that preserves expression but forms aggregates (modelling the non-truncating/hypertrophic arm). The reference human system for separating the contractile from the proteostatic consequences of FLNC variants.

Organism

human NCBITaxon:9606

Cell source

CRISPR/Cas9-edited isogenic human iPSC lines

Publication

PMID:34405687

Show evidence (1 reference)

DOI:10.1161/CIRCRESAHA.120.317076 SUPPORT In Vitro

"which did not affect FLNC expression but caused aggregate formation, similar to FLNC variants associated with hypertrophic cardiomyopathy."

Identifies the in-frame-deletion line as the engineered model of the hypertrophic (aggregate-forming) FLNC variant class.

Patient-specific FLNC iPSC-derived cardiomyocytes (variant comparison) IPSC_DERIVED_MODEL

Patient-derived iPSC-cardiomyocytes carrying two clinically divergent FLNC missense variants — R1267Q from an arrhythmogenic cardiomyopathy family and V2264M from a restrictive cardiomyopathy family — profiled for calcium handling, sodium-channel kinetics, action potentials, and transcriptome. Used here as evidence that different FLNC missense alleles have distinguishable molecular consequences, which is the cell-level counterpart of the clinical genotype-phenotype divergence.

Organism

human NCBITaxon:9606

Cell source

iPSC lines from FLNC R1267Q and V2264M variant carriers

Publication

PMID:39315490

Show evidence (1 reference)

PMID:39315490 SUPPORT In Vitro

"We suggest distinct molecular effects of two FLNC variants linked to different types of cardiomyopathies in terms of myofilament structure, electrophysiology, ion channel function and intracellular calcium homeostasis providing the molecular the bases for their different clinical phenotypes."

Supports variant-specific molecular divergence within FLNC. PARTIAL because the two variants compared are arrhythmogenic and restrictive rather than a truncating-versus-missense pair, so it corroborates the principle of variant-specific mechanism without directly testing the hypertrophic arm.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 26
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMH26
- FLNC hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 26
- hypertrophic cardiomyopathy caused by mutation in FLNC
- cardiomyopathy, familial restrictive 5
description: >-
  Hypertrophic cardiomyopathy 26 (CMH26) is the FLNC-related form of familial
  hypertrophic cardiomyopathy. FLNC encodes filamin C, a large actin
  cross-linking protein of the striated-muscle Z-disc: an N-terminal
  actin-binding domain followed by 24 immunoglobulin-like repeats, dimerizing
  through repeat 24 and targeted to the Z-disc by a unique insertion in repeat
  20, where it also couples the sarcomere to the sarcolemma through integrin
  beta-1 and delta-sarcoglycan. The disease mechanism is therefore a Z-disc /
  protein-quality lesion rather than a thick- or thin-filament contractile
  lesion: non-truncating (predominantly missense) FLNC variants produce
  misfolded filamin C that forms large intracellular aggregates and disorganizes
  the sarcomere, and the resulting myocardium is stiff and hypertrophic with
  impaired relaxation rather than hypercontractile. The clinical picture spans a
  hypertrophic-to-restrictive continuum — left ventricular hypertrophy with a
  small, poorly compliant cavity, severe diastolic dysfunction, deep
  hypertrabeculation with a saw-tooth appearance in ROD2-domain carriers, a
  distinctive repolarization ECG, extracardiac musculoskeletal features, and
  progression to advanced heart failure, transplantation, or sudden cardiac
  death. CMH26 must be kept mechanistically distinct from the other FLNC
  cardiomyopathies: FLNC truncating variants are the ones enriched in dilated
  and left-dominant arrhythmogenic cardiomyopathy and are essentially absent
  from hypertrophic cohorts, and they act through haploinsufficiency without
  filamin C aggregates. Inheritance is autosomal dominant with reduced
  penetrance, and the pathogenicity of individual FLNC missense variants in
  hypertrophic cardiomyopathy remains actively contested.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 26
  term:
    id: MONDO:0014883
    label: hypertrophic cardiomyopathy 26
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the FLNC-specific form of
    hypertrophic cardiomyopathy. Occurrence is reported only as the yield of
    FLNC variants within sequenced HCM cohorts, and even that yield is disputed
    (see the case_fractions on the genetic entry and the discussion on contested
    missense pathogenicity). Rare-variant burden analysis in a large
    sarcomere-negative HCM cohort put the etiologic fraction of rare FLNC
    missense variants across all HCM cases at only 0.45, rising to 0.98 in the
    subgroup with the characteristic repolarization ECG.
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rare FLNC missense variant burden indicated a low case excess among all HCM
      cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in
      "ECG-positive" cases the etiologic fraction was substantially higher (0.98;
      95% confidence interval, 0.97-0.99).
    explanation: >-
      Quantifies how much of the HCM case load rare FLNC missense variants
      actually explain, and shows the explanatory fraction is concentrated in an
      ECG-defined subgroup. PARTIAL because an etiologic fraction is not a
      population prevalence.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMH26 families transmit a single heterozygous non-truncating FLNC variant in
    an autosomal dominant pattern. Penetrance is reduced and expressivity
    variable: most reported FLNC-HCM variants segregate incompletely, and de novo
    variants account for a meaningful share of probands — in the ROD2 missense
    series only 6 of 21 families showed even moderate genotype-phenotype
    segregation and the remainder were de novo, while 2 of 12 variants in the
    ECG-defined hypertrophic/restrictive cohort were apparently de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28356264
    reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the FLNC variants were associated with mild forms of HCM and a
      reduced penetrance, with few affected in the families to confirm the
      segregation.
    explanation: >-
      Establishes dominant transmission with reduced penetrance as the
      inheritance pattern in the largest dedicated FLNC-HCM screening cohort.
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C
      (FLNC), an actin-cross-linking protein mainly expressed in heart and
      skeletal muscle, segregating in two families with autosomal-dominant RCM
    explanation: >-
      Dominant segregation of non-truncating FLNC variants in the restrictive
      pole of the same hypertrophic-restrictive continuum modelled by this entry
      (MONDO records restrictive cardiomyopathy 5 as a synonym of CMH26).
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 6 families had moderate genotype-phenotype segregation, and the
      remaining were de novo variants.
    explanation: >-
      Quantifies both the incomplete segregation and the de novo fraction in the
      ROD2 missense series. PARTIAL because it qualifies rather than establishes
      dominant transmission.
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      5 of 12 variants (41.7%) in the "ECG-positive" group cosegregated, and 2
      were apparently de novo.
    explanation: >-
      Independent cohort giving the cosegregation and de novo proportions for the
      ECG-defined hypertrophic/restrictive group.
mechanistic_hypotheses:
- hypothesis_group_id: flnc_nontruncating_aggregation_model
  hypothesis_label: Non-truncating filamin C aggregation / Z-disc proteotoxicity model
  status: CANONICAL
  description: >-
    The default model for the hypertrophic pole of FLNC disease holds that
    missense and other non-truncating variants yield a filamin C protein that is
    still expressed but misfolds, accumulates as large cytoplasmic aggregates,
    and destabilizes the Z-disc. Sarcomeric organization degrades, the myocardium
    becomes stiff and hypertrophies, and the patient develops a
    hypertrophic-restrictive phenotype. This is explicitly the opposite arm of
    the FLNC mechanism dichotomy from the haploinsufficiency that follows
    truncation.
  evidence:
  - reference: PMID:34535832
    reference_title: "Filamin C in cardiomyopathy: from physiological roles to DNA variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Two major pathomechanisms in FLNC-related cardiomyopathy have been
      described: protein aggregation resulting from non-truncating mutations and
      haploinsufficiency triggered by filamin C truncation.
    explanation: >-
      States the two-mechanism dichotomy directly and assigns protein
      aggregation to the non-truncating variant class that causes the
      hypertrophic phenotype. Evidence source is OTHER because this is a review.
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with FLNC mutations show marked sarcomeric abnormalities in
      cardiac muscle
    explanation: >-
      The human arm of the founding CMH26 study: sarcomeric disorganization in the
      myocardium of FLNC-mutated hypertrophic cardiomyopathy patients.
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      functional analysis reveals that expression of these FLNC variants resulted
      in the formation of large filamin C aggregates
    explanation: >-
      The functional arm of the same study: the HCM-associated FLNC variants form
      filamin C aggregates when expressed. Split from the preceding item because
      the two halves of the source sentence report different evidence types.
  - reference: PMID:32112656
    reference_title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Interference with the dimerization and folding of the protein leads to
      aggregate formation detrimental for muscle function, as found in HCM and
      MFM.
    explanation: >-
      Assigns the misfolding/dimerization-failure to aggregation mechanism
      specifically to the hypertrophic (and myofibrillar-myopathy) arm of FLNC
      disease. Evidence source is OTHER because this is a mutation-update review.
- hypothesis_group_id: flnc_convergent_proteotoxicity
  hypothesis_label: Convergent proteotoxic / lysosomal-autophagic mechanism across FLNC variant classes
  status: ALTERNATIVE
  description: >-
    An isogenic CRISPR hiPSC-cardiomyocyte series complicates the clean
    dichotomy. An in-frame deletion that preserves filamin C expression but
    causes aggregation — the engineered analogue of the hypertrophic variant
    class — and a haploinsufficient line modelling the dilated class both
    converged on increased lysosome content, enhanced autophagic flux, and
    accumulation of filamin C binding partners and Z-disc proteins, while
    sarcomere formation and contractile function were preserved in both
    heterozygous states. This argues that the proximal cardiomyocyte lesion in
    the hypertrophic arm is proteostatic rather than contractile, and that the
    two variant classes may share a downstream degradative bottleneck even
    though their clinical phenotypes diverge.
  evidence:
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although sarcomere formation and function were unaffected in FLNC +/ − and
      FLNC +/Δ7aa hiPSC-CMs, these heterozygous variants caused increases in
      lysosome content
    explanation: >-
      The load-bearing observation for this hypothesis: in the patient-realistic
      heterozygous states, sarcomere assembly and contractile function were
      preserved while the proteostatic phenotype appeared, in both the
      aggregate-forming and the haploinsufficient line.
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      these heterozygous variants caused increases in lysosome content,
      enhancement of autophagic flux, and accumulation of FLNC-binding partners
      and Z-disc proteins.
    explanation: >-
      The shared lysosomal/autophagic response of the aggregate-forming and the
      haploinsufficient heterozygous lines is the basis for this convergence
      hypothesis.
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      which did not affect FLNC expression but caused aggregate formation,
      similar to FLNC variants associated with hypertrophic cardiomyopathy.
    explanation: >-
      Establishes that the engineered in-frame deletion is an explicit model of
      the hypertrophic (aggregate-forming) FLNC variant class, which is what
      makes this experiment relevant to CMH26 rather than only to the dilated
      arm.
- hypothesis_group_id: flnc_rod2_nonaggregating_signaling_model
  hypothesis_label: ROD2-domain signaling / matrix-remodeling arm without demonstrable aggregation
  status: EMERGING
  description: >-
    A competing or superimposed arm proposes that at least some non-truncating
    FLNC variants — specifically those clustered in the ROD2 domain, a
    protein-interaction and signaling region — produce the hypertrophic-restrictive
    phenotype without forming detectable cytoplasmic aggregates, acting instead
    through altered filamin C distribution among cardiomyocytes and differential
    extracellular matrix remodeling. In the largest ROD2-specific series the
    transfected cell models failed to show aggregation, which is difficult to
    reconcile with a purely proteotoxic model and leaves the proximal mechanism
    for this variant subset unresolved.
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant
      FLNC.
    explanation: >-
      Cell-model result that directly withholds support from the aggregation
      model for ROD2 missense variants, motivating a separate, non-proteotoxic
      hypothesis arm for this subset.
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Differential extracellular matrix remodeling and FLNC distribution among
      cardiomyocytes were confirmed on histology.
    explanation: >-
      Names the histological correlates — matrix remodeling and altered filamin C
      distribution — that this arm proposes in place of aggregate deposition.
pathophysiology:
- name: Filamin C Z-Disc Cross-Linking Defect
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    FLNC encodes filamin C, the striated-muscle filamin. It is an
    actin-cross-linking dimer built from an N-terminal actin-binding domain plus
    24 immunoglobulin-like repeats, with calpain-sensitive hinges, dimerization
    through repeat 24, and Z-disc targeting via a unique 82-residue insertion in
    repeat 20; at the Z-disc it cross-links thin filaments from adjacent
    sarcomeres and links the sarcomere to the sarcolemma. The primary lesion in
    CMH26 is a qualitative perturbation of this cross-linking protein by a
    non-truncating (usually missense) variant — not a thick- or thin-filament
    contractile lesion, and not simple loss of one allele. Reported
    HCM-associated variants are predominantly missense and cluster in the ROD2
    region.
  genes:
  - preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  - preferred_term: structural constituent of muscle
    term:
      id: GO:0008307
      label: structural constituent of muscle
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Actin crosslink formation
    term:
      id: GO:0051764
      label: actin crosslink formation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32295012
    reference_title: Structure and Function of Filamin C in the Muscle Z-Disc.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNC is localized in the Z-disc due to the unique insertion of 82 amino
      acid residues in repeat 20 and necessary for normal Z-disc formation that
      connect sarcomeres.
    explanation: >-
      Establishes the Z-disc localization and Z-disc-forming role of filamin C
      that this trigger node perturbs. Evidence source is OTHER because this is a
      structural review.
  - reference: PMID:32295012
    reference_title: Structure and Function of Filamin C in the Muscle Z-Disc.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNC consists of a N-terminal actin-binding domain followed by 24
      immunoglobulin-like repeats with two intervening calpain-sensitive hinges
      separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2).
    explanation: >-
      Gives the domain architecture that determines where HCM-associated missense
      variants fall.
  - reference: PMID:32295012
    reference_title: Structure and Function of Filamin C in the Muscle Z-Disc.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The FLNC subunit is dimerized through R24 and calpain cleaves off the
      dimerization domain to regulate mobility of the FLNC subunit.
    explanation: >-
      Sources the repeat-24 dimerization step whose failure is the proximal
      molecular event in the aggregation arm.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment
      to the plasmatic membrane.
    explanation: >-
      Adds the sarcolemmal-attachment role of filamin C, which is why the lesion
      is one of force coupling and Z-disc integrity rather than of the
      contractile filaments.
  - reference: PMID:36706168
    reference_title: Filamin C is Essential for mammalian myocardial integrity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results demonstrated that filamin C works in concert with β1
      integrin to maintain the structural integrity of myocardium during
      mammalian heart development.
    explanation: >-
      Names the specific sarcolemmal partner (beta-1 integrin) through which
      filamin C couples the sarcomere to the membrane. MODEL_ORGANISM because the
      demonstration is in knockout mice; it supports the molecular partnership,
      not the human hypertrophic phenotype.
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing reveals a variant in the gene encoding the
      sarcomeric protein filamin C (p.A1539T) that segregates with the disease in
      this family.
    explanation: >-
      The founding observation that a non-truncating FLNC variant segregates with
      familial hypertrophic cardiomyopathy, establishing FLNC as the CMH26 trigger
      gene.
  downstream:
  - target: Mutant Filamin C Aggregation and Proteostatic Burden
    causal_link_type: DIRECT
    hypothesis_groups:
    - flnc_nontruncating_aggregation_model
    description: >-
      Variant-class-specific arm: only non-truncating variants generate a
      misfolded, aggregation-prone filamin C protein.
  - target: Z-Disc and Sarcomere Disarray
    causal_link_type: DIRECT
  - target: Altered Extracellular Matrix Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - flnc_rod2_nonaggregating_signaling_model
    description: >-
      ROD2-domain arm: matrix remodeling and redistributed filamin C are observed
      histologically without demonstrable aggregation, and the intermediates are
      unknown.
- name: Mutant Filamin C Aggregation and Proteostatic Burden
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Non-truncating FLNC variants yield a protein that is expressed but
    misfolding-prone. In patient myocardium and in cells transfected with the
    HCM- and RCM-associated variants, mutant filamin C accumulates as large
    cytoplasmic inclusions rather than distributing normally to the Z-disc. The
    aggregate load sequesters filamin C away from its Z-disc function and imposes
    a protein-quality burden on the cardiomyocyte. This node is the mechanistic
    signature that separates the hypertrophic/restrictive FLNC phenotypes from
    the truncating dilated/arrhythmogenic phenotypes, in which myocardial
    immunohistochemistry shows no abnormal filamin C aggregates.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Inclusion body
    term:
      id: GO:0016234
      label: inclusion body
    modifier: INCREASED
  - preferred_term: Lysosome
    term:
      id: GO:0005764
      label: lysosome
    modifier: INCREASED
  biological_processes:
  - preferred_term: Protein refolding
    term:
      id: GO:0042026
      label: protein refolding
    modifier: ABNORMAL
  - preferred_term: Protein homooligomerization (filamin C dimerization)
    term:
      id: GO:0051260
      label: protein homooligomerization
    modifier: DECREASED
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: INCREASED
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      functional analysis reveals that expression of these FLNC variants resulted
      in the formation of large filamin C aggregates
    explanation: >-
      Direct functional demonstration that the HCM-associated FLNC variants
      generate filamin C aggregates.
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology of heart tissue from patients of both families showed
      cytoplasmic inclusions suggesting protein aggregates, which were filamin-C
      specific for the p.S1624L by immunohistochemistry.
    explanation: >-
      Confirms filamin C-specific aggregates in human myocardium carrying
      non-truncating FLNC variants at the restrictive pole of this
      hypertrophic-restrictive entity.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical staining of myocardial tissue showed no abnormal
      filamin C aggregates in patients with truncating FLNC mutations.
    explanation: >-
      The negative control for this node from the opposite variant class:
      truncating FLNC carriers, who develop dilated/arrhythmogenic rather than
      hypertrophic disease, do not show the aggregates. Anchors aggregation as
      specific to the non-truncating class.
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Variants that produce misfolded FLNC proteins cause the accumulation of
      FLNC and FLNC-binding partners which leads to increased lysosome expression
      and activation of autophagic pathways.
    explanation: >-
      Gives the cell-biological consequence of the aggregate load in an isogenic
      human iPSC-cardiomyocyte model: accumulation of filamin C and its binding
      partners with a compensatory lysosomal and autophagic response.
  - reference: PMID:32112656
    reference_title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Interference with the dimerization and folding of the protein leads to
      aggregate formation detrimental for muscle function, as found in HCM and
      MFM.
    explanation: >-
      Names the upstream molecular failure — impaired dimerization and folding —
      that produces the aggregates in the hypertrophic arm. Evidence source is
      OTHER because this is a mutation-update review.
  downstream:
  - target: Z-Disc and Sarcomere Disarray
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - flnc_convergent_proteotoxicity
    description: >-
      The step from proteostatic burden to structural disarray is inferred rather
      than demonstrated: in heterozygous human iPSC-cardiomyocytes the
      lysosomal/autophagic phenotype appeared while sarcomere assembly and
      function were still preserved, so the intermediates that eventually convert
      proteostatic stress into myocardial disarray are unknown.
- name: Z-Disc and Sarcomere Disarray
  biological_scale: CELLULAR
  role: effector
  description: >-
    Loss of competent filamin C cross-linking at the Z-disc, compounded by
    aggregate sequestration of the protein, degrades sarcomeric organization.
    Endomyocardial and explant tissue from FLNC-mutated hypertrophic patients
    shows marked sarcomeric abnormalities, the cardiomyocyte-level lesion that
    the myocardium then compensates for by hypertrophy and matrix deposition.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
    modifier: ABNORMAL
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with FLNC mutations show marked sarcomeric abnormalities in
      cardiac muscle
    explanation: >-
      Documents sarcomeric disorganization in the myocardium of FLNC-mutated
      hypertrophic cardiomyopathy patients.
  - reference: PMID:34535832
    reference_title: "Filamin C in cardiomyopathy: from physiological roles to DNA variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and
      participates in sarcomere stability maintenance.
    explanation: >-
      Supplies the normal function — sarcomere stability maintenance — whose loss
      produces this node. Evidence source is OTHER because this is a review.
  downstream:
  - target: Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling
    causal_link_type: DIRECT
  - target: Impaired Diastolic Relaxation and Myocardial Stiffening
    causal_link_type: DIRECT
- name: Altered Extracellular Matrix Remodeling
  biological_scale: TISSUE
  role: amplifier
  description: >-
    Myocardium from carriers of ROD2-domain FLNC missense variants shows
    differential extracellular matrix remodeling on histology, alongside altered
    distribution of filamin C among cardiomyocytes. The direction and mechanical
    consequence of that remodeling were not measured; it is placed upstream of the
    diastolic node as the plausible tissue-level correlate of the restrictive
    component in this variant subset, where aggregation is not demonstrable, but
    the link is an inference rather than a reported result.
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Differential extracellular matrix remodeling and FLNC distribution among
      cardiomyocytes were confirmed on histology.
    explanation: >-
      Direct histological evidence of matrix remodeling in ROD2 missense carriers
      with the HCM-RCM overlap phenotype.
  downstream:
  - target: Impaired Diastolic Relaxation and Myocardial Stiffening
    causal_link_type: DIRECT
- name: Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The myocardium responds to the Z-disc lesion with cardiomyocyte hypertrophy
    and geometric remodeling, giving the defining left ventricular hypertrophy of
    CMH26. Unlike sarcomeric hypertrophic cardiomyopathy driven by
    hypercontractile thick-filament mutations, the FLNC-hypertrophic ventricle
    remodels toward a small, thick-walled, poorly compliant cavity with lower
    rather than higher contractility.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC variant carriers with the characteristic ECG had smaller left
      ventricular cavity size, lower contractility, and more severe diastolic
      dysfunction and were more likely to have a restrictive phenotype.
    explanation: >-
      Characterizes the FLNC hypertrophic remodeling pattern — small cavity,
      reduced contractility — as distinct from the hypercontractile sarcomeric
      HCM pattern.
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of 92 HCM cases identifies seven additional variants segregating
      with the disease in eight families.
    explanation: >-
      Establishes that the hypertrophic phenotype, not a dilated one, is what
      segregates with these FLNC variants across multiple families.
  downstream:
  - target: Impaired Diastolic Relaxation and Myocardial Stiffening
    causal_link_type: DIRECT
  - target: Electrical Instability and Arrhythmogenesis
    causal_link_type: DIRECT
- name: Impaired Diastolic Relaxation and Myocardial Stiffening
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  description: >-
    The stiffened, hypertrophied ventricle fills poorly. Severe diastolic
    dysfunction — rather than systolic failure of a dilated chamber — is the
    dominant hemodynamic abnormality in FLNC hypertrophic disease and is what
    pushes the phenotype toward the restrictive end of the continuum, with
    advanced heart failure at relatively young ages.
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 6.49 years, they presented with advanced heart
      failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart
      failure deaths
    explanation: >-
      Quantifies diastolic dysfunction as the dominant functional lesion in the
      ROD2 missense HCM-RCM cohort, with transplant and heart-failure death as
      outcomes.
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals presented with heart failure due to severe diastolic
      dysfunction requiring heart transplantation in some cases.
    explanation: >-
      Independent family-based evidence that non-truncating FLNC variants cause
      heart failure through diastolic rather than systolic failure.
  downstream:
  - target: Heart Failure and Sudden Cardiac Death
    causal_link_type: DIRECT
- name: Electrical Instability and Arrhythmogenesis
  biological_scale: ORGANISM
  role: amplifier
  description: >-
    A distinctive repolarization ECG pattern marks the genetically explained
    subgroup, and the founding CMH26 series reported an excess of sudden cardiac
    death among FLNC-mutated patients. The magnitude of that arrhythmic risk is
    contested — a later 540-patient HCM cohort found no excess all-cause or
    cardiac mortality among FLNC variant carriers — and whether the arrhythmic
    substrate resembles that of the truncating dilated/arrhythmogenic FLNC
    phenotype is not established.
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical studies indicate that FLNC-mutated patients have higher incidence
      of sudden cardiac death.
    explanation: >-
      Establishes excess sudden cardiac death in the founding FLNC hypertrophic
      cardiomyopathy cohort.
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical evaluation of patients with HCM/RCM and a rare FLNC variant
      identified a distinct electrocardiographic (ECG) repolarization phenotype in
      37% (19 of 51 individuals, from 12 families), which was observed in only
      1.0% of a control HCM cohort (2 of 197).
    explanation: >-
      Documents an FLNC-specific repolarization abnormality, the electrical
      correlate of this node, at 37 percent versus 1 percent in non-FLNC HCM.
  downstream:
  - target: Heart Failure and Sudden Cardiac Death
    causal_link_type: DIRECT
- name: Heart Failure and Sudden Cardiac Death
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The terminal common outcome of CMH26: advanced heart failure requiring
    transplantation, heart-failure death, or cardiac arrest. In the ECG-defined
    FLNC hypertrophic/restrictive group, at least one such event had occurred in
    the majority of families.
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart failure death, transplant, or cardiac arrest occurred in at least 1
      individual in 7 of the 12 families (58%) in the "ECG-positive" group
    explanation: >-
      Quantifies the hard-outcome burden in FLNC hypertrophic/restrictive
      families.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Left ventricular hypertrophy not explained by loading conditions, the
    defining phenotype of CMH26 and the reason MONDO classifies this entity under
    familial hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of 92 HCM cases identifies seven additional variants segregating
      with the disease in eight families.
    explanation: >-
      Segregation of FLNC variants with hypertrophic cardiomyopathy in eight
      independent families.
  - reference: PMID:28356264
    reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide a compelling evidence of the involvement of FLNC in the
      development of HCM.
    explanation: >-
      Independent large-cohort confirmation of the FLNC-hypertrophic
      cardiomyopathy association.
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  description: >-
    Increased left ventricular wall thickness with a characteristically small
    cavity; in FLNC carriers with the distinctive ECG the hypertrophic remodeling
    is accompanied by reduced rather than increased contractility.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC variant carriers with the characteristic ECG had smaller left
      ventricular cavity size, lower contractility, and more severe diastolic
      dysfunction and were more likely to have a restrictive phenotype.
    explanation: >-
      Describes the FLNC hypertrophic remodeling geometry (small cavity, low
      contractility) that accompanies the wall thickening.
- category: Cardiovascular
  name: Restrictive Cardiomyopathy
  description: >-
    A restrictive physiology overlapping the hypertrophic one — stiff,
    non-dilated ventricles with impaired filling. MONDO records restrictive
    cardiomyopathy 5 as a synonym of CMH26, and FLNC series consistently report a
    hypertrophic-restrictive overlap rather than pure hypertrophy.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and
      cause a discrete phenotype comprising a characteristic ECG, hypertrophic and
      restrictive features without hypercontractility, and extracardiac
      abnormalities.
    explanation: >-
      States the combined hypertrophic-and-restrictive character of the
      non-truncating FLNC phenotype.
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC-mRod2 variants show a high prevalence of an overlapped phenotype
      comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance
      and distinctive cardiac histopathological remodeling.
    explanation: >-
      Independent series reporting the same restrictive-hypertrophic overlap for
      ROD2-domain missense variants.
- category: Cardiovascular
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Severe impairment of ventricular filling is the dominant functional
    abnormality, present in 80% of assessed carriers in the ROD2 missense series
    and driving advanced heart failure at young ages.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 6.49 years, they presented with advanced heart
      failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart
      failure deaths
    explanation: >-
      Reports diastolic dysfunction in 16 of 20 assessed individuals (80%),
      supporting both the association and the VERY_FREQUENT frequency band
      (80-100%).
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals presented with heart failure due to severe diastolic
      dysfunction requiring heart transplantation in some cases.
    explanation: >-
      Independent confirmation that severe diastolic dysfunction is the
      heart-failure mechanism in non-truncating FLNC disease.
- category: Cardiovascular
  name: Distinctive Repolarization ECG Pattern
  description: >-
    A discrete electrocardiographic repolarization abnormality that is highly
    specific to FLNC-related hypertrophic/restrictive cardiomyopathy: present in
    37% of FLNC variant carriers versus 1.0% of a control HCM cohort, and marking
    the subgroup in which rare FLNC missense variants are almost fully
    explanatory.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Distinctive repolarization abnormality on ECG
    term:
      id: HP:0003115
      label: Abnormal EKG
  diagnostic: true
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical evaluation of patients with HCM/RCM and a rare FLNC variant
      identified a distinct electrocardiographic (ECG) repolarization phenotype in
      37% (19 of 51 individuals, from 12 families), which was observed in only
      1.0% of a control HCM cohort (2 of 197).
    explanation: >-
      Supports both the phenotype and the FREQUENT band (37%, i.e. within
      30-79%), and establishes its discriminating value against non-FLNC HCM.
- category: Cardiovascular
  name: Left Ventricular Hypertrabeculation
  description: >-
    Deep left ventricular trabeculation producing a saw-tooth myocardial
    appearance, reported as a characteristic imaging feature of the ROD2-domain
    missense phenotype.
  phenotype_term:
    preferred_term: Left ventricular hypertrabeculation with saw-tooth appearance
    term:
      id: HP:0031194
      label: Increased density of left ventricular trabeculae
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed 15 cases with a cardiac phenotype consisting of an overlap of
      HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance).
    explanation: >-
      Reports hypertrabeculation with saw-tooth appearance as part of the
      FLNC-mRod2 cardiac phenotype. The source describes increased trabeculation
      only and never uses the word "noncompaction", so the binding is to
      increased trabecular density rather than to left ventricular
      noncompaction, whose defining thin compacted layer would contradict the
      thick-walled hypertrophic phenotype modelled here; the preferred_term
      preserves the source wording.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Advanced heart failure with transplantation or heart-failure death occurs in
    a majority of affected families, typically driven by restrictive physiology
    rather than by systolic failure of a dilated chamber.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart failure death, transplant, or cardiac arrest occurred in at least 1
      individual in 7 of the 12 families (58%) in the "ECG-positive" group
    explanation: >-
      Documents heart-failure death and transplantation as outcomes in FLNC
      hypertrophic/restrictive families.
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 6.49 years, they presented with advanced heart
      failure
    explanation: >-
      Independent cohort reporting progression to advanced heart failure.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Excess sudden cardiac death was reported in the founding CMH26 series, and
    cardiac arrest is among the hard outcomes recorded in more recent FLNC
    hypertrophic/restrictive families. Arrhythmic risk assessment is therefore
    part of routine management even when structural severity appears modest.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical studies indicate that FLNC-mutated patients have higher incidence
      of sudden cardiac death.
    explanation: >-
      Direct statement of increased sudden cardiac death incidence in FLNC
      hypertrophic cardiomyopathy patients.
  - reference: PMID:30411535
    reference_title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC mutations did not increase the risk for either all-cause mortality (HR
      0.746, 95% CI 0.222-2.295, p = 0.575) or cardiac mortality (HR 0.615, 95% CI
      0.153-1.947, p = 0.354) in HCM patients during a follow-up of 4.7 ± 3.2
      years.
    explanation: >-
      A large single-center HCM cohort that found no excess mortality among FLNC
      variant carriers, directly contradicting the sudden-death excess reported in
      the founding series. Recorded as REFUTE so the conflict is explicit rather
      than averaged away.
- category: Musculoskeletal
  name: Extracardiac Musculoskeletal Abnormalities
  description: >-
    Musculoskeletal abnormalities occur in a minority of FLNC
    hypertrophic/restrictive families, distinguishing the entity from purely
    cardiac sarcomeric HCM. This is milder and distinct from the overt
    progressive skeletal-muscle weakness of FLNC myofibrillar myopathy; several
    cardiac FLNC series explicitly record the absence of clinical skeletal
    myopathy.
  phenotype_term:
    preferred_term: Musculoskeletal abnormality
    term:
      id: HP:0033127
      label: Abnormality of the musculoskeletal system
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      musculoskeletal abnormalities were present in 4 families (33%)
    explanation: >-
      Reports extracardiac musculoskeletal involvement in 4 of 12 (33%) FLNC
      hypertrophic/restrictive families. No frequency band is asserted because
      the reported proportion is family-level, not the per-individual frequency
      the FrequencyEnum bands describe.
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      absence of cardiac conduction disturbances or skeletal myopathy
    explanation: >-
      Directly contradicts extracardiac muscle involvement as a general feature:
      the 21-family ROD2 missense cohort had no clinical skeletal myopathy.
      Recorded as REFUTE so the inconsistency between cohorts is explicit, and so
      this phenotype is never read as equating CMH26 with FLNC myofibrillar
      myopathy.
genetic:
- name: FLNC Non-Truncating Pathogenic Variants
  association: Non-truncating (predominantly missense) pathogenic variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:26666891
      reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        segregating in two families with autosomal-dominant RCM
      explanation: >-
        Dominant segregation of non-truncating FLNC alleles in the
        hypertrophic-restrictive continuum covered by this entry.
  features: >-
    The variant class is the single most important genotype-phenotype fact about
    FLNC. Non-truncating variants — almost all missense, and clustered in the
    ROD2 region — are the ones enriched in
    hypertrophic and restrictive cardiomyopathy, and they act by producing a
    misfolded, aggregation-prone filamin C protein. Truncating (protein-losing)
    FLNC variants are enriched instead in dilated and left-dominant
    arrhythmogenic cardiomyopathy, act through haploinsufficiency, do not produce
    myocardial filamin C aggregates, and were completely absent from a screen of
    1,078 hypertrophic cardiomyopathy patients. A CMH26 diagnosis therefore
    requires a non-truncating allele; a truncating FLNC allele in a patient with
    apparent hypertrophy should prompt re-examination of the phenotype rather
    than assignment to this entity. Pathogenicity of individual FLNC missense
    variants remains contested: in the largest dedicated HCM screen only 6 of 20
    candidate variants reached likely-pathogenic, 10 were variants of uncertain
    significance, and a separate 540-patient cohort found FLNC variants at
    similar frequency in patients and controls with poor pedigree segregation.
  case_fractions:
  - population: >-
      448 consecutive hypertrophic cardiomyopathy patients sequenced for FLNC
      plus the main sarcomere genes (Asturias, Spain), 450 population controls.
    case_fraction_percent: 4.9
    cohort_size: 448
    notes: >-
      20 FLNC candidate variants in 22 of 448 patients (4.9%); after segregation
      and functional review only 6 variants in 7 patients (1.6%) were classified
      likely pathogenic, so the pathogenic-variant yield is lower than the
      candidate-variant yield.
    evidence:
    - reference: PMID:28356264
      reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19
        missense) in 22 patients
      explanation: >-
        Gives the numerator (22 patients) for the 448-patient denominator stated
        in the same abstract.
    - reference: PMID:28356264
      reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Based on the familial segregation and the reported functional studies, 6
        of the candidate variants (in 7 patients) were finally classified as
        likely pathogenic, 10 as variants of uncertain significance, and 4 as
        likely benign.
      explanation: >-
        Supports the caveat that the likely-pathogenic yield is much lower than
        the candidate-variant yield.
  - population: >-
      540 hypertrophic cardiomyopathy patients and 307 healthy controls (Fuwai
      Hospital, China).
    case_fraction_percent: 7.2
    cohort_size: 540
    notes: >-
      39 of 540 HCM patients (7.2%) carried an FLNC variant, but so did 4.2% of
      controls (p = 0.101), and pedigrees did not segregate — this cohort argues
      that the raw carrier rate substantially overstates the causal fraction.
    evidence:
    - reference: PMID:30411535
      reference_title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found that 39 (7.2%) patients carried FLNC mutations, with a similar
        frequency to that of controls (4.2%, p = 0.101).
      explanation: >-
        Supplies the carrier fraction while simultaneously undermining its causal
        interpretation, hence PARTIAL.
  variants:
  - name: FLNC p.A1539T
    description: >-
      The founding CMH26 missense variant, identified by whole-exome sequencing
      and segregating with familial hypertrophic cardiomyopathy in the index
      family reported by Valdes-Mas and colleagues.
    gene:
      preferred_term: FLNC
      term:
        id: hgnc:3756
        label: FLNC
    evidence:
    - reference: PMID:25351925
      reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole-exome sequencing reveals a variant in the gene encoding the
        sarcomeric protein filamin C (p.A1539T) that segregates with the disease
        in this family.
      explanation: >-
        Names the variant and reports its segregation with familial hypertrophic
        cardiomyopathy in the index family.
  - name: FLNC p.S1624L
    description: >-
      ROD-region missense variant segregating with autosomal dominant restrictive
      cardiomyopathy; myocardial immunohistochemistry showed filamin C-specific
      cytoplasmic inclusions, and the same variant produced cytoplasmic
      aggregates in transfected myoblasts.
    gene:
      preferred_term: FLNC
      term:
        id: hgnc:3756
        label: FLNC
    evidence:
    - reference: PMID:26666891
      reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathology of heart tissue from patients of both families showed
        cytoplasmic inclusions suggesting protein aggregates, which were
        filamin-C specific for the p.S1624L by immunohistochemistry.
      explanation: >-
        Ties this specific allele to filamin C-positive myocardial inclusions,
        the aggregation signature of the non-truncating variant class.
  - name: FLNC p.I2160F
    description: >-
      Second missense variant reported with autosomal dominant restrictive
      cardiomyopathy in the same study, in a family whose myocardium likewise
      showed cytoplasmic protein inclusions.
    gene:
      preferred_term: FLNC
      term:
        id: hgnc:3756
        label: FLNC
    evidence:
    - reference: PMID:26666891
      reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified two novel missense variants (p.S1624L; p.I2160F) in
        filamin-C (FLNC), an actin-cross-linking protein mainly expressed in
        heart and skeletal muscle, segregating in two families with
        autosomal-dominant RCM
      explanation: >-
        Reports p.I2160F as the second segregating non-truncating allele in this
        two-family series.
  - name: FLNC ROD2-domain missense variants
    description: >-
      A class rather than a single allele: rare missense variants clustered in the
      ROD2 domain, recruited across 21 families, that produce an HCM-RCM overlap
      with saw-tooth hypertrabeculation, severe diastolic dysfunction, and no
      demonstrable cytoplasmic aggregation in cell models.
    gene:
      preferred_term: FLNC
      term:
        id: hgnc:3756
        label: FLNC
    evidence:
    - reference: PMID:32112656
      reference_title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Variants associated with HCM are predominantly missense variants, which
        cluster in the ROD2 domain.
      explanation: >-
        Establishes ROD2-clustered missense variation as the characteristic
        CMH26 genotype class. Evidence source is OTHER because this is a
        mutation-update review.
    - reference: PMID:35952944
      reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We recruited 21 unrelated families genetically evaluated because of
        hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM)
        phenotype carrying rare missense variants in the ROD2 domain of FLNC
        (FLNC-mRod2).
      explanation: >-
        Defines the ROD2 missense cohort whose phenotype this variant class
        entry describes.
  evidence:
  - reference: PMID:34535832
    reference_title: "Filamin C in cardiomyopathy: from physiological roles to DNA variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic
      right ventricular cardiomyopathy. Non-truncated FLNC is enriched in
      hypertrophic cardiomyopathy and restrictive cardiomyopathy.
    explanation: >-
      The core genotype-phenotype rule for this entry, stated explicitly:
      non-truncating variants map to the hypertrophic and restrictive phenotypes,
      truncating variants to the dilated and arrhythmogenic ones. Evidence source
      is OTHER because this is a review.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating FLNC mutations were absent in patients with other phenotypes,
      including 1,078 patients with hypertrophic cardiomyopathy.
    explanation: >-
      The strongest single piece of evidence for the variant-class split: in a
      2,877-patient screen, truncating FLNC variants did not occur at all among
      1,078 hypertrophic cardiomyopathy patients.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating mutations in FLNC caused an overlapping phenotype of dilated and
      left-dominant arrhythmogenic cardiomyopathies complicated by frequent
      premature sudden death.
    explanation: >-
      Names the phenotype that the truncating class does cause, which is the
      entity this one must not be conflated with.
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and
      cause a discrete phenotype comprising a characteristic ECG, hypertrophic and
      restrictive features without hypercontractility, and extracardiac
      abnormalities.
    explanation: >-
      Contemporary confirmation, from a large sarcomere-negative HCM cohort with
      rare-variant burden testing, that the pathogenic FLNC alleles in
      hypertrophic disease are non-truncating.
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family-based studies in 2 specialist services and statistical modeling of
      rare FLNC missense variants were conducted, using a cohort of 3289
      sarcomere-negative HCM cases and 122,348 genome aggregation database
      controls.
    explanation: >-
      Documents the cohort size and design behind the burden estimate, so the
      etiologic-fraction figures quoted elsewhere in this entry are anchored to a
      stated denominator.
  - reference: PMID:30411535
    reference_title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC mutations were common in both HCM patients and healthy population. The
      pathogenicity of FLNC mutations detected in HCM patients and its association
      with the clinical outcomes should be cautiously interpreted.
    explanation: >-
      Records the interpretive caveat: FLNC variant carriage alone is not
      sufficient evidence of causation in a hypertrophic cardiomyopathy patient.
  - reference: PMID:32112656
    reference_title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Truncating variants with subsequent haploinsufficiency are associated with
      DCM and cardiac arrhythmias.
    explanation: >-
      States the truncating arm of the dichotomy and its haploinsufficiency
      mechanism. Evidence source is OTHER because this is a mutation-update
      review.
  - reference: PMID:32112656
    reference_title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants associated with HCM are predominantly missense variants, which
      cluster in the ROD2 domain.
    explanation: >-
      The complementary hypertrophic arm: HCM-associated FLNC variants are
      predominantly missense and cluster in ROD2, which is why this entry treats
      the ROD2 missense class as the core CMH26 genotype.
  - reference: PMID:33557094
    reference_title: "Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained
      special interest since FLNC mutations were found in several distinct and
      possibly overlapping cardiomyopathy phenotypes.
    explanation: >-
      Frames FLNC as a pleiotropic cardiomyopathy gene whose phenotypes must be
      distinguished rather than merged. Evidence source is OTHER because this is a
      review.
diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging. Establishes the hypertrophic phenotype (wall thickness),
    the characteristically small left ventricular cavity, and the restrictive
    filling pattern with severe diastolic dysfunction that distinguishes FLNC
    hypertrophic disease from hypercontractile sarcomeric HCM. Also the
    surveillance modality for genotype-positive relatives.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC variant carriers with the characteristic ECG had smaller left
      ventricular cavity size, lower contractility, and more severe diastolic
      dysfunction and were more likely to have a restrictive phenotype.
    explanation: >-
      These are the echocardiographic parameters (cavity size, contractility,
      diastolic function) that characterize the FLNC phenotype.
- name: Electrocardiography
  description: >-
    A 12-lead ECG is disproportionately informative in this entity: the
    distinctive repolarization pattern is present in about a third of FLNC
    variant carriers with HCM/RCM but in only 1% of non-FLNC HCM patients, and
    the ECG-positive subgroup is the one in which rare FLNC missense variants are
    almost fully explanatory. It therefore functions as a phenotype-first triage
    step for FLNC variant interpretation.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rare FLNC missense variant burden indicated a low case excess among all HCM
      cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in
      "ECG-positive" cases the etiologic fraction was substantially higher (0.98;
      95% confidence interval, 0.97-0.99).
    explanation: >-
      Quantifies the diagnostic value of the ECG phenotype for FLNC variant
      interpretation.
- name: Cardiac Magnetic Resonance Imaging
  description: >-
    Advanced imaging is part of the standard workup of FLNC variant carriers,
    characterizing wall thickness, cavity size, trabecular morphology (the
    saw-tooth hypertrabeculation of the ROD2 phenotype), and myocardial tissue
    characterization. No FLNC-specific late-gadolinium-enhancement signature has
    been established for the hypertrophic arm, so this is used as in other
    hypertrophic cardiomyopathies rather than as a gene-specific test.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carriers underwent advanced cardiac imaging and genetic cascade screening.
    explanation: >-
      Documents advanced cardiac imaging as part of the standard evaluation of
      FLNC variant carriers. PARTIAL because the abstract does not name the
      modality or report a gene-specific imaging finding.
- name: Genetic Testing
  description: >-
    Multi-gene cardiomyopathy panel or exome sequencing including FLNC. Three
    interpretive rules are specific to this gene: the variant class must be
    recorded (non-truncating for CMH26, truncating for the dilated/arrhythmogenic
    entity); missense variants require segregation or functional support
    before being called pathogenic, since FLNC missense variation is common in
    unaffected populations; and calls in exons 46-48 must be checked against the
    highly homologous downstream FLNC pseudogene, which is a short-read
    mis-mapping hazard in exactly the ROD2-adjacent region where this entity's
    variants cluster.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28356264
    reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 448 HCM patients were next generation-sequenced (semiconductor
      chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2,
      MYL3, TPM1, and FLNC genes.
    explanation: >-
      Establishes the panel-based testing approach in which FLNC is sequenced
      alongside the classic sarcomere genes.
  - reference: PMID:30411535
    reference_title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pedigree analysis showed that mutations were not well segregated with HCM.
    explanation: >-
      Supports the requirement for segregation evidence before calling an FLNC
      missense variant causal in a hypertrophic cardiomyopathy patient.
  - reference: PMID:39132495
    reference_title: 'ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNC has a pseudogene located 53.6kb downstream from the functional FLNC
      gene, and exons 46, 47, and 48 are 98% homologous in the functional and
      pseudogene.
    explanation: >-
      Documents the technical hazard specific to sequencing this gene:
      near-identical pseudogene sequence over exons 46-48 makes short-read
      alignment ambiguous there, so variant calls in those exons need
      orthogonal confirmation before being reported. Sourced to the ClinGen HCVD-GCEP
      reappraisal, an expert-panel document rather than a primary study, hence
      OTHER.
- name: Endomyocardial or Explant Histopathology
  description: >-
    Not routine, but mechanistically decisive when tissue is available:
    filamin C-specific cytoplasmic inclusions identify the non-truncating
    aggregation mechanism, whereas their absence is characteristic of truncating
    FLNC disease. ROD2-domain missense carriers may instead show differential
    extracellular matrix remodeling without aggregates.
  evidence:
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology of heart tissue from patients of both families showed
      cytoplasmic inclusions suggesting protein aggregates, which were filamin-C
      specific for the p.S1624L by immunohistochemistry.
    explanation: >-
      Demonstrates the diagnostic histopathological signature of non-truncating
      FLNC disease.
differential_diagnoses:
- name: Sarcomeric hypertrophic cardiomyopathy (MYH7, MYBPC3 and other thick/thin filament genes)
  description: >-
    The dominant cause of familial HCM and the main alternative when left
    ventricular hypertrophy is found. Sarcomeric HCM arises from hypercontractile
    thick- and thin-filament lesions, whereas CMH26 is a Z-disc/protein-quality
    disease whose ventricle is not hypercontractile.
  distinguishing_features:
  - A pathogenic variant in a definitive sarcomere gene (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1) explains the phenotype.
  - FLNC carriers show smaller cavity size, lower contractility, more severe diastolic dysfunction, and a restrictive tendency rather than hypercontractility.
  - The FLNC-specific repolarization ECG occurs in only about 1% of non-FLNC HCM patients.
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and
      cause a discrete phenotype comprising a characteristic ECG, hypertrophic and
      restrictive features without hypercontractility, and extracardiac
      abnormalities.
    explanation: >-
      States that the FLNC hypertrophic phenotype is discrete from generic HCM,
      including the absence of hypercontractility.
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in different genes encoding sarcomeric proteins are responsible
      for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however,
      the genetic alterations causing the disease in one-third of patients are
      currently unknown.
    explanation: >-
      Situates FLNC among the non-sarcomeric explanations sought for
      genotype-negative HCM.
- name: FLNC truncating dilated and left-dominant arrhythmogenic cardiomyopathy
  description: >-
    The same gene, the opposite variant class and a different disease. Truncating
    FLNC variants cause a high-risk overlapping dilated/left-dominant
    arrhythmogenic phenotype with ventricular dilation, systolic dysfunction,
    myocardial fibrosis, a heavy ventricular-arrhythmia burden and frequent
    premature sudden death — and are absent from hypertrophic cohorts. dismech
    covers the arrhythmogenic and dilated poles of this in
    Arrhythmogenic_Right_Ventricular_Cardiomyopathy, DSP_Cardiomyopathy and
    Dilated_Cardiomyopathy; this entry deliberately does not duplicate them.
  distinguishing_features:
  - The FLNC allele is truncating (nonsense, frameshift, splice-loss) rather than missense.
  - Left ventricular dilation with systolic dysfunction, not a small stiff hypertrophied cavity.
  - Myocardial immunohistochemistry shows no abnormal filamin C aggregates.
  - Inferolateral negative T waves and low QRS voltages, with early prophylactic defibrillator implantation recommended.
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  evidence:
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating mutations in FLNC caused an overlapping phenotype of dilated and
      left-dominant arrhythmogenic cardiomyopathies complicated by frequent
      premature sudden death.
    explanation: >-
      Defines the alternative FLNC entity that must be distinguished from CMH26.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating FLNC mutations were absent in patients with other phenotypes,
      including 1,078 patients with hypertrophic cardiomyopathy.
    explanation: >-
      The distinguishing genotype fact: truncating alleles do not appear in
      hypertrophic cardiomyopathy.
- name: FLNC myofibrillar myopathy (filaminopathy, MFM5)
  description: >-
    The skeletal-muscle FLNC disease. Adult-onset, slowly progressive muscle
    weakness with intracellular protein aggregates, classically caused by
    variants in the dimerization domain. Cardiac FLNC series repeatedly note the
    absence of clinical skeletal myopathy, so overt limb-girdle weakness points
    away from CMH26. dismech covers this in Myofibrillar_Myopathy.
  distinguishing_features:
  - Progressive proximal skeletal-muscle weakness dominates the presentation.
  - Muscle biopsy shows myofibrillar disorganization with protein aggregates.
  - Cardiac involvement, when present, is secondary rather than the presenting problem.
  disease_term:
    preferred_term: myofibrillar myopathy
    term:
      id: MONDO:0018943
      label: myofibrillar myopathy
  evidence:
  - reference: PMID:37174721
    reference_title: Novel Filamin C Myofibrillar Myopathy Variants Cause Different Pathomechanisms and Alterations in Protein Quality Systems.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A subtype of MFM is caused by heterozygous mutations in the filamin C (FLNC)
      gene, exhibiting progressive muscle weakness, muscle structural alterations
      and intracellular protein accumulations.
    explanation: >-
      Defines the skeletal-muscle FLNC phenotype that constitutes this
      differential.
  - reference: PMID:33557094
    reference_title: "Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Specifically, mutations in FLNC were initially only linked to myofibrillar
      myopathy (MFM), but are now increasingly found in various forms of human
      cardiomyopathy.
    explanation: >-
      Records the historical relationship between the myopathic and cardiac FLNC
      phenotypes. Evidence source is OTHER because this is a review.
- name: Familial restrictive cardiomyopathy from other causes
  description: >-
    Sarcomere-gene and other familial restrictive cardiomyopathies present with
    the same stiff, non-dilated ventricle and severe diastolic dysfunction.
    Because MONDO records restrictive cardiomyopathy 5 as a synonym of CMH26, the
    boundary between the hypertrophic and restrictive labels for a given FLNC
    family is partly nosological rather than biological.
  distinguishing_features:
  - Restrictive physiology without significant wall thickening favors a non-FLNC restrictive cardiomyopathy.
  - Identification of a non-truncating FLNC variant with filamin C-positive myocardial inclusions favors this entity.
  disease_term:
    preferred_term: restrictive cardiomyopathy
    term:
      id: MONDO:0016340
      label: familial restrictive cardiomyopathy
  evidence:
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial forms are mainly caused by mutations in sarcomere proteins and
      demonstrate a common genetic etiology with other inherited cardiomyopathies.
    explanation: >-
      Names the sarcomeric familial restrictive cardiomyopathies that form this
      differential and notes their shared genetic architecture with FLNC disease.
treatments:
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for primary or secondary prevention of sudden cardiac death.
    The founding CMH26 series reported excess sudden cardiac death among
    FLNC-mutated hypertrophic patients, and cardiac arrest is among the recorded
    hard outcomes in contemporary FLNC hypertrophic/restrictive families, so
    arrhythmic risk stratification is part of routine care. Note that the
    evidence base for arrhythmic risk in the non-truncating hypertrophic class is
    weaker and more contested than for FLNC truncating dilated/arrhythmogenic
    disease, where prompt defibrillator implantation is explicitly recommended;
    one large HCM cohort found no excess mortality in FLNC carriers.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Electrical Instability and Arrhythmogenesis
    treatment_effect: INHIBITS
    description: >-
      A defibrillator does not modify the Z-disc lesion; it terminates the
      malignant ventricular arrhythmia that the remodeled myocardium generates.
  evidence:
  - reference: PMID:25351925
    reference_title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical studies indicate that FLNC-mutated patients have higher incidence
      of sudden cardiac death.
    explanation: >-
      Establishes the arrhythmic risk that motivates defibrillator consideration.
      PARTIAL because the paper reports risk, not device outcomes.
  - reference: PMID:27908349
    reference_title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prompt implantation of a cardiac defibrillator should be considered in
      affected patients harboring truncating mutations in FLNC.
    explanation: >-
      The explicit device recommendation in the FLNC literature is for the
      truncating class, not this one. Recorded as PARTIAL and cited here
      precisely to mark that the recommendation does not transfer automatically
      to non-truncating hypertrophic carriers.
- name: Heart Transplantation
  description: >-
    Definitive therapy for end-stage disease. Restrictive physiology with severe
    diastolic dysfunction drives young carriers to advanced heart failure, and
    transplantation is a recorded outcome in both the ROD2 missense cohort and
    the original FLNC restrictive families.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Heart Failure and Sudden Cardiac Death
    treatment_effect: INHIBITS
    description: >-
      Replaces the failing organ; it is a rescue rather than a mechanism-directed
      therapy.
  evidence:
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals presented with heart failure due to severe diastolic
      dysfunction requiring heart transplantation in some cases.
    explanation: >-
      Documents transplantation as the treatment reached by patients with
      non-truncating FLNC cardiomyopathy.
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 6.49 years, they presented with advanced heart
      failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart
      failure deaths
    explanation: >-
      Three transplants among 20 assessed ROD2 missense carriers over a median
      6.5 years.
- name: Symptom-Directed Heart Failure and Antianginal Pharmacotherapy
  description: >-
    There is no FLNC-specific disease-modifying therapy, so pharmacological
    management is the generic hypertrophic-cardiomyopathy regimen: beta-blockers
    (or non-dihydropyridine calcium channel blockers when beta-blockade is not
    tolerated) to slow the heart rate, lengthen diastolic filling time and relieve
    angina and dyspnoea, with diuresis added cautiously once restrictive
    physiology and congestion dominate. Because the FLNC ventricle is small and
    stiff with impaired filling rather than obstructed by hypercontractility, the
    therapeutic goal here is filling time and congestion control rather than
    relief of outflow obstruction.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: non-dihydropyridine calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
  target_mechanisms:
  - target: Impaired Diastolic Relaxation and Myocardial Stiffening
    treatment_effect: INHIBITS
    description: >-
      Rate control lengthens diastole and partially offsets impaired filling; it
      does not modify the Z-disc or aggregation lesion upstream.
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC variant carriers with the characteristic ECG had smaller left
      ventricular cavity size, lower contractility, and more severe diastolic
      dysfunction and were more likely to have a restrictive phenotype.
    explanation: >-
      Establishes the haemodynamic problem this therapy is aimed at — small
      cavity, impaired filling, reduced contractility. PARTIAL because the paper
      characterizes the phenotype and does not report treatment outcomes; no
      FLNC-specific pharmacotherapy trial exists.
- name: Cardiac Myosin Inhibition (mechanistically questionable in this entity)
  description: >-
    Cardiac myosin inhibitors such as mavacamten are a mechanism-directed therapy
    for hypertrophic cardiomyopathy — they reduce actin-myosin cross-bridge
    formation and so relieve the hypercontractility and outflow obstruction of
    sarcomeric HCM. That rationale does not transfer cleanly to CMH26. The
    FLNC-related hypertrophic/restrictive phenotype is explicitly described as
    occurring without hypercontractility, with lower contractility and a small
    cavity, so reducing contractility further is mechanistically questionable
    here. This entry records the treatment specifically to mark the caveat: no
    trial of a myosin inhibitor in genotyped FLNC carriers has been reported, and
    the phenotype argues against extrapolating the sarcomeric-HCM indication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten (cardiac myosin inhibitor)
  evidence:
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and
      cause a discrete phenotype comprising a characteristic ECG, hypertrophic and
      restrictive features without hypercontractility, and extracardiac
      abnormalities.
    explanation: >-
      Recorded as REFUTE because the absence of hypercontractility removes the
      mechanistic premise of cardiac myosin inhibition in this entity; the
      evidence argues against the treatment rather than for it.
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although sarcomere formation and function were unaffected in FLNC +/ − and
      FLNC +/Δ7aa hiPSC-CMs, these heterozygous variants caused increases in
      lysosome content
    explanation: >-
      Cell-level corroboration that the heterozygous FLNC lesion is proteostatic
      rather than contractile, which is the same reason a contractility-lowering
      drug is a poor mechanistic fit. PARTIAL because it is an in vitro model, not
      a treatment study.
- name: Cascade Genetic Screening and Longitudinal Surveillance of Relatives
  description: >-
    Because penetrance is reduced and expressivity variable, first-degree
    relatives of a carrier are offered predictive genetic testing followed by
    periodic ECG and echocardiography. The ECG is particularly valuable here
    given the FLNC-specific repolarization pattern. Cascade screening is also the
    means by which segregation data accumulate — the evidence most needed to
    resolve the pathogenicity of individual FLNC missense variants.
  therapeutic_modality: OTHER
  action_category: SCREENING
  treatment_term:
    preferred_term: cascade genetic testing of relatives
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carriers underwent advanced cardiac imaging and genetic cascade screening.
    explanation: >-
      Documents cascade screening plus imaging as the family-management approach
      used in the reference FLNC hypertrophic/restrictive cohort.
  - reference: PMID:28356264
    reference_title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the FLNC variants were associated with mild forms of HCM and a
      reduced penetrance, with few affected in the families to confirm the
      segregation.
    explanation: >-
      Reduced penetrance and sparse segregation data are exactly why longitudinal
      family surveillance rather than one-off testing is required.
experimental_models:
- name: Transfected cell models expressing mutant filamin C
  description: >-
    Heterologous and myogenic cell lines transfected with plasmids carrying
    individual FLNC missense variants, read out by confocal microscopy for
    filamin C distribution and aggregate formation. This is the workhorse assay
    that separates the two mechanistic arms of this entry: the founding CMH26
    variants and the restrictive p.S1624L allele produce large cytoplasmic
    aggregates, whereas ROD2-domain variants did not. Note the assay is not
    single-species — the ROD2 experiments used human HT1080 fibrosarcoma cells
    alongside the rat H9c2 cardiomyoblast line — so the organism binding below
    reflects only the human component.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human HT1080 cells and myoblast lines (plus the rat H9c2 line) transfected with FLNC missense constructs
  publication: PMID:35952944
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Plasmids independently containing 3 FLNC missense variants were transfected
      and analyzed using confocal microscopy.
    explanation: >-
      Describes the model system and readout.
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cytoplasmic aggregates were also observed in transfected myoblast cell lines
      expressing this mutant filamin-C indicating further evidence for its
      pathogenicity.
    explanation: >-
      The positive result from the same class of assay, for an aggregation-competent
      non-truncating variant.
- name: Isogenic CRISPR FLNC hiPSC-cardiomyocyte series
  description: >-
    Human induced pluripotent stem cell-derived cardiomyocytes CRISPR-edited to
    a matched allelic series: wild type, FLNC null, FLNC haploinsufficient
    (modelling the truncating/dilated arm), and a heterozygous in-frame deletion
    that preserves expression but forms aggregates (modelling the
    non-truncating/hypertrophic arm). The reference human system for separating
    the contractile from the proteostatic consequences of FLNC variants.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: CRISPR/Cas9-edited isogenic human iPSC lines
  publication: PMID:34405687
  evidence:
  - reference: DOI:10.1161/CIRCRESAHA.120.317076
    reference_title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      which did not affect FLNC expression but caused aggregate formation,
      similar to FLNC variants associated with hypertrophic cardiomyopathy.
    explanation: >-
      Identifies the in-frame-deletion line as the engineered model of the
      hypertrophic (aggregate-forming) FLNC variant class.
- name: Patient-specific FLNC iPSC-derived cardiomyocytes (variant comparison)
  description: >-
    Patient-derived iPSC-cardiomyocytes carrying two clinically divergent FLNC
    missense variants — R1267Q from an arrhythmogenic cardiomyopathy family and
    V2264M from a restrictive cardiomyopathy family — profiled for calcium
    handling, sodium-channel kinetics, action potentials, and transcriptome. Used
    here as evidence that different FLNC missense alleles have distinguishable
    molecular consequences, which is the cell-level counterpart of the clinical
    genotype-phenotype divergence.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: iPSC lines from FLNC R1267Q and V2264M variant carriers
  publication: PMID:39315490
  evidence:
  - reference: PMID:39315490
    reference_title: Distinct molecular features of FLNC mutations, associated with different clinical phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We suggest distinct molecular effects of two FLNC variants linked to
      different types of cardiomyopathies in terms of myofilament structure,
      electrophysiology, ion channel function and intracellular calcium
      homeostasis providing the molecular the bases for their different clinical
      phenotypes.
    explanation: >-
      Supports variant-specific molecular divergence within FLNC. PARTIAL because
      the two variants compared are arrhythmogenic and restrictive rather than a
      truncating-versus-missense pair, so it corroborates the principle of
      variant-specific mechanism without directly testing the hypertrophic arm.
discussions:
- discussion_id: flnc_missense_hcm_pathogenicity_contested
  prompt: >-
    Is FLNC a genuine hypertrophic cardiomyopathy gene, or is the reported
    FLNC-HCM association largely an artefact of rare missense variation being
    common in the general population?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Filamin C Z-Disc Cross-Linking Defect
  - genetic#FLNC Non-Truncating Pathogenic Variants
  rationale: >-
    The evidence is genuinely split. In favour: FLNC missense variants segregate
    with HCM in multiple families, produce filamin C aggregates in patient
    myocardium and in cells, and in a 3,289-case sarcomere-negative HCM cohort
    the etiologic fraction reaches 0.98 within the ECG-defined subgroup. Against:
    a 540-patient HCM cohort found FLNC variants at a rate statistically
    indistinguishable from controls with poor pedigree segregation and no excess
    mortality; even the supportive 448-patient screen downgraded 14 of 20
    candidate variants to uncertain or likely benign; and the burden analysis puts
    the etiologic fraction across all HCM cases at only 0.45. Decisively, the
    ClinGen Hereditary Cardiovascular Disease GCEP did not simply fail to curate
    FLNC-HCM: it re-curated FLNC as one of three genes selected for HCM-like
    phenotypes presenting as isolated left ventricular hypertrophy, restricted the
    curation to non-loss-of-function variants (explicitly separating them from the
    loss-of-function arrhythmogenic entity), retained a Definitive classification
    (8.1 genetic + 6 experimental = 14.1 points) — but assigned it to the disease
    entity myofibrillar myopathy, with left ventricular hypertrophy and
    restrictive cardiomyopathy listed as associated features rather than as a
    standalone hypertrophic entity. So the expert-panel position is that the
    non-truncating FLNC cardiac phenotype is the cardiac expression of
    filaminopathy/MFM, not a separate CMH. The emerging resolution is that
    FLNC-related hypertrophic disease is real but narrower than the raw carrier
    rates imply, is best identified phenotype-first (restrictive features plus the
    characteristic repolarization ECG) rather than genotype-first, and is arguably
    better nosologically placed on the filaminopathy spectrum than in the CMH
    numbered series.
  proposed_experiments:
  - experiment_id: exp_cmh26_rod2_segregation_functional
    name: Prospective ROD2-restricted segregation and functional study
    description: >-
      Recruit families carrying ROD2-domain FLNC missense variants — the subset
      with the strongest clustering signal — and collect prospective cascade
      segregation data alongside a standardized functional battery (aggregation
      assay, filamin C distribution, lysosomal/autophagic readouts) in
      patient-derived cardiomyocytes. Powering segregation and function together
      on one variant class is the most direct route to converting the current
      variants of uncertain significance into interpretable calls.
  - experiment_id: exp_cmh26_clingen_hcm_validity_curation
    name: ClinGen gene-disease validity curation of FLNC for the hypertrophic phenotype
    description: >-
      Formal ClinGen Hereditary Cardiovascular Disease GCEP curation of the
      FLNC-hypertrophic cardiomyopathy relationship, matching the existing
      Definitive assertions for FLNC-myofibrillar myopathy and FLNC-dilated
      cardiomyopathy. An expert-panel classification, restricted to
      non-truncating alleles, would settle whether CMH26 should be reported
      clinically and would give this entry a citable validity anchor.
  evidence:
  - reference: PMID:30411535
    reference_title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC mutations were common in both HCM patients and healthy population. The
      pathogenicity of FLNC mutations detected in HCM patients and its association
      with the clinical outcomes should be cautiously interpreted.
    explanation: >-
      The sceptical position in this controversy, stated by its authors.
  - reference: PMID:41672210
    reference_title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rare FLNC missense variant burden indicated a low case excess among all HCM
      cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in
      "ECG-positive" cases the etiologic fraction was substantially higher (0.98;
      95% confidence interval, 0.97-0.99).
    explanation: >-
      The proposed resolution: low explanatory power overall, very high within a
      phenotypically defined subgroup.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNC was curated for non -loss of function variants only, after pre-curation
      supported these variant types as distinct from the arrhythmogenic
      cardiomyopathy disease entity associated with loss of function FLNC
      variants.
    explanation: >-
      The ClinGen expert panel independently adopts the same variant-class split
      this entry is built on, and did so as an explicit pre-curation decision.
      Evidence source is OTHER because this is an expert-panel curation report.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Non- loss of function FLNC variants were definitively associated with
      myofibrillar myopathy, with patients presenting with isolated or combined
      skeletal and/or cardiac features
    explanation: >-
      The sceptical pole of the controversy at expert-panel level: ClinGen assigns
      the non-truncating FLNC allele class Definitive validity for myofibrillar
      myopathy rather than for a standalone hypertrophic entity. PARTIAL because
      it neither affirms nor denies CMH26 directly; it relocates the same allele
      class to a different disease entity.
- discussion_id: cmh26_hypertrophic_vs_restrictive_boundary
  prompt: >-
    Should CMH26 be modelled as a hypertrophic cardiomyopathy, given that MONDO
    lists restrictive cardiomyopathy 5 among its exact synonyms and every large
    series describes a hypertrophic-restrictive overlap rather than pure
    hypertrophy?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Diastolic Relaxation and Myocardial Stiffening
  rationale: >-
    MONDO:0014883 is asserted as a subtype of familial hypertrophic
    cardiomyopathy and carries CMH26 and cardiomyopathy, familial restrictive 5
    as exact synonyms of the same node, reflecting the OMIM 617047 entry. The
    literature supports the merge: the ROD2 series describes an HCM-RCM overlap,
    the 2026 family study describes hypertrophic and restrictive features
    together, and the original FLNC restrictive families carry the same class of
    non-truncating allele. This entry follows MONDO in treating the hypertrophic
    node as primary while curating restrictive physiology as a first-class
    phenotype rather than splitting a second entity. If MONDO later separates the
    restrictive node, this entry should be re-scoped rather than duplicated.
  evidence:
  - reference: PMID:35952944
    reference_title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNC-mRod2 variants show a high prevalence of an overlapped phenotype
      comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance
      and distinctive cardiac histopathological remodeling.
    explanation: >-
      Documents the overlap that motivates treating hypertrophic and restrictive
      presentations as one entity here.
- discussion_id: flnc_animal_models_do_not_model_the_hypertrophic_arm
  prompt: >-
    Do the available Flnc animal models say anything about CMH26, given that
    every published mouse model is a loss-of-function model and therefore
    reproduces the truncating dilated arm rather than the non-truncating
    hypertrophic one?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Mutant Filamin C Aggregation and Proteostatic Burden
  - pathophysiology#Filamin C Z-Disc Cross-Linking Defect
  rationale: >-
    Mouse Flnc genetics has been done exclusively by deletion. Global and
    cardiomyocyte-specific Flnc knockouts die in utero from ruptured ventricular
    myocardium, and an inducible adult cardiac-specific knockout produces rapid
    onset dilated cardiomyopathy with reduced systolic force and Z-disk
    misalignment. Both are loss-of-function, i.e. the haploinsufficiency
    mechanism that in humans causes the dilated and arrhythmogenic phenotypes,
    and neither reproduces hypertrophy, restrictive physiology, or filamin C
    aggregation. No knock-in of a human CMH26 missense allele has been reported.
    The consequence is that the aggregation and proteostasis nodes of this entry
    rest on human myocardium, human iPSC-cardiomyocytes and transfected cell
    lines, with no in vivo corroboration at all — and that mouse Flnc data must
    not be imported into this entry as if it modelled the hypertrophic arm.
  proposed_experiments:
  - experiment_id: exp_cmh26_missense_knockin_mouse
    name: Knock-in mouse carrying a human CMH26 ROD2 missense allele
    description: >-
      Generate a knock-in mouse bearing a segregating human ROD2-domain FLNC
      missense allele (rather than a null allele) and phenotype it for wall
      thickness, diastolic function, trabeculation, filamin C aggregation, and
      lysosomal/autophagic markers. This is the missing in vivo test of whether
      the non-truncating allele class is sufficient to produce the hypertrophic
      and restrictive phenotype in a mammal.
  - experiment_id: exp_cmh26_engineered_heart_tissue_diastolic
    name: Engineered heart tissue from CMH26 patient iPSC-cardiomyocytes
    description: >-
      Build three-dimensional engineered heart tissue from patient-derived
      CMH26 iPSC-cardiomyocytes and measure passive tension and relaxation
      kinetics alongside aggregate and lysosomal readouts, to test whether
      aggregation is sufficient to produce the stiffness that defines the
      clinical phenotype without invoking an animal model.
  evidence:
  - reference: PMID:35055055
    reference_title: Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To determine how FLNC regulates systolic force transmission and DCM
      remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO)
      model to produce a rapid onset of DCM in adult mice.
    explanation: >-
      The best-characterized adult mouse Flnc model is a knockout and produces
      dilated, not hypertrophic, cardiomyopathy — establishing the mismatch this
      discussion records.
  - reference: PMID:36706168
    reference_title: Filamin C is Essential for mammalian myocardial integrity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we demonstrated Flnc global (FlncgKO) and cardiomyocyte-specific knockout
      (FlnccKO) mice died in utero from severely ruptured ventricular myocardium
    explanation: >-
      The complete-loss mouse phenotype is embryonic myocardial rupture, a
      developmental structural failure with no counterpart in adult-onset human
      CMH26, reinforcing that mouse Flnc deletion does not model this entity.
references:
- reference: PMID:25351925
  title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
- reference: PMID:28356264
  title: Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
- reference: PMID:41672210
  title: Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG.
- reference: PMID:35952944
  title: ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.
- reference: PMID:27908349
  title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
- reference: PMID:34535832
  title: "Filamin C in cardiomyopathy: from physiological roles to DNA variants."
- reference: PMID:33557094
  title: "Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy."
- reference: PMID:32295012
  title: Structure and Function of Filamin C in the Muscle Z-Disc.
- reference: PMID:30411535
  title: Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy.
- reference: PMID:26666891
  title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
- reference: PMID:36539187
  title: "Cardiac filaminopathies: lights and shadows in the phenotype associated with the FLNC gene."
- reference: PMID:32112656
  title: A mutation update for the FLNC gene in myopathies and cardiomyopathies.
- reference: DOI:10.1161/CIRCRESAHA.120.317076
  title: Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
- reference: PMID:39132495
  title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
- reference: PMID:39315490
  title: Distinct molecular features of FLNC mutations, associated with different clinical phenotypes.
- reference: PMID:37174721
  title: Novel Filamin C Myofibrillar Myopathy Variants Cause Different Pathomechanisms and Alterations in Protein Quality Systems.
- reference: PMID:35055055
  title: Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy.
- reference: PMID:36706168
  title: Filamin C is Essential for mammalian myocardial integrity.
notes: >-
  Scope. This entry models MONDO:0014883 (hypertrophic cardiomyopathy 26,
  OMIM 617047, FLNC, HGNC:3756), the non-truncating FLNC arm of cardiac
  filaminopathy. It is deliberately scoped away from the other FLNC diseases
  already represented in dismech: Myofibrillar_Myopathy (which carries the
  FLNC/MFM5 subtype and the p.Trp2710Ter dimerization-domain allele),
  Dilated_Cardiomyopathy (which carries the FLNC gene node and the ClinGen
  FLNC-DCM Definitive assertion), and Dilated_Cardiomyopathy_1AA. The existing
  Arrhythmogenic_Right_Ventricular_Cardiomyopathy and DSP_Cardiomyopathy entries
  were checked and contain no FLNC content, so the truncating-FLNC arrhythmogenic
  phenotype is referenced here through the differential diagnosis rather than
  duplicated; a dedicated FLNC truncating cardiomyopathy entry remains a
  reasonable future addition.

  Variant class is the organising fact. Non-truncating (missense) FLNC variants
  cause the hypertrophic and restrictive phenotypes through aggregation of
  misfolded filamin C; truncating variants cause dilated and left-dominant
  arrhythmogenic phenotypes through haploinsufficiency, produce no myocardial
  aggregates, and were absent from 1,078 hypertrophic cardiomyopathy patients in
  the largest screen. Every mechanistic and clinical claim in this entry is
  sourced to a study of the hypertrophic or restrictive phenotype, except where a
  truncating-variant study is cited explicitly to draw the contrast.

  Gene-disease validity, and a nosological caveat. The ClinGen gene-validity
  download carries two FLNC assertions - myofibrillar myopathy (CGGV assertion
  d61672a0, 2023-10-26, Definitive) and dilated cardiomyopathy (CGGV assertion
  edb5197f, 2025-05-30, Definitive) - and no FLNC row in the hypertrophic
  cardiomyopathy gene list, so no CGGV evidence row could be cited for the CMH26
  relationship. That absence is not an oversight. The ClinGen Hereditary
  Cardiovascular Disease GCEP reappraisal (PMID:39132495) selected FLNC as one of
  three genes re-curated for HCM-like phenotypes presenting as isolated left
  ventricular hypertrophy, restricted the curation to non-loss-of-function
  variants, retained a Definitive classification, and assigned it to the disease
  entity myofibrillar myopathy, listing left ventricular hypertrophy and
  restrictive cardiomyopathy as associated features. The expert panel therefore
  treats the non-truncating FLNC cardiac phenotype as the cardiac expression of
  filaminopathy rather than as a distinct CMH. dismech keeps this entry because
  MONDO:0014883 exists as a distinct gene-anchored node and because the clinical
  literature curated here is specifically about the hypertrophic and restrictive
  presentation; the disagreement with ClinGen's lumping is recorded explicitly in
  the flnc_missense_hcm_pathogenicity_contested discussion rather than papered
  over. If MONDO later merges CMH26 into a filaminopathy node, this entry should
  be re-scoped accordingly.

  Reference identifier note. Agarwal et al. 2021 (Circ Res) is cited as
  DOI:10.1161/CIRCRESAHA.120.317076 rather than PMID:34405687 because the PubMed
  record for that paper carries only a graphical abstract, so the PMID cache
  contains no quotable abstract text while the DOI cache does. The reference
  validator skips DOI-prefixed snippets, so the three distinct snippets taken
  from it were verified by hand as whitespace-normalized substrings of
  references_cache/DOI_10.1161_CIRCRESAHA.120.317076.md.

  GeneReviews. A PubMed search for a GeneReviews chapter covering FLNC or CMH26
  returned only PMID:20301672, the retired Myofibrillar Myopathy chapter, which
  is not an appropriate phenotype baseline for this entity. No current
  GeneReviews chapter exists for FLNC-related cardiomyopathy, so the Step 3b
  baseline does not apply.

  Provenance. Deep research used the claude_code provider
  (research/Hypertrophic_Cardiomyopathy_26-deep-research-claude_code.md), not
  falcon: no EDISON_API_KEY or FUTUREHOUSE_API_KEY is available in this
  environment and deep-research-client reported falcon as unavailable. The report
  was treated as leads only; it passed the NEC gene/OMIM/synonym preflight, but
  one of its assertions (that ClinGen classifies FLNC as Definitive for
  hypertrophic cardiomyopathy) failed verification against the ClinGen
  gene-validity download and was not used.

  Unsourced or under-sourced. The description states that filamin C couples the
  sarcomere to the sarcolemma through integrin beta-1 and delta-sarcoglycan; the
  quoted evidence supports sarcolemmal attachment generally (PMID:27908349) but
  the beta-1 integrin partnership is sourced to a mouse knockout study
  (PMID:36706168, cited on the trigger node as MODEL_ORGANISM) and the
  delta-sarcoglycan partnership only to the Ripoll-Vera review (PMID:36539187),
  whose cached full text is Spanish-language and therefore not quoted as an
  evidence snippet. The Altered Extracellular Matrix Remodeling node's placement
  upstream of the diastolic node is a curator inference, flagged as such in that
  node's own description: the source reports differential matrix remodeling on
  histology without measuring its direction or mechanical effect. Frequency bands
  are asserted only where the source reports an explicit per-individual
  proportion; the 33 percent musculoskeletal figure is family-level and therefore
  carries no band. No node conforms to
  cardiomyopathy_maladaptive_remodeling#Neurohormonal Activation, because no
  FLNC-specific evidence for a neurohormonal amplifier step was found; the rest
  of the module chain is followed.

📚

References & Deep Research