KLHL24-Related Hypertrophic Cardiomyopathy — Comprehensive Research Report

1. Disease Information

Overview: KLHL24-related hypertrophic cardiomyopathy (HCM) is a recently described, autosomal recessive cardiomyopathy caused by biallelic loss-of-function variants in KLHL24 (Kelch-like family member 24). It is characterized by early-onset (typically second–third decade) left ventricular hypertrophy, a distinctive histopathology of intracellular polyglucosan body accumulation and desmin intermediate-filament aggregation, and a markedly elevated risk of malignant ventricular arrhythmia and sudden cardiac death relative to classical sarcomeric HCM. The disease was first reported in 2019 by Zetterberg et al. in two unrelated consanguineous families (Iraqi and Iranian) (Human Molecular Genetics; PMID:30715372), and additional cases (including a compound-heterozygous kindred) have since been reported (Frontiers in Cardiovascular Medicine 2026; JACC: Case Reports 2026, JACC: Case Reports 2026).

Key identifiers: - OMIM phenotype: #620236 — Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (CMH29) (OMIM:620236) - OMIM gene: 611295 — KLHL24 (OMIM:611295) - MONDO: MONDO:0859372 (cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies) - HGNC: HGNC:25947 (KLHL24) - Gene location: chromosome 3q27.1 - GenCC/ClinGen classification: KLHL24–autosomal recessive HCM is rated "Moderate" (not yet "Definitive") by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel, based on 3 publications and 4 probands as of the 2024/2025 reappraisal (JACC 2024) - ICD-10/11: No disease-specific code exists; falls under the general hypertrophic cardiomyopathy codes (ICD-10 I42.1/I42.2; ICD-11 BB80–BB81) with a genetic-cardiomyopathy modifier - Note: This entity must be distinguished from the mechanistically opposite KLHL24-related disease, generalized intermediate epidermolysis bullosa simplex 6 with or without cardiomyopathy (EBS6), OMIM #617294, MONDO:0015006, Orphanet:508529 — an autosomal dominant, gain-of-function* disorder (see §2 and §6 for the mechanistic contrast).

Synonyms: "KLHL24-associated hypertrophic cardiomyopathy," "familial hypertrophic cardiomyopathy 29," "recessive KLHL24 cardiomyopathy with polyglucosan bodies," "KLHL24-related desminopathy" (cardiac phenotype only — this term is also loosely used for the dominant EBS/DCM entity, so context matters).

Evidence basis: All currently available data derive from aggregated case reports/small case series in the medical literature (not large-cohort registries or EHR aggregation) — fewer than ~10 kindreds and ~20–35 affected individuals have been published to date.

2. Etiology

Disease causal factor: Biallelic (homozygous or compound heterozygous) loss-of-function variants in KLHL24, inherited in an autosomal recessive pattern. This is a purely monogenic Mendelian cardiomyopathy — no environmental or infectious trigger has been implicated in symptom onset, though arrhythmic events (syncope, sudden death) are precipitated in the setting of physical exertion in several reported cases.

Genetic risk factors: - Homozygous nonsense variant c.1048G>T (p.Glu350*) — truncates the protein just before/within the Kelch repeat domain (Family A, Iraqi) (PMID:30715372) - Homozygous missense variant c.917G>A (p.Arg306His) — affects a residue highly conserved across species and among KLHL family members (Family B, Iranian) (PMID:30715372) - Compound heterozygous variants c.532del (p.His178Ilefs*66), a frameshift in the BACK domain (exon 3; ACMG: Likely Pathogenic, PVS1+PM2_Supporting), and c.1514A>G (p.Tyr505Cys), a missense variant in the Kelch domain (exon 7; ACMG: Likely Pathogenic, PM3+PM2_Supporting+PP3_Strong) — reported in two non-consanguineous brothers, each parent a heterozygous carrier (Frontiers in Cardiovascular Medicine 2026) - Neither of the original founder variants was found in the Greater Middle Eastern Variome or in 500 ethnically matched control exomes, consistent with rare, population-restricted recessive alleles. - Consanguinity is a major risk factor in the founding families (both original kindreds were consanguineous); the 2026 compound-heterozygous case demonstrates the disease can also arise in non-consanguineous families via two independently-inherited rare alleles. - Because genetic evidence to date comes almost entirely from consanguineous Middle Eastern kindreds, ClinGen curators explicitly "down-scored" the evidence to avoid over-inflating gene-disease validity, since the two alleles are unlikely to have arisen independently within a single consanguineous pedigree (JACC 2024).

Protective factors: None reported. Heterozygous carrier parents/relatives in all reported families are clinically asymptomatic, indicating full recessivity with no reported semi-dominant carrier phenotype (in contrast to some desmin-related myopathies).

Gene–environment interactions: Not established; disease expression appears driven primarily by genotype, though exertion appears to be a proximate trigger for documented arrhythmic/sudden-death events in several cases.

3. Phenotypes

Severity/progression: Highly variable — from asymptomatic screening detection to catastrophic sudden death in the 2nd–3rd decade. Disease course is generally progressive, with some patients evolving from a hypertrophic to a mixed/dilated phenotype with declining ejection fraction over years to a decade of follow-up. Extreme hypertrophy (interventricular septum up to 38–42 mm) has been documented in the most severely affected reported patient (age 20).

Quality of life impact: Not formally studied with validated instruments (no EQ-5D/SF-36 data identified); qualitatively, activity restriction, ICD/pacemaker implantation, and progressive heart failure symptoms substantially affect daily functioning in symptomatic patients.

4. Genetic/Molecular Information

Causal gene: KLHL24 (Kelch-like family member 24), HGNC:25947, OMIM *611295, chromosome 3q27.1.

Protein structure: KLHL24 belongs to the BTB-Kelch family of Cullin3-RING E3 ubiquitin ligase (CRL3) substrate adaptors, comprising an N-terminal BTB/POZ domain (binds Cullin3), a BACK domain (structural linker, also implicated in substrate/complex regulation), and a C-terminal Kelch repeat (propeller) domain (six blades, mediates substrate recruitment). In the recessive HCM-causing alleles, the E350* nonsense variant truncates the protein before/at the start of the Kelch domain (loss of substrate-binding function); R306H affects a conserved residue; the compound-heterozygous case combines a BACK-domain frameshift (complete loss of function) with a Kelch-domain missense variant (impaired substrate recognition).

Variant classification (ACMG/AMP): - c.1048G>T (p.Glu350*) — nonsense, loss-of-function - c.917G>A (p.Arg306His) — missense, functionally validated as loss-of-function via zebrafish rescue failure - c.532del (p.His178Ilefs*66) — frameshift, Likely Pathogenic (PVS1+PM2_Supporting) - c.1514A>G (p.Tyr505Cys) — missense, Likely Pathogenic (PM3+PM2_Supporting+PP3_Strong)

Population frequency: None of the reported pathogenic variants appear in gnomAD/1000 Genomes/ExAC at appreciable frequency; the original two founder variants were absent from the Greater Middle Eastern Variome and 500 ethnically matched control exomes, consistent with private/founder recessive alleles.

Origin: All reported variants are germline.

Functional consequence: Loss of function — impaired Cullin3-RING E3 ubiquitin ligase substrate-adaptor activity, resulting in failure to ubiquitinate and target the intermediate filament protein desmin (DES; HGNC:2770) for proteasomal degradation, with consequent pathological desmin accumulation in cardiac and skeletal muscle (confirmed by Western blot showing markedly upregulated desmin protein in patient tissue) (PMID:30715372).

Modifier genes: None specifically established; genetic background/consanguinity structure is a de facto contributing factor to biallelic variant co-occurrence.

Epigenetic information: Not reported for this entity.

Chromosomal abnormalities: None reported; disease is caused by small-scale sequence variants (SNVs/indels), not structural rearrangements.

Suggested gene/ontology annotations: - Gene: KLHL24, hgnc:25947 - Target/interacting protein: DES (desmin), hgnc:2770 - GO Molecular Function: GO:0031625 (ubiquitin protein ligase binding); GO:0004842 (ubiquitin-protein transferase activity, via CRL3 complex) - GO Biological Process: GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process); GO:0045104 (intermediate filament cytoskeleton organization)

5. Environmental Information

No environmental, toxic, occupational, or infectious contributing factors have been identified or reported for this monogenic recessive cardiomyopathy. Lifestyle factor of note: strenuous physical exertion appears to be a proximate trigger for arrhythmic events/sudden death in several reported cases, supporting activity-restriction as a management consideration, though this has not been formally studied.

6. Mechanism / Pathophysiology

Molecular pathway: KLHL24 functions as a substrate-specific adaptor within the Cullin3-RING E3 ubiquitin ligase (CRL3) complex. The BTB domain binds Cullin3/RBX1; the Kelch domain recruits substrate proteins for ubiquitination and subsequent 26S proteasomal degradation. In cardiac and skeletal muscle, the principal validated substrate is desmin, the muscle-specific type III intermediate filament protein that forms the cytoskeletal scaffold linking sarcomeres, the sarcolemma, mitochondria, and the nuclear envelope.

Causal chain (loss-of-function / HCM arm): 1. Biallelic loss-of-function KLHL24 variant → loss of CRL3 substrate-adaptor activity 2. Failure of desmin ubiquitination/proteasomal turnover → pathological desmin accumulation (confirmed by Western blot and immunostaining) in cardiomyocytes and skeletal myocytes 3. Desmin/intermediate-filament aggregation and disordered assembly, together with abnormal intramyocellular polyglucosan (glycogen-derived, alpha-amylase-resistant PAS-positive) body deposition 4. Cardiomyocyte hypertrophy, interstitial fibrosis, and macrophage infiltration → structural left ventricular hypertrophy and outflow tract obstruction in some patients 5. Disrupted cytoskeletal-mechanical and electrical coupling → arrhythmogenic substrate → ventricular tachyarrhythmia and sudden cardiac death 6. In advanced/longstanding disease, progression to reduced systolic function and a mixed/dilated phenotype with heart failure

Contrast — the gain-of-function KLHL24 arm (EBS6/dilated cardiomyopathy): Heterozygous, dominant translation-reinitiation/start-codon variants (e.g., c.1A>G, c.2T>C, c.2T>G) produce an N-terminally truncated KLHL24-ΔN28 protein that escapes its own normal N-terminal-degron-mediated turnover, becoming hyperstable. This gain-of-function protein then excessively degrades intermediate filament substrates — keratin-14 in basal keratinocytes (causing epidermolysis bullosa simplex with skin fragility) and, in the heart, again desmin (causing progressive dilated cardiomyopathy and sudden death, typically in early adulthood) (Human Molecular Genetics 2022; PMC9029237; JCI 2021, PMID:34292882; Cardiovascular Research 2025). Thus both the recessive HCM entity and the dominant EBS/DCM entity converge on desmin dysregulation, but via opposite directions of KLHL24 dosage/activity — too little CRL3 adaptor activity (LOF, → desmin excess/HCM) versus pathologically too much (GOF, → desmin depletion/DCM). This is a striking allelic-series example of bidirectional dosage pathology at a single E3-ligase adaptor locus.

Cellular processes involved: Ubiquitin-proteasome system dysfunction; intermediate filament cytoskeletal organization failure; glycogen/polyglucosan metabolism disruption; myocyte hypertrophic remodeling; fibrosis; macrophage-mediated inflammatory infiltration.

Protein dysfunction: Loss of substrate-adaptor (E3 ligase) function (LOF alleles) vs. hyperstabilized, overactive adaptor (GOF alleles in the allelic EBS/DCM disorder).

Tissue damage mechanism: Accumulation of misfolded/aggregated desmin and polyglucosan material is thought to impair myofibrillar force transmission and mechanical/electrical coupling, driving both structural hypertrophy/fibrosis and a primary arrhythmogenic substrate independent of the degree of hypertrophy — explaining the "genotype outpaces phenotype" pattern of sudden death occurring even with modest structural disease, as highlighted in a 2026 case report title (JACC: Case Reports 2026).

Biochemical abnormality: Pathological glycogen/polyglucosan accumulation (alpha-amylase/diastase-resistant PAS-positive material) — placing this entity in partial mechanistic overlap with glycogen-storage cardiomyopathies (see §10 differential diagnosis).

Molecular profiling: - Gene expression (GTEx): KLHL24 shows highest expression in skeletal muscle, followed by lung, then left ventricular myocardium — consistent with the muscle-predominant phenotype (PMID:30715372). - Western blot: desmin markedly upregulated in patient skeletal and cardiac muscle relative to controls. - HEK293 transfection studies (referenced in review literature) confirm KLHL24-mediated desmin degradation in vitro, with KLHL24 knockdown or desmin overexpression restoring desmin protein levels.

Model system validation (zebrafish): klhl24a is expressed from early developmental stages and, by 22 hours post-fertilization, localizes to the cardiac cone, particularly ventricular myocytes. Morpholino knockdown of klhl24a produced cardiac defects (pericardial edema, altered heart rate, reduced circulation, ventricular failure) in 90% of morphants (n=179) vs. 4% of controls (n=119). Co-injection of wild-type klhl24a mRNA partially rescued the phenotype (51.5% normal hearts vs. 16% with morpholino alone), whereas mRNA encoding the human R306H (c.917G>A) or E350* (c.1048G>T)-equivalent mutations failed to rescue (71.5% and 77.5% of embryos still showed heart defects, respectively) — direct functional evidence that both variants are loss-of-function (PMID:30715372).

Suggested GO/CL terms: - GO:0045104 (intermediate filament cytoskeleton organization) - GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process) - GO:0005978 (glycogen biosynthetic process) / GO:0005980 (glycogen catabolic process) as relevant to polyglucosan pathology - CL:0000746 (cardiac muscle cell); CL:0000188 (skeletal muscle cell / myocyte)

7. Anatomical Structures Affected

Organ level: - Primary: Heart (myocardium — predominantly left ventricle; also right ventricular involvement reported on cardiac MRI in some cases) - Secondary: Skeletal muscle (subclinical to overt myopathic changes, "cogwheel fiber" histology); conduction system (AV conduction disease requiring pacing in some patients) - Body systems: Cardiovascular system (primary); musculoskeletal system (secondary) - Note: skin is not involved in the recessive/LOF HCM entity (unlike the dominant EBS6/DCM entity), a key clinical differentiator confirmed in the compound-heterozygous 2026 case report, where siblings had no cutaneous findings.

Tissue/cell level: - Cardiomyocytes (CL:0000746) — hypertrophy, polyglucosan/glycogen accumulation, desmin aggregation - Skeletal myocytes (CL:0000188) — subsarcolemmal/intermyofibrillar glycogen and desmin accumulation, "cogwheel" fiber morphology - Cardiac interstitial fibroblasts — fibrosis - Macrophages — interstitial infiltration in myocardium

Subcellular level: - Intermediate filament cytoskeleton (GO:0045111, intermediate filament cytoskeleton) — desmin aggregates, tubular structures (8–12 nm filaments on EM) - Cytoplasmic glycogen/polyglucosan deposits - Ubiquitin-proteasome system machinery (cytoplasmic)

Localization (UBERON): - UBERON:0002080 (heart left ventricle) — primary site of hypertrophy - UBERON:0001133 (cardiac muscle tissue) - UBERON:0001134 (skeletal muscle tissue) - Lateralization: Not applicable (bilateral/systemic muscle involvement; LV-predominant cardiac disease, with some RV involvement on imaging)

8. Temporal Development

Onset: Typically second to third decade of life (documented range ~16–36 years in the original cohort); however, more recent reports document presentation in adolescence/childhood (e.g., syncope at age 20 requiring pacemaker; severe biventricular hypertrophy detected on screening at age 18–20 in a sibling pair). Onset pattern is generally insidious, with palpitations/dyspnea/syncope as presenting features, though the first clinical event in some patients is sudden cardiac death.

Progression: Progressive in most reported cases — declining ejection fraction and worsening heart failure symptoms over years (e.g., LVEF decline from 77%→70%→55% over a decade in one proband); a subset progresses to a dilated/mixed cardiomyopathy phenotype with need for transplantation. Disease course is variable in rate — from stable/mild over a decade of follow-up (with ICD/pacemaker support) to rapid deterioration and early sudden death (mid-20s).

Disease stages: Not formally staged in the literature; can be conceptually divided into (1) early/subclinical (structural hypertrophy on screening, asymptomatic), (2) symptomatic hypertrophic phase (palpitations, dyspnea, arrhythmia), and (3) advanced/mixed phase (systolic dysfunction, heart failure, transplant candidacy).

Patterns: No remission pattern described (progressive, non-relapsing disease). No specific critical intervention window has been established, though early genetic diagnosis and cardiac screening are advocated given the disproportionate arrhythmic risk relative to degree of hypertrophy.

9. Inheritance and Population

Epidemiology: No formal prevalence or incidence estimates exist; this is an ultra-rare disease with fewer than 10 kindreds (~20–35 affected individuals) reported in the literature as of 2026. All originally reported affected families were of Middle Eastern origin (Iraqi, Iranian) and consanguineous; a 2026 case report describes a non-consanguineous Chinese family, indicating the disease is not geographically restricted.

Inheritance pattern: Autosomal recessive — confirmed by homozygosity in consanguineous pedigrees and compound heterozygosity (with confirmed biparental inheritance) in a non-consanguineous family.

Penetrance: Appears high among biallelic carriers based on reported pedigrees, though the true penetrance is unknown given the small number of families and potential ascertainment bias toward severely affected probands.

Expressivity: Variable — ranging from mild/stable disease over a decade to catastrophic early sudden death, and from isolated cardiac phenotype to additional skeletal muscle involvement.

Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not reported.

Founder effects: The original two variants (c.1048G>T, c.917G>A) are private/founder-type alleles specific to their respective consanguineous Middle Eastern pedigrees; absent from Greater Middle Eastern Variome and other population databases.

Consanguinity role: Central to disease manifestation in the originally reported families; ClinGen curators specifically note that genetic evidence from these families was discounted to avoid overcounting evidence, since biallelic inheritance of the same rare variant is expected in consanguineous unions.

Carrier frequency: Unknown/not established in any population database given the extreme rarity and lack of large-scale carrier screening data.

Sex ratio: No clear sex predilection reported across the described cases (both male and female probands affected in each family).

Age distribution: Predominantly diagnosed in adolescence through the 4th decade; symptomatic onset clusters in the late teens to 30s.

10. Diagnostics

Clinical/imaging tests: - Echocardiography: Left ventricular hypertrophy (often asymmetric septal), +/- LV outflow tract obstruction, variable systolic function (normal to reduced), occasional mild LV dilation - Cardiac MRI: Extensive subepicardial/transmural late gadolinium enhancement (LGE) in the LV free wall with relative apical sparing; RV inferior wall LGE also described; midapical hypertrabeculation noted in one case - ECG: ST-T changes, prolonged PR interval, widened QRS, low voltages, or evidence of conduction disease; ambulatory (Holter) monitoring reveals frequent polymorphic/dimorphic ventricular ectopy and nonsustained VT - Biomarkers: Elevated high-sensitivity troponin T and NT-proBNP/BNP, correlating with disease severity

Histopathology (endomyocardial/skeletal muscle biopsy — key diagnostic clue): - Cardiomyocyte hypertrophy with PAS-positive, alpha-amylase/diastase-resistant material (polyglucosan bodies) - Desmin-positive immunostaining showing intermediate filament accumulation - Interstitial fibrosis with small macrophage infiltrates - Skeletal muscle: focal subsarcolemmal/intermyofibrillar glycogen accumulation producing a characteristic "cogwheel" fiber appearance — proposed as a diagnostic marker - Electron microscopy: accumulation of glycogen, tubular structures, and irregularly arranged intermediate filaments (8–12 nm diameter) in intermyofibrillar regions

Genetic testing: - Gene panel testing for HCM (including KLHL24) or a broader cardiomyopathy/desminopathy panel is the recommended first-line approach given phenotypic overlap with sarcomeric HCM - Whole exome/genome sequencing appropriate when panel testing is uninformative, particularly in consanguineous families (homozygosity mapping proved diagnostic in the original two kindreds) or when compound heterozygous variants are suspected - Single-gene KLHL24 sequencing reasonable when strong family history/phenotype (recessive pattern, biopsy showing polyglucosan bodies/desmin accumulation) points to this specific gene

Differential diagnosis: - Sarcomeric HCM (MYH7, MYBPC3, TNNT2, etc.) — lacks polyglucosan body/desmin-accumulation histology - Glycogen storage cardiomyopathies: PRKAG2 cardiomyopathy, Danon disease (LAMP2), Pompe disease (GAA) — distinguished by specific glycogen-handling gene defects and differing histology/clinical syndrome (e.g., WPW pre-excitation in PRKAG2, autophagic vacuoles in Danon) - Desmin-related myopathy/desminopathy (primary DES gene mutations) — a key phenocopy given shared desmin-accumulation pathology; distinguished by direct DES sequencing - Other polyglucosan body diseases (adult polyglucosan body disease, GBE1; Lafora disease) — typically have prominent neurological/hepatic involvement not seen in KLHL24-HCM - The dominant KLHL24-EBS/DCM entity (EBS6, OMIM #617294) — distinguished by cutaneous blistering/scarring history, dominant inheritance, and dilated (rather than hypertrophic) phenotype

Screening: Given autosomal recessive inheritance, cascade screening of at-risk siblings in affected families is warranted; targeted variant testing of parents/relatives once a proband is identified. No population-based newborn screening exists given rarity.

11. Outcome/Prognosis

Mortality: Poor prognosis reported in the founding cohort — of 11 affected young adults in the two original families, 3 died suddenly (~27%) and 1 required cardiac transplantation (~9%) due to heart failure (PMID:30715372). Additional individual case reports describe sudden cardiac death in the mid-20s to 50s and heart transplantation in teenagers with rapidly progressive disease.

Disease course: Variable — some patients remain relatively stable for a decade with medical/device therapy (pacemaker/ICD), while others show a malignant course with early sudden death, sometimes with only modest structural hypertrophy at the time of the fatal event (the basis for describing this as a condition where "genotype outpaces phenotype").

Complications: Ventricular tachyarrhythmia, sudden cardiac death, progressive heart failure, conduction system disease requiring pacing, and (in a subset) progression to a dilated/mixed cardiomyopathy phenotype.

Prognostic factors: Disproportionate arrhythmic risk relative to degree of hypertrophy is repeatedly emphasized as a defining and clinically important feature — implying that conventional HCM risk-stratification tools (which weight hypertrophy severity heavily) may underestimate sudden death risk in KLHL24-HCM patients, supporting a lower threshold for ICD consideration.

Quality of life/functional outcomes: Formal outcome measures not reported; qualitatively, patients on device therapy and guideline-directed heart failure therapy have maintained NYHA Class I–II status over 1–2 year follow-up in reported pediatric cases.

12. Treatment

No disease-specific approved therapy exists; management is supportive/symptomatic, following general HCM/heart failure and inherited-arrhythmia-syndrome principles:

Pharmacotherapy: - Beta-blockers (e.g., metoprolol succinate) — NCIT:C15986 (Pharmacotherapy); CHEBI-bindable agent (metoprolol) - ACE inhibitors / mineralocorticoid receptor antagonists (spironolactone) — standard heart failure therapy - Diuretics (furosemide) and vasopressin antagonists (tolvaptan) in decompensated/severely hypertrophied cases - Antiarrhythmic considerations as per general HCM arrhythmia management (not disease-specific)

Device/interventional therapy: - Implantable cardioverter-defibrillator (ICD) for primary or secondary prevention of sudden cardiac death — used in multiple reported cases given documented nonsustained VT and high SCD risk — NCIT:C50592 (or closest device/procedure term) - Permanent pacemaker implantation for conduction system disease/syncope - Cardiac transplantation for end-stage heart failure — NCIT:C15289 (Organ Transplantation) — performed in at least 2 reported cases (one at age 26, one pediatric case)

Supportive care: - Activity/exercise restriction given exertion-associated arrhythmic risk - Regular cardiac surveillance (echocardiography, Holter monitoring, cardiac MRI) in affected individuals and at-risk relatives

Genetic counseling: Recommended for families given autosomal recessive inheritance, recurrence risk (25% for siblings of an affected proband), and implications for cascade testing — NCIT:C15240 (Genetic Counseling)

Experimental/targeted therapy: None specific to KLHL24-HCM currently in clinical trials (no NCT identifiers identified). Given the mechanistic understanding of desmin dysregulation, this represents a theoretical target for future precision therapeutics, but no such approach has reached clinical development.

Treatment outcomes: Limited data; reported ICD-treated pediatric patients have remained stable without device discharges over 1–2 years; pacemaker therapy abolished recurrent syncope in one adult proband over a decade of follow-up, though cardiac function gradually declined.

13. Prevention

• Primary prevention: Genetic counseling and carrier testing in families with a known proband, particularly relevant in consanguineous unions or populations/communities where founder alleles have been identified (Iraqi, Iranian kindreds to date)
• Secondary prevention: Cascade cardiac and genetic screening of at-risk siblings/relatives of an affected proband, given the significant risk of sudden death as a first clinical manifestation
• Tertiary prevention: ICD implantation to prevent sudden death in individuals with documented ventricular arrhythmia or high-risk features; guideline-directed heart failure therapy to slow progression to end-stage disease
• Screening: No population-based screening program exists; risk stratification is currently informed by general HCM criteria, though the literature suggests these may be insufficiently sensitive for this specific genotype (disproportionate arrhythmic risk relative to hypertrophy severity)
• Reproductive options: Preimplantation genetic diagnosis/prenatal testing could be offered to carrier couples once a familial variant is identified, though not specifically documented in the literature for this disease

14. Other Species / Natural Disease

No naturally occurring animal disease (companion animal, livestock, or wildlife) attributable to KLHL24 loss-of-function has been reported in the veterinary or OMIA literature identified in this search. No spontaneous non-human model of KLHL24-HCM is described.

15. Model Organisms

Zebrafish (Danio rerio): The principal functional/disease model used to validate pathogenicity. - klhl24a (zebrafish ortholog) is expressed from early developmental stages, localizing to the cardiac cone (particularly ventricular myocytes) by 22 hours post-fertilization - Morpholino knockdown model: Produces cardiac defects (pericardial edema, altered heart rate, reduced circulation, and — in the majority — ventricular failure) in 90% of morphants vs. 4% of controls - mRNA rescue/complementation assay: Co-injection of wild-type human/zebrafish klhl24 mRNA partially rescues the knockdown phenotype (~51.5% normal hearts vs. 16% with morpholino alone); mRNA encoding the human pathogenic variants (equivalent to R306H and E350*) fails to rescue, providing direct functional confirmation of loss-of-function pathogenicity for both disease-causing alleles (PMID:30715372) - Applications: This model has been used specifically to functionally validate variant pathogenicity (rescue assay) and to demonstrate a conserved, essential role for klhl24 in early cardiac development/function - Limitations: As an early-developmental knockdown/complementation model, it captures acute cardiac dysfunction but does not recapitulate the adult-onset, chronic hypertrophic/fibrotic/arrhythmogenic disease course, the polyglucosan body pathology, or the skeletal muscle phenotype seen in human patients

Mouse: No Klhl24 cardiac-specific knockout/knock-in mouse model was identified in this search. A relevant comparator model is the desmin-null (Des⁻/⁻) mouse, which develops cardiomyopathy and skeletal myopathy due to loss of the same downstream substrate protein implicated in KLHL24-HCM pathogenesis, though this is not a direct KLHL24 model.

Cellular/iPSC models: hiPSC-derived engineered heart tissue models have been used to study the gain-of-function KLHL24 variants (relevant to the allelic EBS/DCM disorder), demonstrating KLHL24-mediated desmin degradation and tissue dilation (JCI 2021, PMID:34292882); no iPSC-cardiomyocyte model specific to the loss-of-function HCM-causing alleles was identified in this search — representing a clear model-system gap for this specific disease entity.

Resource note: Given the paucity of species/model-organism data specific to the recessive HCM phenotype, this represents an area of active knowledge gap suitable for flagging as a KNOWLEDGE_GAP in a knowledge-base curation context (particularly the absence of a chronic/adult-onset mammalian model recapitulating the polyglucosan-body and arrhythmogenic phenotype).

Summary Table of Key Citations

Data gaps flagged for curation: (1) No large-cohort prevalence/incidence data exist — true population prevalence unknown; (2) no adult/chronic mammalian model exists specific to the LOF cardiac phenotype; (3) no disease-specific therapeutic trials; (4) genotype-phenotype correlation (e.g., nonsense vs. missense vs. compound heterozygous severity) remains preliminary given the very small number of published cases.