Hypertrophic Cardiomyopathy 20

1. Disease Information

Overview

Hypertrophic cardiomyopathy 20 (CMH20) is the OMIM phenotype-series designation for hypertrophic cardiomyopathy attributed to heterozygous mutation in NEXN (nexilin F-actin binding protein), a Z-disc rather than a sarcomeric thick/thin-filament gene. Conceptually it belongs to the "non-sarcomeric HCM" hypothesis of the late 2000s–early 2010s, in which Z-disc structural genes (NEXN, CSRP3, TCAP, LDB3, MYOZ2, ACTN2, VCL) were proposed to account for part of the ~50% of HCM with no myofilament mutation. Of these, only ACTN2 and CSRP3 have retained meaningful HCM validity in ClinGen reappraisal; NEXN has not.

The clinical phenotype, as described in the founding report, is conventional HCM: asymmetric left ventricular hypertrophy, predominantly septal, without a hemodynamic explanation, with dyspnea, syncope, palpitations, chest pain, and risk of sudden cardiac death.

Key Identifiers

MONDO parent axis: is_a MONDO:0024573 (familial hypertrophic cardiomyopathy); intersection_of MONDO:0005045 + RO:0004003 HGNC:29557.

Synonyms

CMH20 · Cardiomyopathy, familial hypertrophic, 20 · Cardiomyopathy, hypertrophic, 20 · Hypertrophic cardiomyopathy type 20 · NEXN hypertrophic cardiomyopathy · Hypertrophic cardiomyopathy caused by mutation in NEXN.

Information Provenance

Almost entirely aggregated disease-level (OMIM/MONDO/MedGen ontology records propagating a single 2010 primary report). The only genuinely patient-level datasets are the three multicenter cohorts — Hermida 2024 (French national sequencing network, n=9,516 index cases; PMID:38059363), Perotto 2025 (12 referral centers, n=60 carriers; PMID:40680702), and the original two-family pedigree study (PMID:20970104). No EHR-derived or registry-derived CMH20-specific cohort exists.

2. Etiology

Disease Causal Factors

Proposed (Limited-validity) primary cause: heterozygous missense variants in NEXN at 1p31.1 (GRCh38: chr1:77,888,624–77,943,895), inherited in an autosomal dominant pattern. The proposed molecular lesion is disruption of nexilin's F-actin/α-actin binding at the cardiac Z-disc, destabilizing the Z-disc under contractile mechanical load.

Wang et al. framed the rationale (PMID:20970104, cached):

"Nexilin, encoded by NEXN, is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere."

"In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved."

Countervailing evidence: the more robustly supported causal role of NEXN is in DCM/NDLVC via truncating variants, and in a lethal fetal cardiomyopathy via biallelic loss of function. The HCM claim rests on two missense variants, one of which (p.Arg279Cys) is now population-frequent.

Risk Factors

Genetic - The two originally reported variants: c.391C>G p.(Gln131Glu) (exon 5, actin-binding domain 1) and c.835C>T p.(Arg279Cys) (exon 8, coiled-coil domain). ⚑ p.(Arg279Cys) has ~141 occurrences in gnomAD and is now widely regarded as too common to be pathogenic — reclassified toward VUS/benign. - Family history of HCM or SCD — in Family A the proband's mother died suddenly at 38; in Family B the grandmother died suddenly at ~40 (⚑ PMID:20970104 full text). - Digenic/oligogenic burden: Hermida 2024 found 2 of 31 NEXN carriers had double NEXN variants, and these had "severe and early onset phenotypes" (PMID:38059363, cached). This is a plausible dose-dependence signal. - Genetic background/modifier burden (common-variant polygenic score for LV wall thickness) is an established modifier in HCM generally, but has not been studied in CMH20.

Environmental / demographic - Male sex (general HCM: males over-represented in referral cohorts; Hermida cohort 16/29 male). - Age — LVH is typically absent in childhood and manifests through adolescence into mid-adulthood. - Intense/competitive exercise — a classical trigger consideration in HCM; the 2024 AHA/ACC guideline (PMID:38718139) has substantially liberalized exercise restriction relative to prior guidance. - Systemic hypertension and obesity as phenotype amplifiers (general HCM; not CMH20-specific). - Mechanical strain is mechanistically specific here: Hassel et al. showed "Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma" (PMID:19881492, cached). This is the strongest available biological rationale for a load/exercise gene–environment interaction in NEXN disease.

Protective Factors

No CMH20-specific protective genetic or environmental factor has been reported. Not available for this disease. By extension from general HCM: avoidance of dehydration/vasodilators in obstructive physiology; weight management; blood-pressure control.

Gene–Environment Interactions

The only mechanistically grounded GxE hypothesis is nexilin haploinsufficiency/dysfunction × mechanical afterload: a partially destabilized Z-disc is predicted to fail preferentially under high wall stress. This is supported by model-organism data (PMID:19881492) but has never been tested clinically in NEXN carriers. This is a genuine, curatable knowledge gap — an appropriate discussions entry with kind: KNOWLEDGE_GAP and proposed_experiments (e.g. exercise-stress CMR in NEXN carriers; strain-conditioned iPSC-CM engineered heart tissue).

3. Phenotypes

Phenotype Table with HPO Terms (all IDs OAK-verified against sqlite:obo:hp)

Adjacent NEXN phenotypes (for cross-linking, not CMH20 proper): Dilated cardiomyopathy HP:0001644; Endocardial fibroelastosis HP:0001706; Cardiomegaly HP:0001640.

Phenotype Characteristics

Age of onset. Adolescent to mid-adult. In the founding pedigrees the youngest carriers were 12 and 16 years old; probands were 37 and 45. Across the broader NEXN cohort, median age at diagnosis was 32.0 years (IQR 26.0–49.0) (PMID:38059363, cached) and 45 years (IQR 36–55) for NEXN-tv DCM/NDLVC (PMID:40680702, cached). HPO onset: Adult onset / Juvenile onset.

Severity. Variable. Reported wall thicknesses spanned 14–21 mm (Family A) and 17–22 mm (Family B) ⚑ — i.e. mild-to-marked, with at least one proband reaching the ≥20 mm threshold that itself constitutes an SCD risk marker in the 2024 guideline.

Progression. Progressive hypertrophy through adolescence/early adulthood, then plateau; a minority progress to systolic dysfunction ("burnt-out" HCM), consistent with the reduced-LVEF entry in the OMIM clinical synopsis.

Frequency among affected individuals. Explicitly not quantifiable for CMH20. With ~7 reported HCM carriers worldwide with segregation data plus 3 non-segregating probands (Hermida), no phenotype frequency band can be honestly assigned. Per the dismech frequency-evidence SOP, omit frequency: rather than fabricate. Where a frequency IS defensible, cite the NEXN-CMP cohort figures explicitly and label them as NEXN cardiomyopathy broadly, not CMH20: - Myocardial fibrosis 64%; ICD implantation 53%; malignant ventricular arrhythmias 25%; NYHA I 71% (all PMID:40680702, DCM/NDLVC arm).

Quality of life. No CMH20-specific QoL data. General HCM QoL is measured with the KCCQ (Kansas City Cardiomyopathy Questionnaire) and HCMSQ (HCM Symptom Questionnaire); EQ-5D and SF-36 are used secondarily. EXPLORER-HCM established KCCQ and pVO₂ improvement with mavacamten. Not available for CMH20 specifically.

4. Genetic / Molecular Information

Causal Gene

NEXN — nexilin F-actin binding protein - HGNC: hgnc:29557 · OMIM gene: 613121 · NCBI Gene: 91624 · Ensembl: ENSG00000162614 · UniProt: Q0ZGT2 (NEXN_HUMAN) - Location: 1p31.1, GRCh38 chr1:77,888,624–77,943,895 - MANE Select transcript: NM_144573.4 - Structure: 13 exons, encoding two N-terminal actin-binding domains (ABD), a central coiled-coil domain (CC), and a C-terminal Ig-superfamily/IGcam domain - Originally identified in 1998 as a novel filamentous-actin-binding protein; re-identified as a cardiac Z-disc protein in 2009 (PMID:19881492)

Pathogenic Variants — CMH20 (the two founding variants)

Verbatim from the founding paper (PMID:20970104, cached — safe to quote):

"Two missense mutations, c.391C>G (p.Q131E) and c.835C>T (p.R279C), were identified in exons 5 and 8 of NEXN, respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes."

"In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious."

The 384-control-chromosome standard was adequate in 2010 but is radically underpowered by current ACMG/AMP criteria — this is precisely why p.R279C survived initial filtering and later failed.

Functional consequences. p.Q131E is a loss of actin binding with a probable dominant-negative ("poison peptide") component — the mutant protein is expressed, mislocalizes into cytoplasmic aggregates, and fails to bind its ligand:

"Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to α-actin and abolished the interaction between the fragment of actin-binding domain and α-actin." (PMID:20970104, cached; evidence_source: IN_VITRO)

Dominant-negative action for NEXN missense alleles is independently supported in vivo by the zebrafish rescue/overexpression experiments of Hassel et al. (PMID:19881492, cached; evidence_source: MODEL_ORGANISM):

"Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations."

Note carefully: Hassel's variants were DCM variants, not the HCM variants. Do not transfer that quote to a CMH20 mechanism node without stating the DCM provenance.

NEXN Variant Landscape Beyond CMH20 (for contrast and cross-linking)

• DCM 1CC (OMIM:613122, MONDO:0013147) — AD, ClinGen Strong (2026-03-04). Truncating variants enriched: 0.39% in DCM/NDLVC vs 0.09% in gnomAD NFE, P = 0.0001 (PMID:40680702, cached).
• p.(Gly650del) — a recurrent/founder-like German DCM allele; ⚑ 6/994 German DCM patients vs 168/1,613,646 population controls, OR ≈ 57.9, late-onset (mean 51 y) (PMID:40161564 review).
• Biallelic loss of function → lethal fetal cardiomyopathy with cardiomegaly + endocardial fibroelastosis — Johansson et al. 2022, Swedish family with three consecutive intrauterine fetal deaths, homozygous NEXN (PMID:35166435). Two further homozygous infants with novel alleles c.1156dup p.(Met386fs) and c.1579_1584del p.(Glu527_Glu528del) had, atypically, a favorable course (PMID:39183344, Ital J Pediatr 2024).
• ClinVar — ⚑ ≥31 NEXN variants classified P/LP as of April 2024, "most being loss-of-function variants" (PMID:40161564). The P/LP mass is LoF/DCM, not missense/HCM — a decisive asymmetry for the CMH20 record.

Population Constraint (gnomAD v4.0, via ClinGen)

This constraint profile is discordant with a highly penetrant dominant HCM gene and is corroborating evidence for the Limited classification. It is compatible with the observed reality: heterozygous LoF gives mild, incompletely penetrant DCM/NDLVC; biallelic LoF is lethal.

Modifier Genes

None established. Candidate mechanism: NEXN's partners RYR2 and JPH2 (junctional membrane complex) and Z-disc partners are plausible modifiers, but no modifier study exists. Not available.

Epigenetics

No CMH20-specific DNA-methylation, histone-modification, or chromatin data. Of note, ⚑ NEXN expression in smooth muscle is regulated by myocardin-family coactivators and YAP (Sci Rep 2018, doi:10.1038/s41598-018-31328-2) — a transcriptional-regulation lead, not an epigenetic disease mechanism. Not available for CMH20.

Chromosomal Abnormalities

No recurrent CNV, translocation, or aneuploidy associated with CMH20. ClinGen reports 0 dosage-sensitivity classifications for NEXN (neither haploinsufficiency nor triplosensitivity curated). Whole-gene deletions at 1p31.1 are not an established CMH20 mechanism. Not applicable.

5. Environmental Information

• Environmental factors: none causally implicated. CMH20 is a monogenic hypothesis; no toxin, radiation, pollutant, or occupational exposure has been linked. Not applicable.
• Lifestyle factors: high-intensity isometric/competitive exercise is the classical HCM consideration and is mechanistically attractive here given nexilin's role in mechanical protection (PMID:19881492), but is unstudied in NEXN carriers. Alcohol, obesity, and hypertension act as general HCM phenotype amplifiers.
• Infectious agents: none. Not applicable.

6. Mechanism / Pathophysiology

The Proposed Causal Chain (CMH20 — hypothesis-grade)

[MOLECULAR] NEXN missense variant in actin-binding domain (p.Q131E)
    ↓ loss of F-actin / α-actin binding + cytoplasmic mislocalization (dominant-negative)
[MOLECULAR] Impaired nexilin–actin anchoring at the cardiac Z-disc
    ↓
[CELLULAR] Z-disc destabilization under sarcomere-generated mechanical force
    ↓
[CELLULAR] Disturbed mechanotransduction / myofibril and sarcomere disorganization
    ↓
[CELLULAR] Cardiomyocyte hypertrophic response
    ↓
[TISSUE]   Myocyte hypertrophy + myofiber disarray + interstitial fibrosis
    ↓
[ORGAN]    Asymmetric septal LV hypertrophy; diastolic dysfunction; arrhythmogenic substrate
    ↓
[ORGANISM] Dyspnea, chest pain, syncope, palpitations; AF; ventricular arrhythmia; SCD

Epistemic status of each step. Steps 1–2 are supported by direct in-vitro evidence (PMID:20970104, IN_VITRO). Step 3 is supported in model organisms but from DCM alleles (PMID:19881492, MODEL_ORGANISM). Steps 4–6 are inferred by analogy to sarcomeric HCM and have never been demonstrated for a NEXN allele in human or animal tissue. No animal model has ever reproduced a hypertrophic phenotype from a NEXN lesion — every one produces dilated cardiomyopathy (see §15). This is the mechanistic heart of the Limited classification and should be recorded as a HUMAN_MODEL_MISMATCH discussion, not a KNOWLEDGE_GAP: model evidence exists in abundance, but it points to the wrong phenotype.

The Well-Supported NEXN Mechanism (DCM arm — for the module/comorbidity cross-link)

Nexilin is now understood as far more than a Z-disc actin anchor. Liu et al. (Circulation 2019; PMID:30982350) established it as a junctional membrane complex (JMC) component:

"Membrane contact sites are fundamental for transmission and translation of signals in multicellular organisms." ⚑

⚑ Loss of Nexn produced progressive DCM; NEXN interacted with junctional sarcoplasmic-reticulum proteins and was essential for calcium transients and the initiation of T-tubule formation. Spinozzi et al. (Circ Heart Fail 2020; PMID:32635769) extended this to the adult heart:

"NEXN was essential for optimal contraction and calcium handling, and was required for maintenance of T-tubule network organization (transverse tubular component in icKO reduced by 40% with respect to CTRLs, p<0.05)." ⚑

"Results here reported revealed NEXN to be a pivotal component of adult junctional membrane complexes required for maintenance of transverse-axial tubular architecture." ⚑

⚑ Per the 2025 review (PMID:40161564), NEXN interacts with ryanodine receptor 2 (RYR2) and junctophilin 2 (JPH2), both "essential for T-tubule formation and calcium homeostasis."

Curation implication: if a NEXN pathophysiology graph is built, the defensible mechanism is Z-disc + JMC/T-tubule + excitation–contraction-coupling failure → contractile deficit → chamber dilation and arrhythmogenesis, which conforms to cardiomyopathy_maladaptive_remodeling (dilated arm), not to a hypertrophic pathway. The high fibrosis rate (64%) and arrhythmia-out-of-proportion-to-dysfunction profile also make fibrotic_response and cardiac_ion_channel_repolarization (arrhythmogenic-substrate node) plausible conformance targets.

Molecular Pathways

• Sarcomere/Z-disc structural pathway — actin cytoskeleton anchoring; no canonical named signaling cascade (Wnt/MAPK/mTOR) has been implicated in NEXN disease.
• Z-disc mechanosensing — the Z-disc is "postulated to play a key role in both cell signaling and sarcomere assembly" and "may act as a mechanosensor that converts myosin-generated force into the intracellular signaling that drives hypertrophy." ⚑ (Front Physiol 2023, doi:10.3389/fphys.2023.1143858). In sarcomeric HCM the downstream effectors are calcineurin–NFAT, MEF2, and CaMKII; whether NEXN engages these is unknown.
• Excitation–contraction coupling / calcium cycling — RyR2, SERCA2, JPH2 dysregulation demonstrated in Nexn-null adult mice ⚑.
• KEGG: hsa04260 (Cardiac muscle contraction), hsa05410 (Hypertrophic cardiomyopathy), hsa04261 (Adrenergic signaling in cardiomyocytes). Reactome: R-HSA-390522 (Striated muscle contraction).

Cellular Processes and GO Terms (all OAK-verified against sqlite:obo:go)

Protein Dysfunction

Nexilin (Q0ZGT2, 675 aa canonical) — two N-terminal ABDs, coiled-coil, C-terminal IGcam. p.Q131E lies in ABD1 and destroys F-actin binding outright; the full-length mutant still binds α-actin, but weakly. The mislocalization into cytoplasmic aggregates is the key gain-of-toxicity feature distinguishing this from simple haploinsufficiency. No experimental structure of the nexilin ABD in complex with actin is deposited in the PDB; AlphaFold model AF-Q0ZGT2-F1 is available. No misfolding/amyloid mechanism.

Metabolic Changes, Immune Involvement, Biochemical Abnormalities

• Metabolic: no CMH20-specific metabolomic data. General HCM shows impaired myocardial energetics (reduced PCr/ATP by ³¹P-MRS) and increased ATP cost of tension — mechanistically attributed to myosin, not Z-disc, lesions. Not available for CMH20.
• Immune: no autoimmune or immunodeficiency component. Fibrosis in NEXN-CMP implies secondary reparative/inflammatory signaling but no primary immune mechanism. Not applicable.
• Biochemical: the defect is a protein–protein interaction failure (nexilin↔F-actin/α-actin), not an enzyme deficiency, receptor defect, or ion-channel mutation. Secondary Ca²⁺-handling protein dysregulation (RyR2, SERCA2) is documented in mouse ⚑.

Tissue Damage Mechanisms

Mechanical Z-disc failure under contractile load → myocyte injury → replacement and interstitial fibrosis (myocardial fibrosis in 64% of NEXN-tv carriers by CMR-LGE, PMID:40680702) → arrhythmogenic scar substrate. In the biallelic/null setting, endocardial fibroelastosis is the signature lesion (PMID:35166435; PMID:26659360).

Molecular Profiling

• Transcriptomics: RNA-seq performed on Nexn-KO mouse hearts (PMID:30982350) ⚑ — no human CMH20 transcriptomic dataset. GTEx confirms NEXN expression is highest in heart and skeletal muscle.
• Proteomics: mass spectrometry defined the NEXN interactome in mouse heart (PMID:30982350) ⚑, identifying junctional SR partners. No human CMH20 proteomic study.
• Metabolomics / lipidomics: Not available.
• Single-cell / spatial transcriptomics / multi-omics / CRISPR screens: no NEXN- or CMH20-specific studies. Not available. (Note: the CRISPR work cited below is targeted gene editing in zebrafish, not a functional-genomics screen.)

7. Anatomical Structures Affected

Organ Level

• Primary: heart (UBERON:0000948) — specifically the left ventricle (UBERON:0002084) and interventricular septum (UBERON:0002094), with asymmetric septal predominance.
• Secondary: left atrium (dilation → AF); lungs (pulmonary congestion); brain (cardioembolic stroke from AF); systemic circulation (low-output states).
• Body system: cardiovascular. Skeletal muscle is a potential subclinical target given nexilin's skeletal Z-disc role under strain (PMID:19881492) — but no human skeletal myopathy has been reported in NEXN carriers.

Tissue and Cell Level

Endocardium (UBERON:0002165) is the target in the biallelic/EFE phenotype, not CMH20.

Subcellular Level

Z disc (GO:0030018) — primary; T-tubule (GO:0030315); sarcoplasmic reticulum (GO:0016529); longitudinal SR (GO:0014801); junctional membrane complex (dyad — no clean GO CC term; nearest is GO:0030315 + GO:0016529); actin cytoskeleton (GO:0015629).

Localization and Lateralization

Bilateral in the sense of being a whole-heart genetic lesion, but phenotypically left-dominant and regionally asymmetric. The hallmark is asymmetric septal hypertrophy — a within-organ asymmetry, not a body-lateralization phenomenon. Right ventricular involvement (HP:0011663) is not a reported CMH20 feature. The NEXN-tv DCM/NDLVC phenotype is likewise left-sided (mild LV dilation, indexed EDV 69 mL, LVEF 44%).

8. Temporal Development

Onset. Adolescent-to-adult; insidious. Youngest reported carriers with detectable hypertrophy were 12 and 16 ⚑. Median age at diagnosis across NEXN carriers: 32.0 years (IQR 26.0–49.0) (PMID:38059363, cached). HPO onset: Juvenile onset (HP:0003621) / Adult onset (HP:0003581). Note the sharp contrast with biallelic NEXN disease, which is fetal/prenatal onset (PMID:35166435, PMID:39183344) — a striking allelic-dose–onset gradient worth curating explicitly.

Progression. - Early: subclinical/genotype-positive–phenotype-negative; normal wall thickness; possible ECG abnormalities preceding hypertrophy. - Intermediate: established LVH with diastolic dysfunction; exertional symptoms; AF risk rises with LA dilation. - Advanced: progressive fibrosis; arrhythmic burden; in a minority, systolic decline ("burnt-out" phase → reduced LVEF, the phenotype captured in the OMIM synopsis). - End-stage: refractory heart failure requiring transplant, or SCD.

Rate. Slow and variable; hypertrophy typically stabilizes after adolescent growth. In the NEXN-tv DCM/NDLVC arm the striking feature is arrhythmia out of proportion to dysfunction: "Compared with TTN-CMP, NEXN-CMP exhibited earlier and more frequent MVAs at higher ejection fractions" (PMID:40680702, cached). If this arrhythmia-forward signature generalizes to NEXN-HCM, it would carry real management weight.

Course. Chronic, lifelong, progressive with episodic arrhythmic events. Median follow-up in the cohorts: 45 months (Perotto) and 6.0 years (Hermida).

Remission. No spontaneous remission of hypertrophy. Treatment-induced reverse remodeling is achievable — in the NEXN DCM arm, LVEF "improved with treatment in 13 (61.9%)" of 21 patients (PMID:38059363, cached), a genuinely favorable and quotable finding. Mavacamten produces reversible reduction in LV mass and LVOT gradient in obstructive HCM.

Critical periods. Adolescence through the third decade — the window of hypertrophy development, hence the anchor for cascade-screening intervals. A second window is the peri-diagnostic period for SCD risk stratification.

9. Inheritance and Population

Epidemiology

CMH20-specific prevalence is not established and should be recorded as UNKNOWN / CASES_IN_LITERATURE. Fewer than ~10 individuals have ever been reported with a segregating NEXN-HCM variant.

The only defensible numerator/denominator figures:

For context, HCM overall has a prevalence of ~1 in 500 (≈200 per 100,000), with recent imaging-informed estimates spanning 1 in 200 to 1 in 500 (PMID:25814232 and subsequent). If CMH20 were real and accounted for 0.14% of HCM, its population prevalence would be ~0.28 per 100,000 — but given the absence of case-control enrichment, even that is an overestimate. Suggested dismech prevalence_class: NOT_YET_DOCUMENTED or UNKNOWN, with measure_type: CASES_IN_LITERATURE and the 0.14% figure recorded in notes.

Genetic Etiology Parameters

• Inheritance pattern: Autosomal dominant (HP:0000006) for CMH20. ClinGen curates the NEXN-HCM MOI as AD. Autosomal recessive (HP:0000007) applies to the distinct lethal fetal cardiomyopathy phenotype. Consider curating both as separate Inheritance blocks with a note on the allelic-dose gradient.
• Penetrance: Incomplete and age-dependent. Family A: 3 affected carriers including a 16-year-old; Family B: 4 carriers including a 12-year-old — early-adolescent carriers may simply be pre-penetrant rather than mildly affected. Reliable penetrance estimates are not available.
• Expressivity: Variable. OMIM notes CMH20 has "inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death" ⚑ — though this is boilerplate carried across the CMH series, not CMH20-specific observation.
• Genetic anticipation: No. Not a repeat-expansion disorder. Not applicable.
• Germline mosaicism: Not reported. Not available.
• Founder effects: None for the HCM alleles. For DCM, ⚑ p.(Gly650del) behaves as a recurrent German allele (OR ≈ 57.9). The Johansson biallelic allele arose in a Swedish family (PMID:35166435) — consanguinity/endogamy plausible but not characterized as a founder event.
• Consanguinity: Relevant only to the biallelic fetal phenotype.
• Carrier frequency: For the recessive lethal fetal phenotype, no carrier-frequency estimate exists. gnomAD LOEUF 0.88 / pLI 0 indicate NEXN LoF alleles are not strongly depleted, so heterozygous LoF carriers are not vanishingly rare — consistent with the observed mild, incompletely penetrant heterozygous phenotype.

Population Demographics

• Affected populations: The two founding families were Han Chinese (PMID:20970104). Subsequent NEXN cohorts are predominantly European (French, Italian, Dutch, Spanish, UK, Hungarian) and one Swedish family. No population shows established CMH20 excess.
• Geographic distribution: No endemic pattern. Reporting bias tracks cardiogenetics infrastructure.
• Sex ratio: Roughly balanced in the available data — 16/29 male in the Hermida single-variant cohort (55%); 53% male in the Perotto NEXN-tv DCM/NDLVC arm. Consistent with autosomal dominant inheritance and no strong sex effect. (HCM broadly shows male over-representation in referral cohorts, generally attributed to ascertainment.)
• Age distribution: Diagnoses cluster in the third-to-fifth decades (median 32; IQR 26–49).

10. Diagnostics

Clinical Tests

Imaging (primary diagnostic modality) - Transthoracic echocardiography — the diagnostic cornerstone: maximal LV wall thickness ≥15 mm (or ≥13 mm with family history) unexplained by loading conditions; assessment of asymmetric septal hypertrophy, SAM of the mitral valve, LVOT gradient at rest and with provocation (Valsalva, exercise), diastolic function, LA size. - Cardiac MRI with late gadolinium enhancement (CMR-LGE) — tissue characterization, apical/anterolateral hypertrophy missed by echo, and fibrosis quantification; LGE extent ≥15% of LV mass is an SCD risk modifier in the 2024 guideline. Highly relevant here — 64% of NEXN-tv carriers had myocardial fibrosis (PMID:40680702). - Exercise stress echocardiography — provocable obstruction; functional capacity.

Electrophysiology - 12-lead ECG — abnormal in >90% of HCM; LVH voltage criteria, repolarization abnormalities, pathological Q waves. ECG changes may precede hypertrophy in genotype-positive individuals. - Ambulatory Holter (≥24–48 h, extended monitoring) — mandatory for NSVT detection (SCD risk factor) and AF screening. Given the arrhythmia-forward NEXN signature, arguably warrants intensified surveillance. - Electrophysiology study — not routine.

Laboratory / biomarkers - NT-proBNP (LOINC 33762-6) and BNP (LOINC 30934-4) — prognostic in HCM, elevated with wall stress/diastolic dysfunction. - High-sensitivity cardiac troponin T/I (LOINC 67151-1) — subclinical myocyte injury; associated with LGE burden. - No NEXN- or CMH20-specific biochemical biomarker exists. Not available. - Phenocopy exclusion panel: serum/plasma alpha-galactosidase A activity and GLA testing (Fabry), serum/urine free light chains + technetium-pyrophosphate scintigraphy + TTR genotyping (ATTR amyloidosis), creatine kinase (Danon, glycogen storage), lysosome-associated membrane protein 2 (Danon).

Biopsy / pathology - Endomyocardial biopsy is not indicated for HCM diagnosis; reserved for suspected infiltrative/inflammatory phenocopy. Classic HCM histopathology: myocyte hypertrophy, myofiber disarray (HP:0031318), interstitial and replacement fibrosis, intramural small-vessel disease. No CMH20-specific histopathology has ever been published — a notable gap given that the Z-disc hypothesis would predict ultrastructural Z-disc abnormalities on EM. Hassel et al. did report that "Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish" (PMID:19881492, cached) — but again, in DCM carriers.

Genetic Testing

Recommended approach. Per the 2024 AHA/ACC HCM guideline (PMID:38718139), genetic testing is a Class 1 recommendation for patients with clinically diagnosed HCM, coupled with genetic counseling, primarily to enable cascade screening of relatives.

• Multi-gene HCM panel — first-line. Critically: NEXN is increasingly excluded from contemporary HCM panels. ⚑ The 2025 review states NEXN "is consequently not included in HCM panels" (PMID:40161564), and the ClinGen reappraisal advises that "Clinical laboratories are discouraged from reporting variants in genes with disputed HCM-association" — with Limited genes treated as genes of uncertain significance. Core validated HCM panel content: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 (Definitive), plus phenocopy genes (GLA, LAMP2, PRKAG2, TTR, PTPN11/RASopathies, GAA).
• NEXN single-gene testing — appropriate only when the clinical suspicion is DCM/NDLVC, or for cascade testing in a family with an established segregating variant, or for fetal/perinatal cardiomyopathy with EFE (biallelic).
• WES/WGS — reserved for panel-negative cases, syndromic presentations, or research. Genome sequencing offers no proven incremental yield over panels in isolated HCM.
• Chromosomal microarray, karyotyping, FISH — not indicated for isolated HCM; consider CMA if syndromic/dysmorphic features suggest a contiguous-gene disorder. Not applicable to CMH20.
• Mitochondrial DNA testing — indicated only if maternal inheritance, lactic acidosis, or multisystem involvement suggests mitochondrial cardiomyopathy (a phenocopy).
• Repeat expansion testing — Not applicable. Not a repeat disorder. (Friedreich ataxia GAA expansion is the one repeat disorder with an HCM phenotype and should be considered a phenocopy, not CMH20.)

Variant-interpretation caution specific to this gene: because most NEXN P/LP variants in ClinVar are LoF and the HCM claims rest on missense alleles — one of which is population-frequent — apply PM2/BS1 rigorously and weight gnomAD frequency heavily. p.(Arg279Cys) is the cautionary example.

Omics-Based Diagnostics

None validated. RNA-seq/proteomics/metabolomics/epigenomics/liquid biopsy have no established diagnostic role in CMH20. Not available.

Clinical Criteria

• Diagnostic criteria: 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline (PMID:38718139) and 2023 ESC cardiomyopathy guideline — unexplained LV wall thickness ≥15 mm (adults; ≥13 mm with family history or positive genotype), or z-score ≥2 in children, not explained by loading conditions.
• Differential diagnosis (essential to exclude):

Screening

• Cascade family screening — the primary preventive intervention. If a pathogenic variant is identified: predictive genetic testing of first-degree relatives; genotype-negative relatives discharged. If no variant identified (the common situation for CMH20-suspected families given the Limited validity): serial clinical screening with ECG + echocardiography — every 1–2 years ages 12–21, every 3–5 years thereafter.
• Newborn screening: not applicable.
• Carrier screening: not applicable for the dominant phenotype; relevant only for reproductive counseling in families with the recessive lethal fetal phenotype.

11. Outcome / Prognosis

CMH20-Specific Data

Essentially absent. No survival curve, mortality rate, or outcome study exists for CMH20. The only outcome data points are the two pedigree SCDs (mother at 38, grandmother at ~40) ⚑ from PMID:20970104 — anecdotal and unadjudicated.

NEXN-Cardiomyopathy Outcomes (DCM/NDLVC arm — the best available proxy, and it is an imperfect one)

From Perotto et al. 2025 (PMID:40680702, cached): - Mild disease at baseline: indexed LVEDV 69 mL (IQR 46–87), LVEF 44% (IQR 31–53), NYHA I in 71% - Myocardial fibrosis in 64% - Over 45-month median follow-up: 53% received an ICD; 25% had malignant ventricular arrhythmias - Key comparative finding: "Compared with TTN-CMP, NEXN-CMP exhibited earlier and more frequent MVAs at higher ejection fractions, and no significant differences were found against FLNC-CMP." - Conclusion: "NEXNtvs were significantly associated with DCM/NDLVC, characterized by mild cardiac abnormalities, infrequent heart failure, common fibrosis, and arrhythmias."

This FLNC-equivalence is the clinically actionable finding in the entire NEXN literature. FLNC truncating variants are a recognized arrhythmogenic-cardiomyopathy genotype warranting a lowered ICD threshold. If NEXN behaves similarly, NEXN carriers merit arrhythmia-forward risk stratification even with preserved EF.

From Hermida et al. 2024 (PMID:38059363, cached): - "For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%)." - "Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events." - "Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants."

General HCM Prognostic Context

Contemporary HCM management has driven disease-related mortality to ~0.5% per year across all age groups, "lower than in the other cardiac or noncardiac risks of living, and largely confined to nonobstructive patients with progressive heart failure, including those awaiting heart transplant" ⚑ (PMID:38368039, 2024). Most HCM patients now "achieve normal or extended life expectancy without major disability" ⚑.

Complications

Sudden cardiac death (HP:0001645); malignant ventricular arrhythmia (HP:0004308); atrial fibrillation (HP:0005110) with cardioembolic stroke; progressive heart failure (HP:0001635); infective endocarditis (obstructive HCM with SAM); "burnt-out" systolic dysfunction requiring transplant.

Prognostic Factors

Established HCM SCD risk markers (2024 AHA/ACC): prior cardiac arrest/sustained VT; family history of SCD; unexplained syncope; maximal wall thickness ≥30 mm; LV apical aneurysm; LVEF <50%; extensive CMR-LGE (≥15% LV mass); NSVT on monitoring. The ESC HCM Risk-SCD calculator provides a 5-year risk estimate. None of these has been validated in NEXN carriers, and the Perotto finding of arrhythmia at preserved EF suggests conventional EF-based thresholds may underestimate risk in this genotype.

Prognostic Biomarkers

NT-proBNP and hs-troponin (general HCM). CMR-LGE burden. No NEXN-specific prognostic biomarker.

12. Treatment

There is no genotype-specific therapy for CMH20. Management follows the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM guideline (PMID:38718139) and, where the phenotype is actually dilated/hypokinetic, guideline-directed medical therapy for heart failure.

Pharmacotherapy

Mavacamten mechanism — "Cardiac myosin inhibitors inhibit actin-myosin interaction to decrease cardiac contractility and reduce left ventricular outflow tract obstruction, with mavacamten currently being the only FDA-approved agent" ⚑ (2024 guideline coverage). Approved on the EXPLORER-HCM (NCT03470545) and VALOR-HCM (NCT04349072) trials. Aficamten, a second-generation cardiac myosin inhibitor (SEQUOIA-HCM, NCT05186818), has completed phase 3.

Important mechanistic caveat for curation: mavacamten targets the actin–myosin cross-bridge, i.e. the hypercontractility of sarcomeric HCM. A Z-disc structural lesion is not obviously a hypercontractility disease, and there is no evidence that myosin inhibition benefits NEXN carriers. Do not curate a target_mechanisms link from mavacamten to a NEXN Z-disc node — that would assert an untested mechanism.

Drugs to avoid in obstructive HCM: vasodilators (nitrates, dihydropyridine CCBs, ACE inhibitors in obstructive physiology), high-dose diuretics, digoxin, and positive inotropes — all worsen the outflow gradient.

Pharmacogenomics

Mavacamten is dosed by CYP2C19 metabolizer status — the FDA label incorporates CYP2C19 poor-metabolizer dose adjustment, and concomitant strong CYP2C19/CYP3A4 inhibitors are contraindicated or require dose modification. This is the one genuinely actionable PGx element in HCM care (PharmGKB). No NEXN-related pharmacogenomics.

Advanced Therapeutics

• Gene therapy (NCIT:C15238): AAV9-MYBPC3 gene replacement is in early clinical development for MYBPC3 HCM (e.g. TN-201, NCT05836259). No NEXN gene therapy program exists. Note that NEXN's cDNA (~2 kb) is well within AAV packaging capacity, making it theoretically tractable — but there is no program and no preclinical proof of concept for the HCM phenotype.
• Gene editing / base editing: preclinical only for sarcomeric HCM; nothing for NEXN.
• RNA-based therapies (ASO/siRNA): none for NEXN. For a dominant-negative missense allele such as p.Q131E, allele-selective knockdown would be the mechanistically apt strategy — a legitimate hypothesis, but entirely speculative.
• Cell therapy, targeted therapy, immunotherapy: Not applicable.

Surgical and Interventional

"Invasive septal reduction therapies (surgical septal myectomy and alcohol septal ablation), when performed by experienced HCM teams at dedicated centers, can provide safe and effective symptomatic relief for patients with drug-refractory or severe outflow tract obstruction" ⚑ (2024 guideline).

Supportive, Rehabilitative, Counseling

• Supportive care NCIT:C15747; cardiac rehabilitation NCIT:C15315; genetic counseling NCIT:C15240 — Class 1 and especially important here, because a Limited-validity NEXN result must be communicated as not diagnostic and must not be used to release relatives from clinical surveillance.
• The 2024 guideline liberalized exercise recommendations: mild-to-moderate recreational exercise is beneficial; competitive-sport participation is now a shared decision-making conversation rather than a blanket prohibition.

Experimental Treatments

No CMH20-specific trial exists. Relevant HCM trials: EXPLORER-HCM (NCT03470545), VALOR-HCM (NCT04349072), SEQUOIA-HCM (NCT05186818, aficamten), ODYSSEY-HCM (NCT05582395, mavacamten in nonobstructive HCM), MAPLE-HCM (NCT05767346, aficamten monotherapy). None enrolls by genotype, and none has reported NEXN-carrier subgroups.

Treatment Strategy

Obstructive HCM: BB or verapamil → add disopyramide or mavacamten → septal reduction therapy. Nonobstructive HCM: symptom-directed; treat diastolic HF; consider mavacamten (ODYSSEY-HCM pending). AF: rate/rhythm control + anticoagulation. SCD prevention: risk-stratify → ICD. If the NEXN carrier's phenotype is actually dilated/hypokinetic, switch entirely to four-pillar HF GDMT and consider an FLNC-like lowered ICD threshold.

13. Prevention

Primary prevention. Not possible — the germline variant is present from conception. Reproductive options for known carriers: preimplantation genetic testing for monogenic disorders (PGT-M) and prenatal diagnosis, which are far more compelling for the biallelic lethal fetal phenotype (recurrence risk 25%) than for the Limited-validity dominant HCM claim.

Secondary prevention (the mainstay). Cascade genetic testing and serial clinical screening of first-degree relatives (ECG + echocardiography; intervals per §10). Early detection permits pre-symptomatic risk stratification and ICD placement before a first arrhythmic event.

Tertiary prevention. ICD for SCD prevention; anticoagulation for AF-related stroke; septal reduction to prevent progressive HF; GDMT to prevent adverse remodeling; endocarditis awareness in obstructive disease with SAM.

Immunization. Not disease-specific; routine influenza/COVID/pneumococcal vaccination is standard for chronic cardiac disease. Not applicable as a targeted intervention.

Genetic screening. Cascade predictive testing (only when a genuinely pathogenic variant is identified — a high bar for NEXN missense alleles); PGT-M and prenatal testing for the recessive fetal phenotype. NCIT:C15240 Genetic Counseling.

Risk stratification. ESC HCM Risk-SCD calculator; 2024 AHA/ACC major risk marker enumeration; CMR-LGE quantification. Unvalidated in NEXN carriers.

Behavioral interventions. Blood-pressure and weight control; avoid dehydration and provocative vasodilators in obstructive physiology; individualized exercise prescription; avoid stimulants.

Public health / environmental interventions. Community AED deployment and CPR training reduce out-of-hospital cardiac-arrest mortality in HCM populations. Pre-participation athletic ECG screening remains contested (endorsed in Italy, not in the US). No environmental intervention applies.

14. Other Species / Natural Disease

Taxonomy and Orthology

Nexilin's cardiac Z-disc function is deeply conserved across the vertebrate lineage — the zebrafish loss-of-function phenotype (Z-disc destabilization + heart failure) directly recapitulates the mammalian one, which is why zebrafish was the discovery system (PMID:19881492).

Natural Disease in Other Species

No naturally occurring NEXN-associated cardiomyopathy has been reported in any non-human species. A targeted search of OMIA and the veterinary literature returned no NEXN entry for dogs, cats, or livestock. This is notable because feline HCM (especially MYBPC3 in Maine Coon and Ragdoll cats) and canine DCM (Doberman PDK4/TTN, Boxer STRN) are both well-characterized natural models — NEXN simply is not among their known loci.

• Breed (VBO): Not applicable — no NEXN-associated breed predisposition identified.
• Veterinary relevance: none established. Not applicable.

Comparative Biology

• Comparative pathology: the striking cross-species observation is that every NEXN loss-of-function model — zebrafish, mouse global KO, mouse cardiomyocyte-specific KO, mouse inducible adult KO, mouse G650del knock-in — produces dilated, not hypertrophic, cardiomyopathy, frequently with endomyocardial/endocardial fibroelastosis. Human biallelic loss also produces dilated cardiomyopathy with EFE (PMID:35166435, PMID:39183344). This convergence across four model systems and two human genotypes is the single most compelling argument against a NEXN-HCM mechanism.
• Evolutionary conservation: the affected residues Q131 and R279 are "highly conserved amino acid residues" across species (PMID:20970104, cached) — conservation supports functional importance but, given the population frequency of R279C, is clearly insufficient for pathogenicity.

Transmission

Not applicable — monogenic, non-communicable. No zoonotic potential; no cross-species susceptibility.

15. Model Organisms

Available Models

Model Types Available

• Genetic: knockout (global and conditional), knock-in (G650del), morpholino knockdown, CRISPR/Cas9 constitutive KO, transgenic mutant overexpression.
• Cellular: C2C12 myoblast transfection (the only system in which the HCM alleles have ever been studied).
• Not available: humanized mouse; iPSC-derived cardiomyocytes carrying a NEXN HCM variant; engineered heart tissue with NEXN lesions; organoids; rat models; induced (drug/surgical) models.

Phenotype Recapitulation — the Central Problem

No model recapitulates hypertrophic cardiomyopathy. Every in vivo NEXN model produces a dilated phenotype:

"Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure." (PMID:19881492, cached)

"Global and cardiomyocyte specific loss of Nexn in mice leads to a rapidly progressive dilated cardiomyopathy and premature death." ⚑ (PMID:32635769)

The only experimental evidence bearing directly on the HCM alleles is the C2C12 in-vitro work in the original paper — a myoblast transfection assay showing loss of actin binding, with no cardiomyocyte, no hypertrophy readout, and no in vivo component. In ClinGen terms, this is why NEXN's experimental evidence score was capped at 1.0 point.

This is a textbook HUMAN_MODEL_MISMATCH, not a KNOWLEDGE_GAP. Abundant model evidence exists; it consistently indicates the opposite phenotype from the one the disease entity asserts. Recommended discussions block:

discussions:
- kind: HUMAN_MODEL_MISMATCH
  attaches_to: "pathophysiology#Cardiomyocyte Hypertrophic Response"
  prompt: >
    Every in vivo NEXN loss-of-function model (zebrafish morphant and CRISPR KO;
    mouse global, cardiomyocyte-specific, inducible adult, and G650del knock-in)
    produces DILATED cardiomyopathy with T-tubule and calcium-handling failure —
    never hypertrophy. Does any NEXN allele actually produce a hypertrophic
    phenotype in a human-relevant cardiomyocyte system?
  rationale: >
    The only experimental support for the CMH20 hypertrophic mechanism is a C2C12
    myoblast transfection assay (PMID:20970104) showing loss of F-actin binding —
    a non-cardiomyocyte system with no hypertrophy readout. The phenotypic
    direction of every in vivo model is opposite to the asserted disease. This
    mismatch is a principal basis for the ClinGen "Limited" classification.
  proposed_experiments:
    - Generate isogenic iPSC-CM lines carrying NEXN p.Gln131Glu and assay
      cell size, sarcomere organization, and hypertrophic gene program
      (NPPA/NPPB/MYH7) versus corrected controls.
    - Engineered heart tissue under graded afterload to test the
      mechanical-strain gene-environment hypothesis (PMID:19881492).
    - Knock-in mouse carrying the orthologous Q131E allele with serial
      echocardiography to test whether hypertrophy ever emerges.

Model Limitations

Mouse constitutive KO is perinatally lethal, truncating the window for adult-phenotype study — the explicit rationale for the zebrafish CRISPR model (PMID:38114601). Zebrafish hearts are two-chambered with no T-tubules in the mammalian sense, limiting translation of the JMC findings. C2C12 is a skeletal myoblast line, not a cardiomyocyte. No model of the human HCM alleles in a cardiac context exists at all.

Research Applications

Available models support study of: Z-disc mechanobiology and strain resistance; T-tubule/TATS biogenesis and maintenance; junctional membrane complex assembly and RyR2/JPH2 interaction; excitation–contraction coupling; endocardial fibroelastosis pathogenesis; DCM natural history. They do not support study of NEXN-related hypertrophy.

Model Databases

MGI (Nexn, MGI:1919060); IMPC; ZFIN (nexn); RGD; Alliance of Genome Resources; IMSR/MMRRC for strain availability; Cellosaurus for C2C12 (CVCL_0188).

Consolidated Ontology Term Suggestions

All IDs below were verified with OAK against the repository's configured adapters (sqlite:obo:hp, :cl, :go, :uberon, :mondo, :ncit) — none is hallucinated.

Disease: MONDO:0013477 hypertrophic cardiomyopathy 20

Gene: hgnc:29557 NEXN (note lowercase prefix per repo convention)

Phenotypes (HP): HP:0001639 · HP:0001712 · HP:0032092 · HP:0005110 · HP:0012664 · HP:0001645 · HP:0001279 · HP:0002094 · HP:0100749 · HP:0001962 · HP:0004308 · HP:0004756 · HP:0001685 · HP:0031318 · HP:0025168 · HP:0001635 · HP:0001695

Inheritance: HP:0000006 Autosomal dominant inheritance (CMH20); HP:0000007 Autosomal recessive inheritance (biallelic lethal fetal phenotype)

Cell types (CL): CL:0000746 cardiac muscle cell · CL:0002098 regular cardiac myocyte · CL:0002548 fibroblast of cardiac tissue

Anatomy (UBERON): UBERON:0000948 heart · UBERON:0002084 heart left ventricle · UBERON:0002094 interventricular septum · UBERON:0002349 myocardium · UBERON:0006566 left ventricle myocardium · UBERON:0001133 cardiac muscle tissue

Biological processes / components (GO): GO:0030018 Z disc · GO:0030315 T-tubule · GO:0016529 sarcoplasmic reticulum · GO:0014801 longitudinal sarcoplasmic reticulum · GO:0051015 actin filament binding · GO:0045214 sarcomere organization · GO:0030239 myofibril assembly · GO:0060048 cardiac muscle contraction · GO:0055117 regulation of cardiac muscle contraction · GO:0070296 sarcoplasmic reticulum calcium ion transport · GO:0086001 cardiac muscle cell action potential · GO:0003300 cardiac muscle hypertrophy

Treatments (NCIT): NCIT:C15986 Pharmacotherapy · NCIT:C174901 Mavacamten · NCIT:C61845 Metoprolol · NCIT:C928 Verapamil · NCIT:C61730 Disopyramide · NCIT:C51591 Myectomy · NCIT:C80435 Implantable Cardioverter-Defibrillator Placement · NCIT:C15289 Organ Transplantation · NCIT:C15240 Genetic Counseling · NCIT:C15747 Supportive Care · NCIT:C49236 Therapeutic Procedure · NCIT:C15238 Gene Therapy

Candidate module conformance: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling (dilated arm — for the well-supported NEXN-DCM mechanism); fibrotic_response (64% fibrosis); cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity (arrhythmia-at-preserved-EF signature). Do not conform a CMH20 entry to a hypertrophy module without flagging the model mismatch.

Evidence Register — PMIDs, Status, and Verification Requirements

Structured-source citations available without fetching: CGGV: for the ClinGen NEXN gene-disease validity assertions (HCM/Limited and DCM 1CC/Strong) — check references_cache/ for the matching assertion IDs, or refresh with just clingen-rebuild. These give snippet-validatable rows for the two classifications that anchor this entry.

Recommended Curation Posture

1. Create the entry — CMH20 is a legitimate MONDO/OMIM entity and belongs in the KB. Absence would be a gap.
2. Lead with the validity caveat — record the ClinGen Limited classification as a first-class, evidence-backed claim (CGGV: snippet), not a footnote.
3. Curate the mechanism as hypothesis-grade — a mechanistic_hypotheses block with status: DISPUTED or EMERGING, and causal edges opting into that hypothesis group via downstream[].hypothesis_groups.
4. Include the refuting evidence — Perotto 2025 and Hermida 2024 as supports: REFUTE / supports: PARTIAL items. The schema supports this; use it. An entry that cites only the 2010 founding paper would misrepresent the state of the field.
5. Add the HUMAN_MODEL_MISMATCH discussion — the model-phenotype inversion is the most curatable insight in this entry.
6. Cross-link, don't merge — keep CMH20 distinct from a future Dilated_Cardiomyopathy_1CC entry, where the NEXN mechanism is genuinely well supported and the Z-disc/JMC/T-tubule pathophysiology can be curated with confidence.
7. Re-verify every ⚑ quote with just fetch-reference + just validate-references before it enters YAML. The five cached PMIDs are safe to quote as written above.

Sources

• OMIM #613876 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 20; CMH20
• OMIM *613121 — NEXILIN F-ACTIN-BINDING PROTEIN; NEXN
• MedGen 462617 — Cardiomyopathy, familial hypertrophic, 20
• ClinGen — NEXN (HGNC:29557) curation results
• ClinGen HCD GCEP: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy (PMC11312670)
• Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal (JACC 2025)
• Ingles et al. — Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes (PMID:30681346)
• Wang et al. 2010 — Mutations in NEXN, a Z-disc gene, are associated with HCM (PMC2978958)
• Hermida et al. 2024 — NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths
• Perotto et al. 2025 — Genetic and Phenotypic Characterization of NEXN-Related Cardiomyopathy
• Năstasie et al. 2025 — Nexilin mutations, a cause of chronic heart failure (PMC11947951)
• Rahimzadeh et al. 2024 — Nexilin in cardiomyopathy (Heart Fail Rev)
• Liu et al. 2019 — Nexilin Is a New Component of Junctional Membrane Complexes (PMID:30982350)
• Spinozzi et al. 2020 — Nexilin is necessary for maintaining the TATS (PMC7583668)
• Aherrahrou et al. 2016 — Knock-out of nexilin in mice (PMID:26659360)
• Liu et al. 2020 — Homozygous G650del nexilin variant causes cardiomyopathy in mice (JCI Insight)
• CRISPR/Cas9-mediated nexilin deficiency in zebrafish (PMID:38114601)
• Johansson et al. 2022 — Loss of Nexilin function, recessive lethal fetal cardiomyopathy
• Biallelic NEXN variants and fetal onset dilated cardiomyopathy (PMID:39183344)
• 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of HCM (PMID:38718139)
• Advances in the Management of HCM Leading to Low Disease-Related Mortality in 2023 (PMID:38368039)
• New perspectives on the prevalence of hypertrophic cardiomyopathy (PMID:25814232)
• Structural and signaling proteins in the Z-disk and their role in cardiomyopathies (Front Physiol 2023)
• Orphanet — Rare hypertrophic cardiomyopathy (ORPHA:217569)
• GeneCards — NEXN
• Genomics England PanelApp — NEXN in Hypertrophic cardiomyopathy panel