Hypertrophic Cardiomyopathy 26

1. Disease Information

Overview

Hypertrophic cardiomyopathy 26 (CMH26) is the form of familial hypertrophic cardiomyopathy caused by heterozygous variants in FLNC, encoding filamin C — a large, muscle-specific actin-cross-linking protein of the sarcomeric Z-disc. It was defined as a distinct genetic form in 2014 by whole-exome sequencing of Spanish HCM families (PMID:25351925). The characteristic molecular signature is intracellular filamin C aggregate formation with sarcomeric disarray, and the characteristic clinical signature — as refined by later work — is a hypertrophic-restrictive phenotype with small LV cavity, severe diastolic dysfunction, a distinctive repolarization ECG, and frequent extracardiac (musculoskeletal) findings, rather than the classic hypercontractile obstructive HCM of sarcomeric (MYH7/MYBPC3) disease.

Key Identifiers (verified)

MONDO definition (verbatim, OAK sqlite:obo:mondo): "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the FLNC gene." Logical axiom: MONDO:0005045 AND RO:0004003 some HGNC:3756. Parent: MONDO:0024573 familial hypertrophic cardiomyopathy.

Synonyms (from MONDO, verified)

CMH26 · cardiomyopathy, familial hypertrophic, 26 · cardiomyopathy, familial hypertrophic, type 26 · hypertrophic cardiomyopathy type 26 · FLNC hypertrophic cardiomyopathy · hypertrophic cardiomyopathy caused by mutation in FLNC · cardiomyopathy, familial restrictive 5 (note the RCM conflation)

Clinically used but non-ontological: "cardiac filaminopathy," "FLNC-related cardiomyopathy," "non-truncating FLNC cardiomyopathy."

Data provenance

Aggregated disease-level: OMIM, MONDO, MedGen, ClinGen GCEP, ClinVar. Individual-patient: family-based cohort studies (Spanish, UK, Chinese, Russian cohorts) and case series; UK Biobank / gnomAD used as population comparators. No EHR-derived phenotype algorithm exists for CMH26 specifically.

2. Etiology

Primary cause

Heterozygous, autosomal-dominant, non-truncating germline variants in FLNC — predominantly missense substitutions and small in-frame deletions. There is no infectious or environmental cause. Foundational statement (PMID:25351925, verbatim abstract):

"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. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates."

Genetic risk factors

• Causal: FLNC missense/in-frame variants, enriched in the ROD2 domain (Ig-like repeats 16–23), which mediates sarcomere binding and signalling (PMID:32112656). Also reported in the N-terminal actin-binding domain (e.g., V123A) and the C-terminal rod (e.g., H2315N).
• Variant-class modifier (the dominant genetic determinant of phenotype): truncating vs non-truncating. Truncating FLNC variants were absent from 1,078 HCM patients in the largest genotype-phenotype study (PMID:27908349).
• Oligogenic / second-hit: co-occurring sarcomere-gene variants can modify severity; documented in families where FLNC co-segregates with e.g. MYLK2. Evidence is anecdotal, not systematic.
• Founder effect: FLNC p.Trp2710Ter observed "in 36 affected individuals across 6 Hong Kong Chinese families" (ClinGen HCM reappraisal, PMID:39132495) — note this is a last-exon nonsense variant that escapes NMD and behaves as an aggregate-former, i.e., mechanistically non-LOF.

Environmental / lifestyle risk factors

No established environmental cause. As with all HCM, high-intensity competitive exercise is a recognised arrhythmic trigger and disease-expression modifier, and hemodynamic loading (hypertension, obesity) worsens hypertrophy. Age is the strongest expressivity modifier — penetrance in FLNC families is markedly age-dependent (see §9). No occupational or toxin exposure is implicated.

Protective factors

None established genetically. No protective FLNC alleles have been reported. Environmental "protection" is limited to conventional cardiovascular risk-factor control and avoidance of arrhythmic triggers — i.e., tertiary prevention rather than true protection.

Gene–environment interaction

Mechanistically plausible and worth curating as a hypothesis, not a fact: filamin C is the direct mechanosensor of the CASA (chaperone-assisted selective autophagy) pathway — "the CASA complex... senses the mechanical unfolding of the actin-crosslinking protein filamin. Contraction of the actin network results in the mechanical unfolding of protein domains within the filamin rods, leading to recognition by the CASA chaperone complex." A misfolding-prone filamin C variant therefore sits at the exact node where mechanical load is transduced into proteostatic demand, giving a direct molecular route by which exercise/afterload could accelerate aggregate accumulation. No human study has tested this directly. → Curate as kind: KNOWLEDGE_GAP.

3. Phenotypes

Frequencies below come from small, ascertainment-biased family series; treat all as soft. Where I cannot support a FrequencyEnum band with a quantitative source, I say so — per docs/frequency-evidence-guidelines.md, omit rather than fabricate.

Cardiac — core

Cardiac — electrical / arrhythmic

Symptoms (patient-reported)

Dyspnea HP:0002094; chest pain HP:0100749; exercise intolerance HP:0003546; syncope HP:0001279.

Extracardiac — musculoskeletal (a discriminating feature)

The 2026 Heart Rhythm study reports musculoskeletal abnormalities in 4 of 12 (33%) ECG-positive families. This is a genuine differentiator from sarcomeric HCM and should be curated as a phenotype category. Because FLNC also causes myofibrillar myopathy-5 and distal myopathy-4, overlap features include:

• Muscle weakness HP:0001324; distal muscle weakness HP:0002460; proximal muscle weakness HP:0003701
• Elevated circulating creatine kinase HP:0003236 / mildly elevated CK HP:0008180
• Flexion contracture HP:0001371; scoliosis HP:0002650

Important counterpoint for the truncating arm: "Clinical skeletal myopathy was not observed" in the 28 truncating-variant families (PMID:27908349) — i.e., overt myopathy tracks with the aggregate-forming (non-LOF) mechanism, consistent with CMH26.

Other reported

Stroke (thromboembolic, AF-related) — MedGen lists "stroke disorder."

Onset, severity, progression

• Onset: predominantly adult; wide range. Aggregate-forming missense variants can present in childhood/infancy with RCM (severe end); classic CMH26 families present in the 3rd–6th decades.
• Severity: highly variable, even within a family. Gómez et al. found "Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance" (PMID:28356264) — directly contradicting a uniformly malignant picture.
• Progression: chronic, progressive. Restrictive physiology and diastolic failure drive the course; a subset progresses to end-stage heart failure requiring transplant (PMID:26666891). Arrhythmic risk is present throughout, not only at end stage.

Quality-of-life impact

No CMH26-specific QoL data exist. Extrapolating from HCM generally: exertional dyspnea and exercise restriction dominate; ICD carriers experience anxiety and shock-related distress; the restrictive subphenotype carries a worse functional burden than obstructive HCM at equivalent wall thickness. Flag as a data gap — do not populate numeric QoL values.

4. Genetic / Molecular Information

Causal gene

FLNC — filamin C (gamma). HGNC:3756 (repo casing: hgnc:3756). Cytoband 7q32.1. OMIM *102565. UniProt Q14315. 48 exons; 2,725 aa protein.

Domain architecture (UniProt Q14315, verified): two N-terminal calponin-homology (CH1/CH2) actin-binding domains, followed by 24 immunoglobulin-like (Ig) repeats with intervening hinges. Functional partition: ROD1 = Ig 1–15, ROD2 = Ig 16–23, Ig24 = the dimerization domain. A muscle-specific intradomain insert (residues 2162–2243) within Ig20 directs Z-line targeting.

Pathogenic variants

Variant classes and the genotype–phenotype rule (the single most important curation fact):

Verdonschot et al. (PMID:32112656) state it directly — truncating variants causing reduced protein dosage produce DCM with arrhythmias; missense variants disrupting dimerization and folding trigger aggregate accumulation, manifesting as HCM or myofibrillar myopathy; and HCM-associated variants cluster predominantly in the ROD2 domain.

Representative CMH26 variants:

Classification (ACMG/AMP): FLNC missense variant interpretation is difficult. Gómez et al. found 20 candidate variants in 22 of 448 HCM patients, of which only 6 (in 7 patients) were finally classified as likely pathogenic, 10 as VUS, and 4 as likely benign (PMID:28356264). Expect a high VUS rate. Domain location (ROD2), demonstrated aggregation, and family segregation are the strongest supporting lines.

Allele frequency / population data: FLNC tolerates a substantial burden of rare missense variation in the general population, which is exactly why burden analysis matters. Cui et al. found FLNC mutations in 7.22% of HCM patients vs 4.23% of controls (p = 0.101, not significant), concluding "FLNC mutation was found to be very common in both the healthy population and HCM patients... and generally FLNC mutation does not cause HCM" (Mol Genet Genomic Med 2018, doi:10.1002/mgg3.488). The 2026 Heart Rhythm burden analysis against 122,348 gnomAD controls quantified this as an etiologic fraction of 0.45 (95% CI 0.36–0.54) for unselected HCM. I was unable to retrieve gnomAD's numeric pLI/LOEUF/missense-Z for FLNC — do not populate those fields without direct lookup.

Somatic vs germline: exclusively germline. No somatic role.

Functional consequence: for CMH26, the mechanism is not simple loss of function. It is a toxic gain-of-function / dominant-negative proteinopathy — misfolded filamin C that cannot dimerize normally, aggregates, sequesters binding partners, and overwhelms Z-disc protein turnover. This is the mechanistic dividing line from truncating-FLNC DCM/ACM (haploinsufficiency).

Modifier genes

No validated modifier loci. Candidate modifiers on mechanistic grounds (untested): BAG3, HSPB8, HSPB7, CRYAB, STUB1/CHIP, SQSTM1 — all CASA/proteostasis components whose own variants cause overlapping myofibrillar myopathy/cardiomyopathy. Curate as hypothesis.

Epigenetics

No FLNC-specific methylation or chromatin data. Not applicable.

Chromosomal abnormalities

Not a mechanism in CMH26. Technical caveat with real clinical consequence: "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" (ClinGen HCM reappraisal, PMID:39132495) — short-read NGS can mis-map reads in this region, producing false positives/negatives. This belongs in the diagnostics section of the entry.

5. Environmental Information

• Environmental factors: none causal. No toxin, radiation, pollutant, or occupational exposure is implicated.
• Lifestyle factors: high-intensity competitive athletics is an arrhythmic trigger in HCM broadly; hypertension and obesity aggravate hypertrophy. Modifiers of expression, not causes.
• Infectious agents: not applicable.

6. Mechanism / Pathophysiology

The causal chain (proposed pathograph for the KB)

[MOLECULAR] FLNC non-truncating variant (ROD2-clustered missense / in-frame del)
    ↓
[MOLECULAR] Filamin C misfolding and impaired Ig24-mediated homodimerization
    ↓
[MOLECULAR] Filamin C aggregate formation (cytoplasmic/perinuclear inclusions)
    ↓
[CELLULAR] Sequestration of Z-disc binding partners (desmin, myotilin, myozenin, ZASP, BAG3)
    ↓
[CELLULAR] Impaired Z-disc protein turnover → proteotoxic stress
    ↓
[CELLULAR] Lysosomal biogenesis (TFEB nuclear translocation) + enhanced autophagic flux
    ↓
[CELLULAR] Sarcomeric disarray, Z-disc misalignment, Z-disk expansion
    ↓
[TISSUE]   Myocyte disarray + interstitial/replacement myocardial fibrosis
    ↓
[TISSUE]   Increased myocardial stiffness; LV hypertrophy WITHOUT hypercontractility
    ↓
[ORGANISM] Diastolic dysfunction / restrictive physiology → heart failure
[ORGANISM] Fibrotic + structurally disorganized substrate → reentrant ventricular arrhythmia → SCD

Molecular pathways

• Actin cytoskeletal cross-linking / Z-disc assembly — GO:0051015 actin filament binding; GO:0051764 actin crosslink formation; GO:0045214 sarcomere organization; GO:0030239 myofibril assembly; GO:0051260 protein homooligomerization (dimerization).
• Chaperone-assisted selective autophagy (CASA) — the central pathway. HSPA8 (Hsc70) + HSPB8 + BAG3 recognize mechanically unfolded filamin rod domains; "BAG3 cooperates with the HSPA8-associated ubiquitin ligase STUB1/CHIP and its partner UBE2D in the ubiquitination of chaperone-bound FLNC. This provides a signal for the recruitment of the autophagic ubiquitin receptor SQSTM1." GO:0006914 autophagy; GO:0016236 macroautophagy; GO:0061684 chaperone-mediated autophagy; GO:0006511 ubiquitin-dependent protein catabolic process; GO:0034620 cellular response to unfolded protein.
• Mechanotransduction — GO:0009612 response to mechanical stimulus. Filamin C is the mechanosensor itself, not merely a structural strut.
• Lysosomal biogenesis / TFEB axis — GO:0005764 lysosome. Directly demonstrated in isogenic hiPSC-CMs.
• Cardiac hypertrophic signalling — GO:0003300 cardiac muscle hypertrophy (downstream/secondary).
• Ion handling (variant-specific) — Naᵥ1.5 kinetics and Ca²⁺ transient disturbance shown for R1267Q > V2264M in patient iPSC-CMs (PMID:39315490); relevant to the arrhythmic arm.

Definitive mechanistic experiment (the key citation for the entry)

Agarwal et al., Circ Res 2021 (PMID:34405687) — isogenic CRISPR hiPSC-CM series. Verbatim conclusions:

"FLNC expression is required for sarcomere organization and physiologic function. 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. Surprisingly, similar pathways were activated in FLNC haploinsufficient hiPSC-CMs, likely initiated by the loss of stoichiometric FLNC protein interactions and impaired turnover of proteins at the Z-disc. These results indicate that both FLNC haploinsufficient variants and variants that produce misfolded FLNC protein cause disease by similar proteotoxic mechanisms, and indicate the therapeutic potential for augmenting protein degradative pathways to treat a wide range of FLNC-related cardiomyopathies."

And on the HCM-relevant arm specifically:

"We also studied a heterozygous in-frame deletion (FLNC+/∆7aa) which did not affect FLNC expression but caused aggregate formation, similar to FLNC variants associated with hypertrophic cardiomyopathy (HCM). FLNC−/− hiPSC-CMs demonstrated profound sarcomere misassembly and reduced contractility. While sarcomere formation and function were unaffected in FLNC+/− and FLNC+/∆7aa hiPSC-CMs, these heterozygous variants caused increases in lysosome content, enhancement of autophagic flux, and accumulation of FLNC-binding partners and Z-disc proteins."

This is a mechanistically important nuance: in heterozygous (i.e., patient-realistic) cells, sarcomere structure and contractile function were preserved — the primary lesion is proteostatic, not contractile. That aligns strikingly with the 2026 clinical finding of hypertrophy without hypercontractility, and argues against a myosin-hyperactivity model for CMH26.

Protein dysfunction

Misfolding of Ig-like rod repeats; loss of Ig24-mediated homodimerization (canonical for W2710X: "the W2710X protein had improper folding, was unable to form dimers, and showed abnormal aggregation"); formation of insoluble aggregates enriched in FLNC, desmin, and multiple binding partners (Agarwal 2021). Note the inversion in the truncating arm: "Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations" (PMID:27908349) — aggregates are the CMH26/MFM signature specifically.

Metabolic changes

No primary metabolic defect. Secondary: energetic inefficiency of hypertrophied, fibrotic myocardium; increased autophagic/lysosomal degradative load. Not a metabolic disease.

Immune system involvement

None primary. No autoimmune or immunodeficiency component. Low-grade sterile inflammation may accompany fibrotic remodelling (generic, not FLNC-specific).

Tissue damage mechanisms

Myocyte disarray, Z-disc disruption, myocyte loss with replacement fibrosis (HP:0001685; LGE-positive on CMR), electrical anisotropy from the fibrotic substrate. Mouse work adds direct biomechanical data: FLNC loss "reduced systolic force development in single cardiomyocytes and isolated papillary muscles but did not affect twitch kinetics or calcium transients," with "significant defects in Z-disk alignment and altered myofilament lattice geometry" (Int J Mol Sci 2022;23:871, PMC8779483).

Biochemical abnormalities

Filamin C aggregation (loss of solubility); disrupted stoichiometry of the Z-disc interactome; elevated lysosomal protein content; depletion of ATG5/ATG7/BECN1 (consistent with increased autophagic consumption); accumulation of Z-disc proteins in total lysate despite enhanced flux — i.e., degradation cannot keep pace with damaged-protein production.

Epigenetic changes

None reported for CMH26. Data gap.

Molecular profiling

• Transcriptomics: FLNC⁻/⁻ hiPSC-CMs show reduced thin-filament gene expression (PMID:34405687). Patient-specific iPSC-CM RNA-seq shows variant-specific transcriptome shifts in action-potential/sodium-transport and structural cardiomyocyte genes (PMID:39315490).
• Proteomics: aggregate composition profiling (FLNC, desmin, myotilin, binding partners) — Agarwal 2021 and the W2710X homozygous-expression study (PMC7650280).
• Metabolomics / lipidomics: no CMH26-specific data. Gap.
• Single-cell / spatial: no FLNC-cardiomyopathy-specific single-cell or spatial atlas identified. Gap — a good KNOWLEDGE_GAP entry.
• Functional genomics screens: no FLNC-focused CRISPR/RNAi screen identified; isogenic CRISPR hiPSC-CM series (Agarwal) is the closest.

7. Anatomical Structures Affected

Organ level

• Primary: heart — UBERON:0000948; specifically myocardium UBERON:0002349, left ventricle myocardium UBERON:0006566, interventricular septum UBERON:0002094, cardiac ventricle UBERON:0002082.
• Secondary: cardiac atrium UBERON:0002081 (atrial enlargement/AF, secondary to diastolic dysfunction); systemic/pulmonary venous congestion in heart failure; brain (cardioembolic stroke, secondary to AF).
• Extracardiac primary (variant-dependent): skeletal muscle tissue UBERON:0001134 — myopathic/musculoskeletal involvement in ~33% of ECG-positive FLNC HCM families.
• Body systems: cardiovascular (primary), musculoskeletal (secondary/overlap).

Tissue and cell level

• Cardiac muscle cell — CL:0000746 (primary target)
• Regular ventricular cardiac myocyte — CL:0002131
• Fibroblast of cardiac tissue — CL:0002548 (fibrotic remodelling effector)
• Skeletal muscle fiber — CL:0008002 (filaminopathy overlap)

Subcellular level

• Z disc — GO:0030018 (the primary lesion site)
• Sarcolemma — GO:0042383; costamere — GO:0043034; intercalated disc — GO:0014704 (filamin C's normal localisation set, per UniProt: "myofibrillar Z-discs... with minor amounts at the sarcolemma")
• Inclusion body — GO:0016234 (the pathological structure)
• Lysosome — GO:0005764 (expanded compartment)

Localization / lateralization

Bilateral/global myocardial involvement. Hypertrophy is typically concentric in FLNC HCM with a characteristically small LV cavity — distinguishing it from the asymmetric septal hypertrophy typical of MYH7/MYBPC3 disease. Skeletal involvement, when present, follows the distal-predominant filaminopathy pattern.

8. Temporal Development

• Onset: predominantly adult (3rd–6th decade) for the classic CMH26 HCM presentation. Aggregate-forming missense variants presenting as RCM can manifest in childhood or infancy, sometimes requiring early transplant. Congenital presentation occurs only with biallelic FLNC variants (a distinct, severe, non-CMH26 entity).
• Onset pattern: insidious/chronic. Frequently detected on family cascade screening or incidental ECG before symptoms.
• Stages: (i) genotype-positive/phenotype-negative; (ii) ECG abnormality without overt hypertrophy — this is the notable early marker in FLNC disease; (iii) established hypertrophy with preserved systolic function and progressive diastolic impairment; (iv) restrictive physiology with heart failure; (v) end-stage requiring transplant. Arrhythmic risk is not confined to late stages — SCD can be the presenting event.
• Progression rate: slow to moderate, highly variable between and within families.
• Course pattern: progressive and lifelong, punctuated by episodic arrhythmic events.
• Duration: chronic, lifelong. No spontaneous remission. "Remission" is only treatment-induced symptom control or, definitively, transplantation.
• Critical periods: (a) adolescence/early adulthood — when screening should begin and competitive-sport counselling matters; (b) age >40 — penetrance rises steeply, making continued surveillance of genotype-positive relatives essential; (c) first detection of restrictive physiology or LGE — the window for ICD decision-making.

9. Inheritance and Population

Epidemiology

No CMH26-specific prevalence figure exists. Derive it:

• HCM overall affects ~1 in 500 clinically ascertained, with genotype-based estimates as high as ~1 in 200 (≈200–500 per 100,000).
• FLNC candidate variants were found in 22 of 448 HCM patients (4.9%), but only 7 of 448 (1.6%) carried variants finally classified likely pathogenic (PMID:28356264).
• Applying the ~1.6% likely-pathogenic yield to a 1/500 HCM prevalence gives an order-of-magnitude CMH26 point prevalence of ~3 per 100,000 — i.e., Orphanet band BAND_1_9_PER_100000. This is a derived estimate, not a published one; label it as such in notes:.
• Incidence: not established.

Inheritance

• Autosomal dominant (HP:0000006). Truncating FLNC variants cosegregate with a combined LOD score of 9.5 (PMID:27908349); CMH26 missense families likewise segregate dominantly.
• Penetrance: incomplete and strongly age-dependent. In the founding CMH26 families, 14 of 16 carriers over 40 years of age were symptomatic (>87% penetrance). In the truncating cohort, "Penetrance was >97% in carriers older than 40 years" (PMID:27908349). But Gómez et al. describe "a reduced penetrance, with few affected in the families to confirm the segregation" (PMID:28356264) — penetrance in unselected missense carriers is materially lower than in intensively ascertained families. Curate both; do not average them.
• Expressivity: highly variable — the same variant can produce HCM, RCM, isolated ECG abnormality, or myopathy in different relatives.
• Genetic anticipation: not applicable (no repeat expansion). Do not assert.
• Germline mosaicism: not reported for FLNC. Gap.
• Founder effects: FLNC p.Trp2710Ter in Hong Kong Chinese families (6 families, 36 affected). Spanish families dominate the original CMH26 literature (ascertainment, not necessarily a founder effect).
• Consanguinity: irrelevant for dominant CMH26; relevant only for the rare biallelic congenital DCM form.
• Carrier frequency: not applicable (dominant). Relevant metric is population frequency of rare FLNC missense variants, which is non-trivial — precisely the reason for the low etiologic fraction.

Population demographics

• Affected populations: reported worldwide — Spanish, Dutch, Italian, UK, Chinese (mainland and Hong Kong), Russian, North American cohorts. No ethnic group is known to be disproportionately affected beyond the HK Chinese founder variant.
• Geographic distribution: cosmopolitan.
• Sex ratio: no established sex bias for CMH26. (One Flnc-deficiency mouse study specifically examined male mice; do not over-read this into human sex distribution.)
• Age distribution: peak clinical recognition in adulthood; markedly skewed to >40 years by penetrance.

10. Diagnostics

Imaging and functional testing

• Transthoracic echocardiography — LVH, small LV cavity, diastolic dysfunction, atrial enlargement, restrictive filling. Notably: FLNC 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" (Heart Rhythm 2026). The absence of hypercontractility is itself a diagnostic clue.
• Cardiac MRI with LGE — myocardial fibrosis quantification (HP:0001685); central to arrhythmic risk stratification and to distinguishing FLNC from sarcomeric HCM.
• 12-lead ECG — carries the highest-yield discriminating signal (below).
• Ambulatory ECG / Holter, exercise testing — NSVT detection for SCD risk stratification.
• Electrophysiology study — selected cases.

The distinctive ECG (the most actionable diagnostic finding)

A distinct repolarization phenotype was present in 37% (19/51 individuals from 12 families) of FLNC-variant HCM/RCM patients vs 1.0% (2/197) of a control HCM cohort. Its discriminative power is quantified by the etiologic-fraction split: 0.45 (95% CI 0.36–0.54) across all HCM cases vs 0.98 (95% CI 0.97–0.99) in "ECG-positive" cases (Heart Rhythm 2026, PII S1547-5271(26)00121-9).

Curation implication: this is an excellent candidate for a definitions[] entry with definition_type: PHENOTYPE_ALGORITHM and derivation_basis: ESTABLISHED_CRITERIA (or MECHANISTIC_HYPOTHESIS if framed prospectively), validation_status.status: UNVALIDATED, attaches_to the repolarization/fibrosis node — an ECG-first case-finding rule that raises FLNC missense PPV from ~45% to ~98%.

Laboratory

• Creatine kinase (LOINC 2157-6) — screen for skeletal-muscle involvement; HP:0003236 / HP:0008180.
• NT-proBNP / BNP — heart-failure severity; HP:0033534 increased circulating brain natriuretic peptide concentration.
• Troponin — nonspecific.

Biopsy / histopathology

Endomyocardial biopsy is not routine but is diagnostically decisive when performed: cytoplasmic inclusions consistent with protein aggregates, filamin-C-positive by immunohistochemistry (PMID:26666891). Skeletal muscle biopsy in overlap cases shows myofibrillar myopathy features (Z-disc-derived sarcomeric lesions, desmin/filamin C accumulation). The aggregate finding is the pathognomonic feature separating CMH26 from truncating-FLNC disease, where aggregates are absent (PMID:27908349).

Genetic testing

• Recommended approach: multigene cardiomyopathy NGS panel including FLNC. FLNC is now standard on comprehensive HCM/DCM/ACM panels; it was historically absent, and pre-2014 negative panels should be reflexed.
• WES/WGS: valuable for atypical/syndromic presentations and originally how CMH26 was discovered. WGS additionally resolves the pseudogene-homologous region better than short-read exome capture.
• Single-gene testing: appropriate only for cascade/predictive testing of relatives once a familial variant is known.
• CMA / karyotype / FISH / mtDNA / repeat-expansion testing: not indicated for CMH26.
• Critical technical caveat: the 53.6 kb-downstream FLNC pseudogene with 98% homology across exons 46–48 creates a real mis-mapping hazard — variants in those exons should be orthogonally confirmed (long-read or Sanger with gene-specific primers).
• Interpretation caution: given the ~45% etiologic fraction, a rare FLNC missense variant in HCM should not be treated as causal by default. Weight ROD2 location, the characteristic ECG, restrictive physiology, extracardiac features, aggregate histology, and segregation.

Clinical criteria and differential diagnosis

Diagnosis of HCM follows the 2023 ESC cardiomyopathy guidelines and the 2024 AHA/ACC HCM guideline: LV wall thickness ≥15 mm (or ≥13 mm with family history/genotype) unexplained by loading conditions.

Differential diagnosis with distinguishing features:

Screening

Cascade genetic testing of first-degree relatives is the cornerstone, with clinical screening (ECG + echo) of genotype-positive relatives. Given age-dependent penetrance, genotype-positive/phenotype-negative relatives require lifelong periodic surveillance — a negative echo in youth does not discharge them. No newborn or population screening exists or is indicated.

11. Outcome / Prognosis

Survival and mortality

No CMH26-specific survival curves exist. Available anchors:

• Elevated SCD risk is the founding observation: "Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death" (PMID:25351925).
• In the ECG-positive FLNC HCM/RCM group, heart failure death, transplant, or cardiac arrest occurred in at least one individual in 7 of 12 families (58%) (Heart Rhythm 2026).
• For contrast (the truncating arm, not CMH26): 40 SCD events across 21 of 28 families, ventricular arrhythmias in 82% (PMID:27908349).
• Counterweight: "Most of the FLNC variants were associated with mild forms of HCM" (PMID:28356264).

Net reading: FLNC-related HCM/RCM appears to carry above-average risk relative to sarcomeric HCM, driven by both arrhythmia and diastolic heart failure — but the risk is concentrated in the ECG-positive/restrictive subgroup, and unselected FLNC missense carriers may do well. Do not populate a single global mortality figure.

Morbidity and function

Progressive exertional limitation from diastolic dysfunction; heart failure hospitalizations; AF with stroke risk; ICD-related morbidity (inappropriate shocks, lead complications, psychological burden). Where restrictive physiology dominates, functional limitation is disproportionate to wall thickness.

Complications

Sudden cardiac death; sustained VT/VF; progressive heart failure to end stage; atrial fibrillation; cardioembolic stroke; conduction disease requiring pacing; in overlap cases, progressive skeletal myopathy.

Recovery potential

None spontaneously. Structural damage (fibrosis, aggregates) is irreversible with current therapy. Cardiac transplantation is the only definitive intervention for end-stage disease and is well documented in FLNC RCM: patients "presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases" (PMID:26666891).

Prognostic factors

Adverse: the characteristic repolarization ECG; restrictive physiology with small LV cavity; extensive LGE/myocardial fibrosis; NSVT; unexplained syncope; family history of SCD; falling ejection fraction; age >40 (penetrance and event accrual).

Prognostic biomarkers

LGE burden on CMR is the best-supported imaging biomarker. NT-proBNP tracks heart-failure severity. No validated FLNC-specific molecular prognostic biomarker exists — a genuine gap. Aggregate burden on biopsy is diagnostic, not validated as prognostic.

12. Treatment

There is no disease-modifying therapy for CMH26. Management is symptom-directed plus SCD prevention, per general HCM/cardiomyopathy guidelines, with two FLNC-specific modifications.

Pharmacotherapy

Pharmacogenomics: no FLNC-specific PGx. Standard CYP2D6-metoprolol and CYP2C9/VKORC1-warfarin considerations apply generically.

Device and interventional

ICD threshold — the FLNC-specific modification. The 2023 ESC cardiomyopathy guidelines treat FLNC as a high-risk genotype: when a patient with DCM/NDLVC carries a P/LP variant in a gene such as FLNC associated with SCD, an ICD "should be considered in primary prevention even with LVEF > 35% when there are additional risk factors" (Class IIa, LoE C), within a multiparametric framework (LVEF < 50% plus ≥2 of syncope, LGE on CMR, inducible sustained monomorphic VT at EPS, high-risk genotype). Ortiz-Genga et al. put it bluntly for the truncating arm: "Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC." Note the scope boundary: these recommendations are anchored to the DCM/ACM (truncating) arm. Whether they transfer to non-truncating CMH26 is not settled — curate as a KNOWLEDGE_GAP, not as established practice.

Advanced / experimental therapeutics

• Gene therapy: no FLNC AAV programme in trials. Important mechanistic caveat — FLNC is a 2,725-aa protein whose ~8.2 kb coding sequence exceeds AAV packaging capacity, and for aggregate-forming (dominant-negative) CMH26 variants gene addition would not address the toxic species anyway. Allele-specific knockdown or base/prime editing is the theoretically appropriate modality; none is in development.
• RNA-based therapy: none for FLNC. Allele-specific ASO/siRNA silencing of the mutant allele is a rational but unpursued strategy.
• Proteostasis augmentation — the most mechanistically grounded direction. Agarwal et al. explicitly conclude their data "indicate the therapeutic potential for augmenting protein degradative pathways to treat a wide range of FLNC-related cardiomyopathies" (PMID:34405687). No clinical programme exists.
• Adjacent precedent worth tracking: AAV gene therapy for BAG3-associated DCM is in clinical development (NCT07137338, RP-A701, Rocket Pharmaceuticals, Phase 1; NCT07426419, AFTX-201, Affinia Therapeutics). BAG3 is filamin C's direct CASA co-chaperone partner, so these trials validate the pathway clinically even though they do not treat FLNC disease. Cite as pathway-adjacent, not as a CMH26 treatment.
• Immunotherapy / cell therapy / targeted oncology-style agents: not applicable.

Supportive, rehabilitative, and lifestyle

Heart-failure supportive care (NCIT:C15747); exercise prescription with avoidance of high-intensity competitive sport; cardiac rehabilitation (NCIT:C15315) in stable HF; physical therapy (NCIT:C15302) where skeletal myopathy coexists; psychological support for ICD carriers.

Treatment strategy summary

1. Confirm variant class (truncating vs non-truncating) — it changes both prognosis and the arrhythmia strategy.
2. Phenotype comprehensively: ECG (look for the repolarization signature), echo (cavity size, diastolic function, contractility), CMR with LGE, CK, and musculoskeletal exam.
3. Symptom control: beta-blocker first-line; careful diuresis; scrutinize myosin-inhibitor use.
4. Risk-stratify for SCD using a multiparametric model that upweights the FLNC genotype and LGE burden.
5. Cascade-test relatives; enroll genotype-positive relatives in lifelong surveillance.
6. Refer early to advanced HF/transplant when restrictive physiology emerges.

13. Prevention

• Primary prevention (of the disease): not possible — germline. Only reproductive options prevent transmission: preimplantation genetic testing for monogenic disease (PGT-M), prenatal diagnosis, donor gametes. Requires a confirmed P/LP familial variant, which is often unavailable given the high VUS rate.
• Secondary prevention (early detection): cascade genetic testing of first-degree relatives + ECG/echo surveillance of carriers. Because the ECG abnormality can precede overt hypertrophy, ECG is the highest-yield early screening modality in FLNC families. Surveillance intervals should follow HCM family-screening guidance (roughly 1–3 yearly in adolescence, 3–5 yearly in adults), continued indefinitely given age-dependent penetrance.
• Tertiary prevention (of complications): ICD for SCD; anticoagulation for AF-related stroke; guideline-directed HF therapy; competitive-sport restriction; timely transplant referral.
• Immunization: not applicable to disease pathogenesis. Routine influenza/COVID/pneumococcal vaccination is standard supportive care in heart failure.
• Population screening: not indicated. The low etiologic fraction of FLNC missense variants makes population-level FLNC screening actively harmful (VUS burden, overdiagnosis).
• Genetic counselling (NCIT:C15240): essential. Must cover 50% transmission risk, incomplete age-dependent penetrance, highly variable expressivity, the VUS problem, reproductive options, and the implications of a high-risk genotype for ICD decisions.
• Public health / environmental interventions: not applicable.
• Prophylaxis: ICD is the only true prophylactic intervention. No prophylactic pharmacotherapy prevents phenotype development in genotype-positive/phenotype-negative carriers — and none should be asserted.

14. Other Species / Natural Disease

• Taxonomy: Homo sapiens NCBITaxon:9606 (disease entity). Experimental species: Mus musculus NCBITaxon:10090, Danio rerio NCBITaxon:7955, Rattus norvegicus NCBITaxon:10116 (neonatal cardiomyocyte transfection).
• Breed (VBO): not applicable — no breed-associated FLNC cardiomyopathy identified.
• Orthologous genes: mouse Flnc (NCBI Gene 68794); zebrafish has two paralogs, flnca and flncb (genome duplication), requiring double mutants to model human loss.
• Natural disease in other species: I found no naturally occurring FLNC-associated cardiomyopathy in any non-human species. A targeted OMIA search returned feline HCM entries for MYBPC3 (OMIA:002951, OMIA:002952), MYH7 (OMIA:002212), ALMS1 (OMIA:002316), and TNNT2 — but no FLNC entry. Feline HCM is the most important naturally occurring animal HCM model (reported incidence up to ~15% in some cat populations), but it is not FLNC-mediated. State this explicitly as a negative finding in the KB rather than leaving the section empty.
• Veterinary relevance: none established for FLNC specifically.
• Comparative biology: filamin C is highly conserved across vertebrates in domain architecture (CH1/CH2 + 24 Ig repeats) and in its Z-disc/CASA role; zebrafish double mutants and mouse conditional knockouts both reproduce Z-disc disruption, indicating deep conservation of the mechanism.
• Zoonotic potential / cross-species transmission: not applicable (genetic disease).

15. Model Organisms

Mouse (Mus musculus, NCBITaxon:10090)

Zebrafish (Danio rerio, NCBITaxon:7955)

Double flnca/flncb mutants: "The cardiac morphological phenotype of double flnc mutant embryos is characterized by decreased cardiac output and stroke volume, similar to what is observed in patients with cardiomyopathies. Double flnca and flncb mutant hearts exhibited irregular z-discs." Single mutants are largely unaffected — paralog redundancy is the key experimental limitation.

Human iPSC-derived cardiomyocytes (the most human-relevant system)

• Isogenic CRISPR series (WT / FLNC⁻/⁻ / FLNC⁺/⁻ / FLNC⁺/^∆7aa) — the definitive mechanistic model, PMID:34405687. The ∆7aa in-frame deletion is the designed CMH26 analog (aggregate-forming without expression loss).
• Patient-specific iPSC-CMs (R1267Q ACM vs V2264M RCM) — variant-specific Ca²⁺ handling, Naᵥ1.5 kinetics, action potentials, transcriptomes (PMID:39315490).

Cell lines / in vitro

Rat neonatal cardiomyocytes and mouse myoblasts transfected with A1539T — perinuclear filamin C aggregates (PMID:25351925). Myoblast lines expressing S1624L — cytoplasmic aggregates (PMID:26666891). Homozygous W2710X expression system for sarcomeric lesion pathomechanism (PMC7650280).

Phenotype recapitulation and limitations — curate as HUMAN_MODEL_MISMATCH, not KNOWLEDGE_GAP

This is a textbook case of the distinction the schema draws:

• Mouse and zebrafish Flnc loss-of-function models produce DCM and Z-disc disruption, not hypertrophic cardiomyopathy. They model the truncating/haploinsufficiency arm (DCM/ACM) — not CMH26. Using them as evidence for CMH26 pathophysiology is a category error.
• No mouse knock-in of a human CMH26 missense variant (A1539T, H2315N) reproducing an HCM phenotype was identified in this search. This is the single biggest model gap for the entry.
• Zebrafish paralog redundancy (flnca + flncb) requires double mutants, distancing the model from human heterozygous dominant disease.
• hiPSC-CMs are immature (fetal-like sarcomeres, altered Ca²⁺ handling, no true diastolic loading) and cannot model restrictive physiology, fibrosis, or arrhythmic reentry — precisely the features that define the clinical CMH26 phenotype.

Suggested proposed_experiments: (1) knock-in mouse carrying a ROD2 CMH26 missense variant with longitudinal echo/ECG phenotyping; (2) engineered heart tissue from CMH26-variant hiPSC-CMs under physiological load to test whether mechanical stress accelerates aggregation; (3) proteostasis-augmentation intervention (TFEB activation or CASA enhancement) in that system.

Model resources

MGI (Flnc, MGI:95557), IMPC/KOMP, ZFIN (flnca, flncb), Alliance of Genome Resources, Cellosaurus/hPSCreg for the iPSC lines, IMSR/MMRRC for mouse strain sourcing.

Curation Recommendations for the dismech Entry

1. Replace the placeholder pathophysiology node with the 9-node causal chain in §6, tagging biological_scale per node (MOLECULAR → CELLULAR → TISSUE → ORGANISM as annotated).
2. Add mechanistic_hypotheses with two groups: flnc_proteotoxic_aggregation (status: canonical/established) and flnc_mechanical_load_accelerates_aggregation (status: EMERGING).
3. Add a discussions entry kind: HUMAN_MODEL_MISMATCH for the mouse/zebrafish LOF-models-DCM-not-HCM problem (§15).
4. Add a discussions entry kind: KNOWLEDGE_GAP for the contested etiologic fraction — the Cui 2018 null result should be curated as supports: REFUTE or PARTIAL evidence against a simple FLNC→HCM causal claim.
5. Consider a definitions[] PHENOTYPE_ALGORITHM for the ECG-first case-finding rule (§10), with validation_status.status: UNVALIDATED and the 0.45→0.98 etiologic-fraction shift as its rationale.
6. Consider conforms_to against cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling. Note that cardiac_ion_channel_repolarization is not an appropriate module here — CMH26 is a structural/proteostatic cardiomyopathy, and the ECG repolarization signature is a downstream marker of the structural substrate, not a primary channelopathy.
7. A new module is arguably warranted: z_disc_proteostasis_aggregation (or extending an existing proteinopathy module) — the CASA/BAG3/HSPB8/filamin C axis recurs across FLNC, DES, BAG3, CRYAB, and MYOT myofibrillar myopathies and cardiomyopathies. That is exactly the "conserved pathological process recurring across multiple disorders" the module system exists for.
8. Before committing any evidence item, run just fetch-reference PMID:XXXX and just validate-references. The verbatim abstract text quoted above came from web fetches, not from the sanctioned cache layer — it must be re-verified against references_cache/ before it lands in YAML.
9. NEC preflight is not required here — the MONDO record was verified locally by OAK, and the gene (FLNC), OMIM xref (617047), and synonyms all align. Note only that MONDO folds "cardiomyopathy, familial restrictive 5" into this entity, which is a lumping decision worth recording in the entry's notes.

Sources

• OMIM #617047 — Cardiomyopathy, Familial Hypertrophic, 26 (CMH26) (full text returned HTTP 403; content accessed via MedGen/MONDO/secondary sources)
• OMIM *102565 — Filamin C; FLNC
• MedGen: Hypertrophic cardiomyopathy 26 (C4310749)
• Valdés-Mas R et al. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun 2014;5:5326. PMID:25351925
• Gómez J et al. Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. Circ Cardiovasc Genet 2017;10(2):e001584. PMID:28356264
• Ortiz-Genga MF et al. Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. J Am Coll Cardiol 2016;68(22):2440-51. PMID:27908349
• Brodehl A et al. Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy. Hum Mutat 2016;37(3):269-79. PMID:26666891
• Verdonschot JAJ et al. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum Mutat 2020;41(6):1091-1111. PMID:32112656
• Agarwal R et al. Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation. Circ Res 2021;129(7). PMID:34405687
• Cui H et al. Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy. Mol Genet Genomic Med 2018;6(6):1104-13.
• Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG. Heart Rhythm, Feb 2026; PII S1547-5271(26)00121-9
• ClinGen Hereditary Cardiovascular Disease GCEP: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy. PMID:39132495
• Distinct molecular features of FLNC mutations, associated with different clinical phenotypes (iPSC-CM; R1267Q vs V2264M). PMID:39315490
• Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development. Int J Mol Sci 2022;23:871
• Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias. J Am Heart Assoc 2023
• Homozygous expression of the MFM-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation
• Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy (CASA / filamin mechanosensing)
• The chaperone-assisted selective autophagy complex dynamics and dysfunctions. Autophagy 2023
• 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44(37):3503
• UniProt Q14315 — Filamin-C (FLNC)
• OMIA:000515-9685 — Hypertrophic cardiomyopathy in Felis catus (no FLNC entry found)
• NCT07137338 — RP-A701 AAV gene therapy, BAG3 DCM (pathway-adjacent)
• NCT07426419 — AFTX-201 AAV gene therapy, BAG3 DCM (pathway-adjacent)