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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

CMH29 requires two damaged KLHL24 alleles. The founding report identified homozygous variants in two consanguineous families and showed that the parents of affected individuals were heterozygous carriers and unaffected; an additional branch of the Iranian family independently produced a homozygous affected offspring of heterozygous parents, which is what established the recessive pattern rather than assumed it. Subsequent families confirm the same architecture in a non-consanguineous setting: a Chinese sibship carried compound heterozygous variants inherited one from each clinically asymptomatic parent, and an Indian case carried compound heterozygous truncating variants with no family history of hypertrophic cardiomyopathy. This is the point of greatest clinical consequence in the entry. Because the disease is recessive and the parents are unaffected, a young adult with unexplained septal hypertrophy and no family history is exactly the presentation in which a dominant sarcomeric aetiology is assumed and in which KLHL24 will be missed unless the panel includes it. Penetrance in biallelic individuals appears complete on the evidence available - every reported homozygote or compound heterozygote had a demonstrable cardiac phenotype - but the total number of biallelic individuals ever described is small enough that this should be read as an absence of counterexamples rather than as a penetrance estimate. Heterozygous carriers are not reported to be affected, and no carrier phenotype has been sought systematically. Provenance for this assertion. The HPO annotation file for OMIM:620236 records HP:0000007 sourced to PMID:30715372 (retrieved 2026-08-01), and the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel curated the KLHL24 gene-disease relationship specifically under an AR mode of inheritance. No dominant mode of inheritance is asserted for this entity; the dominant KLHL24 disease is the allelic skin disorder EBS6 (MONDO:0015006), curated below as a differential.

Autosomal recessive inheritance

Show evidence (4 references)

PMID:30715372 SUPPORT Human Clinical

"we identified homozygous mutations in KLHL24 in two consanguineous families with HCM"

Homozygous variants segregating in two consanguineous families is the primary observation establishing autosomal recessive inheritance for this entity.

CGGV:assertion_f1d4ce43-4c2d-41a0-b821-a11ac8eb8fca-2023-09-28T160000.000Z SUPPORT Other

ClinGen's expert panel independently assigned an autosomal recessive mode of inheritance to the KLHL24 hypertrophic cardiomyopathy relationship. Note the term mismatch - ClinGen curated against the broad HCM term MONDO:0005045 rather than against MONDO:0859372 - so this row supports the gene, the MOI and the strength of evidence, not the entity boundary.

PMID:40176835 SUPPORT Human Clinical

"two sisters are diagnosed with autosomal recessive KLHL24-related hypertrophic cardiomyopathy"

An independent consanguineous family, on a different continent from the founding families, replicates the recessive inheritance pattern.

+ 1 more reference

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Discussions and Knowledge Gaps

6

Why does loss of a CUL3 substrate adaptor produce polyglucosan bodies in cardiomyocytes, when KLHL24 has no known role in glycogen metabolism and no canonical polyglucosan storage gene is involved?

KNOWLEDGE GAP OPEN klhl24-polyglucosan-pathogenesis-unknown

Attached to

pathophysiology#Intermyofibrillar Glycogen and Polyglucosan Storage

This is the central unexplained fact about the disease, and it is the feature that OMIM chose to put in its name. The founding authors sequenced a dedicated nine-gene polyglucosan storage panel, found nothing, and stated plainly that the pathogenesis of the storage remains unknown and that it may serve as a diagnostic marker. Seven years later a PubMed search for `KLHL24 AND polyglucosan` returns zero records, so nobody has taken the question up. Three explanations are live and they have different consequences. First, the polyglucosan may be a secondary consequence of proteostatic failure - stalled autophagic or proteasomal flux is known to permit abnormal polysaccharide to accumulate, in which case the storage is epiphenomenal and the diagnostic marker is real but mechanistically empty. Second, KLHL24 may have an unidentified substrate in glycogen handling, which would make it a bona fide, if unconventional, glycogen-metabolism gene. Third, the polysaccharide may simply be trapped by the disorganised intermediate filament and tubular meshwork, a physical rather than metabolic explanation. Resolving this determines whether CMH29 should be classified among the inherited metabolic disorders at all - a classification this entry currently withholds for exactly this reason.

Proposed experiments

Biochemical characterisation of the stored polysaccharide in KLHL24-null myocardium

klhl24-cardiac-glycogen-biochemistry

Determine chain-length distribution, branching ratio and phosphate content of the polysaccharide isolated from KLHL24-deficient cardiac tissue, and compare directly against material from PRKAG2 and GBE1 hearts. If the material is biochemically identical to classical polyglucosan the metabolic hypothesis gains ground; if it differs, the trapping hypothesis does.

Unbiased ubiquitylome and interactome of KLHL24 in cardiomyocytes

klhl24-substrate-proteomics-glycogen-enzymes

Perform diGly proteomics and proximity labelling in wild-type versus KLHL24-null human iPSC-derived cardiomyocytes to ask whether any enzyme of glycogen synthesis, branching or degradation is a KLHL24 substrate. A comparable proteomic approach has already been applied to the gain-of-function allele and yielded a candidate substrate list, so the method is established for this gene.

The authors' statement of ignorance is in the discussion section of the full text of PMID:30715372 (PMC6812045, read 2026-08-01) and is not in the cached abstract, so this discussion carries no evidence item.

Why do opposite perturbations of the same KLHL24-desmin axis produce opposite cardiac morphologies - hypertrophic with a small cavity when the ligase is dead, dilated when it is hyperactive - and is there a therapeutic window between them?

KNOWLEDGE GAP OPEN klhl24-bidirectional-desmin-proteostasis

Attached to

pathophysiology#Failure of Desmin Intermediate Filament Turnover pathophysiology#Loss of CUL3-KLHL24 Substrate Adaptor Function

KLHL24 is an unusually clean natural experiment: one gene, two directions, two cardiomyopathies. Excess adaptor activity depletes desmin, synemin and vimentin and gives dilated cardiomyopathy with mitochondrial mislocalisation and sarcomere shortening; absent adaptor activity lets desmin accumulate and gives hypertrophic cardiomyopathy with intermyofibrillar storage. The two have never been studied side by side in the same experimental system, and the intermediate states have never been probed at all. The question has direct therapeutic relevance in both directions: reducing KLHL24 abundance rescues the gain-of-function phenotype in engineered heart tissue, which implies a dose-response curve with an optimum somewhere between the two diseases, and mapping that curve is what would show whether a partial modulator is conceivable. It also bears on whether desmin abundance itself, rather than KLHL24 activity, is the proximate determinant of ventricular geometry.

Proposed experiments

Isogenic KLHL24 allelic series in engineered heart tissue

klhl24-allelic-series-eht

Build an isogenic iPSC panel spanning KLHL24 null, biallelic CMH29 missense, heterozygous, wild-type, and deltaN28 gain-of-function, and measure desmin abundance, tissue geometry, force generation and calcium handling in dynamically loaded engineered heart tissues across the whole series. The gain-of-function end of this panel already exists and has been characterised, so only the loss-of-function arm is new.

Direct titration of cardiomyocyte desmin abundance

klhl24-desmin-dose-titration

Independently of KLHL24, titrate desmin levels up and down in cardiomyocytes and engineered tissues to test whether desmin abundance alone is sufficient to move tissue geometry between the hypertrophic and dilated poles, or whether other KLHL24 substrates are required.

Why is skeletal muscle histologically severely abnormal but clinically normal in CMH29, when KLHL24 is expressed more highly in skeletal muscle than in heart?

KNOWLEDGE GAP OPEN klhl24-silent-skeletal-muscle

Attached to

pathophysiology#Skeletal Muscle Cogwheel Fibre Pathology

Every individual biopsied showed cogwheel fibres with desmin and glycogen accumulation affecting the majority of both fibre types, yet none had weakness or wasting and nerve conduction studies were normal. The HPO annotation set records muscle weakness at 0 of 8. This is not a minor curiosity: it is a counterexample to the assumption that intermediate filament accumulation causes muscle dysfunction, and it means the tissue with the highest KLHL24 expression is the tissue that tolerates its loss best. Candidate explanations include redundancy from another KLHL family adaptor in skeletal muscle, a lower mechanical demand for continuous desmin turnover in skeletal than in cardiac muscle, or subclinical dysfunction that nobody has looked for because no one has performed quantitative myometry, creatine kinase measurement or exercise testing in these individuals. It also has a practical consequence, which is that the absence of weakness must not be used to exclude the diagnosis.

Proposed experiments

Quantitative skeletal muscle phenotyping of biallelic KLHL24 individuals

klhl24-skeletal-muscle-deep-phenotyping

Quantitative myometry, serum creatine kinase, muscle MRI and cardiopulmonary exercise testing in living biallelic individuals, to establish whether the skeletal muscle is genuinely unaffected functionally or merely unassessed.

Test for KLHL paralogue redundancy in skeletal muscle

klhl24-paralogue-redundancy-screen

Ask whether another KLHL family adaptor substitutes for KLHL24 in skeletal but not cardiac muscle, by comparing KLHL family expression between the two tissues and by testing whether co-depletion of a candidate paralogue unmasks a skeletal phenotype in a model system.

The absence of weakness and the normal nerve conduction studies are stated in the full text of PMID:30715372 (PMC6812045, read 2026-08-01) and are corroborated by the HPO annotation file for OMIM:620236, which records HP:0001324 at 0/8 (retrieved 2026-08-01). Neither source is quotable as a snippet from the cached abstract, so this discussion carries no evidence item.

Does any model system represent the genotype that defines this disorder, given that the only in vivo work is an embryonic zebrafish morpholino knockdown and every cardiac cell model carries the gain-of-function allele instead?

HUMAN MODEL MISMATCH OPEN klhl24-no-model-of-the-human-genotype

Attached to

pathophysiology#Intermyofibrillar Glycogen and Polyglucosan Storage pathophysiology#Ventricular Electrical Instability and Malignant Arrhythmia

This is a model-fidelity problem rather than an absence of evidence, which is why it is recorded as HUMAN_MODEL_MISMATCH. Informative in vivo and in vitro work on KLHL24 in the heart exists, but none of it models CMH29. The zebrafish experiment is a transient knockdown assayed at 48 to 72 hours post fertilisation; it reports ventricular developmental failure, not adult-onset hypertrophy, and morphant desmin was unchanged over that window. Every human cardiac cell model published - the dynamically loaded engineered heart tissues, the patient iPSC lines, the proteomic characterisation of failing myocardium - carries the dominant KLHL24-deltaN28 gain-of-function allele, which produces the opposite molecular lesion. No mouse model of KLHL24 loss of function was identified during this curation. Consequently there is no system in which the polyglucosan storage, the desmin accumulation, the hypertrophy or the arrhythmia of this disease has ever been reproduced, and every mechanistic claim in this entry beyond the substrate identity rests on human histopathology from two families.

Proposed experiments

Knock-in mouse carrying a CMH29-equivalent biallelic genotype

klhl24-knockin-mouse-cmh29

Generate homozygous p.Arg306His and null mice and phenotype the heart longitudinally with echocardiography, telemetry for arrhythmia, and PAS-diastase and desmin histology, to ask whether the polyglucosan and the arrhythmic phenotype are reproducible outside humans.

KLHL24-null human engineered heart tissue

klhl24-null-ipsc-eht

Build the loss-of-function counterpart of the existing gain-of-function engineered heart tissue system and measure desmin accumulation, tissue geometry, contractile force, calcium handling and arrhythmic propensity, to give the disease its first cardiac cell model.

How should sudden death risk be stratified in biallelic KLHL24 individuals, given that malignant arrhythmia may precede structural severity and conventional hypertrophic cardiomyopathy risk models therefore underestimate it?

KNOWLEDGE GAP OPEN klhl24-arrhythmic-risk-stratification

Attached to

pathophysiology#Ventricular Electrical Instability and Malignant Arrhythmia phenotypes#Sudden cardiac death

Three of eleven young adults in the founding cohort died suddenly, and an independently reported adolescent received a prophylactic defibrillator on genotype grounds despite low conventional risk markers. Neither observation amounts to a risk model. The established HCM sudden-death calculators weight maximal wall thickness, left atrial size, outflow gradient, unexplained syncope, non-sustained ventricular tachycardia and family history of sudden death - and the last of those behaves differently in a recessive disease, where affected relatives are siblings rather than ancestors, and where a family with a single affected child has no family history to weight at all. The reported fibrosis burden also varies from minimal to extensive independently of hypertrophy, so late gadolinium enhancement may not carry its usual weight either. Whether every biallelic individual warrants a primary-prevention defibrillator is an open and consequential question, currently answered case by case.

Proposed experiments

International registry of biallelic KLHL24 individuals

klhl24-international-registry

Pool the small number of reported and unreported families into a genotype-defined registry with systematic prospective collection of arrhythmic events, device therapies, imaging and outcomes, which is the only realistic route to a risk model for a disease this rare.

Systematic electrophysiological phenotyping

klhl24-electrophysiological-phenotyping

Prospective ambulatory monitoring, signal-averaged electrocardiography and, where devices are implanted, interrogation-derived arrhythmia burden in biallelic individuals, to establish whether the arrhythmic substrate is detectable before structural disease.

What evidence would move KLHL24 from moderate to strong or definitive gene-disease validity for hypertrophic cardiomyopathy, and is the disease entity being curated the same one ClinGen assessed?

KNOWLEDGE GAP OPEN klhl24-gene-disease-validity-moderate

Attached to

genetic#KLHL24

ClinGen's Hereditary Cardiovascular Disease expert panel classified KLHL24 as moderate for hypertrophic cardiomyopathy with autosomal recessive inheritance in 2023, and the 2025 reappraisal publication confirms that placement. Moderate is the correct level and it constrains how this entry should be read: the human genetic evidence is a handful of small families and the functional evidence is a morpholino knockdown. Two things would move it - additional unrelated probands with segregating biallelic variants, which are accumulating steadily, and a cardiac functional model of the loss-of-function genotype, which does not yet exist. There is also a term mismatch worth flagging for anyone reusing this entry computationally: ClinGen curated against MONDO:0005045, the broad hypertrophic cardiomyopathy term, whereas the entity curated here is MONDO:0859372, a much narrower descendant two is_a steps below it (MONDO:0859372 is_a MONDO:0024573 is_a MONDO:0005045, per `runoak -i sqlite:obo:mondo paths -p i --target MONDO:0005045 MONDO:0859372`). The classification supports the gene and the mode of inheritance; it does not adjudicate the entity boundary, and nothing in this entry should be read as claiming that it does.

Proposed experiments

ClinGen re-curation incorporating post-2023 probands

klhl24-reappraisal-with-new-probands

Re-run the gene-disease validity curation including the Brazilian family and the two families reported from China and India after the 2023 assessment, and the cardiac functional data that has appeared since, to test whether the classification now supports an upgrade.

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Pathophysiology

10

Biallelic Loss-of-Function KLHL24 Variants

The primary lesion is biallelic damage to KLHL24 at 3q27.1, reported against transcript NM_017644.3. The founding alleles are a homozygous nonsense variant c.1048G>T (p.Glu350*) in the Kelch-repeat region and a homozygous missense variant c.917G>A (p.Arg306His) at a residue conserved both across vertebrates and across the KLHL protein family. Later families add a frameshift in the BACK domain and a missense in the Kelch domain in trans, and compound heterozygous truncating alleles. All reported CMH29 genotypes therefore damage the BACK or Kelch portions of the protein - the substrate adaptor machinery - and none of them affects the translation initiation codon, which is the region mutated in the dominant skin disease. That positional separation is the structural basis of the allelic contrast that runs through this entry. The alleles behave as true loss of function rather than as dominant-negatives: heterozygous parents are unaffected, and both founding alleles failed to rescue zebrafish klhl24a knockdown when the equivalent substitutions were engineered into the fish transcript, whereas wild-type klhl24a mRNA did rescue.

KLHL24 hgnc:25947

Downstream

Loss of CUL3-KLHL24 Substrate Adaptor Function Nonsense and frameshift alleles remove the substrate-binding apparatus outright; the p.Arg306His and p.Tyr505Cys missense alleles sit in conserved Kelch-repeat positions and are predicted to disrupt the substrate-binding pocket of the beta-propeller. Either way the CUL3 complex loses its ability to select this adaptor's substrates.

Show evidence (3 references)

PMID:30715372 SUPPORT Human Clinical

"Here, we show that mutations in KLHL24 cause HCM in humans."

Establishes KLHL24 as the causal gene for this hypertrophic cardiomyopathy entity.

PMID:42158087 SUPPORT Human Clinical

"The c.532del frameshift variant truncates the BACK domain, resulting in complete loss of function (LOF) of the mutant allele."

Assigns a reported CMH29 allele to a specific functional domain and classifies its consequence as complete loss of function, which is the variant class that defines this entity.

PMID:42158087 SUPPORT Human Clinical

"This case demonstrates that biallelic, loss-of-function KLHL24 mutations can cause severe, early-onset recessive HCM, even in the absence of the cutaneous features typically associated with dominant gain-of-function variants."

States the loss-of-function versus gain-of-function contrast directly and ties the cardiac-only presentation to the loss-of-function allele class.

Loss of CUL3-KLHL24 Substrate Adaptor Function

KLHL24 is a BTB-BACK-Kelch protein. Its BTB and BACK domains dock onto CUL3, and its C-terminal six-bladed Kelch beta-propeller selects substrates; the assembled CUL3-RBX1-KLHL24 complex then transfers ubiquitin onto those substrates and commits them to the 26S proteasome. KLHL24 is not a housekeeping component of that machinery but a specificity module: which proteins are degraded depends on which Kelch adaptor is loaded. Losing KLHL24 therefore does not impair ubiquitination in general - it removes one branch of substrate selection, which is why the disease is tissue-restricted despite the ubiquity of the proteasome. KLHL24 is most highly expressed in skeletal muscle, then lung, then left ventricle, so the branch that is lost is the one that operates in striated muscle.

KLHL24 hgnc:25947 CUL3 hgnc:2553

CUL3-RBX1-KLHL24 E3 ubiquitin ligase GO:0031463

substrate polyubiquitination by the CUL3-KLHL24 ligase GO:0000209 ↓ DECREASED proteasomal degradation of KLHL24 substrates GO:0043161 ↓ DECREASED

ubiquitin-protein transferase activity GO:0004842 ↓ DECREASED

Downstream

Failure of Desmin Intermediate Filament Turnover The only KLHL24 substrate identified in striated muscle is desmin. With the adaptor gone, desmin escapes ubiquitin-dependent clearance and accumulates.

Intermyofibrillar Glycogen and Polyglucosan Storage An unexplained parallel consequence. The stored polysaccharide appears in the same intermyofibrillar compartment as the accumulated filaments, but no mechanistic link between adaptor loss and polysaccharide handling has been demonstrated, and this edge is asserted only as temporal and spatial co-occurrence.

Show evidence (3 references)

PMID:30715372 SUPPORT Human Clinical

"KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases."

Establishes the molecular function of the gene product as a substrate-selecting adaptor for a Cullin-RING E3 ubiquitin ligase.

PMID:41348940 SUPPORT Other

"KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase."

Independent statement of the substrate-adaptor function from a cardiac rather than a dermatological group. Tagged OTHER rather than IN_VITRO because this sentence sits in the paper's AIMS section and is background framing of established biology, not a result generated by the study's own hiPSC experiments.

PMID:42158087 SUPPORT Human Clinical

"KLHL24 encodes a substrate adaptor of the Cullin3 (CUL3) E3 ubiquitin ligase complex, with two core functional domains: the N-terminal BACK domain and the C-terminal KELCH repeat domain"

Names the two functional domains that CMH29 alleles disrupt and identifies CUL3 as the cullin scaffold, which is the structural basis for treating these variants as adaptor-function loss.

Failure of Desmin Intermediate Filament Turnover

Desmin is the muscle-specific type III intermediate filament that links adjacent Z-discs to each other, to the sarcolemma at costameres, and to mitochondria and nuclei, transmitting force laterally and maintaining myofibrillar register. It is a dynamic polymer whose subunits are continuously exchanged, and that exchange requires a route for disposal of displaced subunits. KLHL24 supplies that route in muscle: it is the cardiac and skeletal-muscle counterpart of the KLHL24-keratin-14 relationship characterised in basal keratinocytes, desmin standing to the myocyte as keratin-14 stands to the keratinocyte. In KLHL24-null myocytes the polymer is not disposed of. Immunohistochemistry on heart and skeletal muscle from the founding families showed desmin accumulating in the intermyofibrillar and subsarcolemmal spaces, electron microscopy resolved irregularly arranged 8-12 nm filaments in the same compartment, and Western blotting showed desmin markedly upregulated in both tissues relative to controls. This is the inverse of the lesion in KLHL24 gain-of-function disease, in which desmin is depleted roughly tenfold in patient-derived engineered heart tissue and in explanted myocardium. The same protein pair therefore produces two cardiomyopathies of opposite morphology depending on the direction in which turnover fails.

Cardiomyocyte CL:0000746

DES hgnc:2770

intermediate filament cytoskeleton organization GO:0045104 ⚠ ABNORMAL

desmin intermediate filament GO:0005882 Z disc GO:0030018

Downstream

Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling Accumulated intermediate filament protein contributes to the increase in myocyte size and to the mechanical stiffening that produces a small-cavity, thick-walled ventricle.

Myocardial Fibrosis and Focal Macrophage Infiltration Myocytes burdened with filamentous and polysaccharide inclusions attract focal macrophage infiltration and are replaced by patchy scar.

Skeletal Muscle Cogwheel Fibre Pathology The same substrate failure occurs in skeletal muscle, where KLHL24 expression is highest, producing striking histological change without clinical weakness.

Show evidence (4 references)

PMID:30715372 SUPPORT Human Clinical

"Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."

Direct human tissue evidence that loss of KLHL24 results in accumulation rather than clearance of desmin intermediate filaments in both affected striated muscles.

PMID:42158087 SUPPORT Human Clinical

"including desmin—the cardiac homolog of keratin-14"

States the substrate correspondence that makes desmin the expected cardiac substrate of KLHL24, by analogy with the keratin-14 relationship established in skin.

PMID:34292882 SUPPORT In Vitro

"Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients' explanted heart."

Establishes the opposite pole of the same axis. Excess KLHL24 activity depletes cardiac desmin; this entity's loss of KLHL24 activity is accompanied by desmin accumulation. Marked as supporting because it demonstrates that desmin abundance in cardiomyocytes is set by KLHL24 activity, which is the premise of this node.

+ 1 more reference

Intermyofibrillar Glycogen and Polyglucosan Storage

Alongside the accumulated filaments, the intermyofibrillar space of CMH29 cardiomyocytes fills with glycogen and with discrete polyglucosan bodies - periodic-acid-Schiff-positive material that resists alpha-amylase digestion, identifying it as the amylopectin-like, poorly branched, poorly soluble polysaccharide called polyglucosan rather than as ordinary glycogen. Skeletal muscle shows the same focal subsarcolemmal and intermyofibrillar glycogen accumulation. This node is deliberately marked HYPOTHETICAL, because its mechanism is genuinely unknown and the founding authors say so. Cardiomyopathies with polyglucosan accumulation are otherwise essentially confined to disorders of glycogen metabolism, and eight genes are canonically associated with muscle polyglucosan storage - GYG1, GBE1, RBCK1, PFKM, EPM2A, EPM2B, PRDM8 and PRKAG2. None of those was mutated in the founding families; a dedicated nine-gene polyglucosan-storage panel was screened and excluded before KLHL24 was reached. KLHL24 has no known role in glycogen metabolism, and no experiment has connected loss of its ligase-adaptor function to polysaccharide handling. Three explanations remain open and are set out in the knowledge-gap discussion below. Until one is demonstrated, the polyglucosan is curated as a reproducible diagnostic marker of the disease and as an unexplained co-occurrence, not as a step in the causal chain.

Cardiomyocyte CL:0000746

glycogen metabolic process GO:0005977 ⚠ ABNORMAL

Downstream

Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling Stored polysaccharide adds mass and volume to the myocyte independently of contractile-protein content, contributing to wall thickening that is partly storage rather than partly true hypertrophy.

Show evidence (3 references)

PMID:26278982 SUPPORT Other

"Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2."

Enumerates the canonical polyglucosan-storage gene set, written by the same group that later described CMH29. KLHL24 is absent from it, which is what makes the polyglucosan in this disease anomalous rather than expected.

PMID:26278982 SUPPORT Other

"Polyglucosan is an amylopectin-like polysaccharide associated with defective glycogen metabolism and, unlike normal glycogen, it is to some extent resistant to"

Defines the stored material and the biochemical property - resistance to amylase digestion - on which its histological identification depends.

PMID:26278982 SUPPORT Other

"These diseases frequently involve both skeletal and cardiac muscle tissue, causing myopathy with muscle weakness and wasting, and cardiomyopathy with arrhythmia, conduction block, and cardiac failure."

Marked PARTIAL. The cardiac half of this description - arrhythmia and cardiac failure with skeletal muscle involvement - matches CMH29 closely, but the skeletal muscle weakness and wasting that characterise the classical polyglucosan storage myopathies were explicitly absent in the CMH29 families, so the analogy holds only in part.

Sarcoplasmic Reticulum-Derived Tubular Aggregation

A third species accumulates in the same intermyofibrillar compartment: arrays of tubular membranous structures. Their origin was inferred histochemically in the founding study - the accumulated material stained for NADH-tetrazolium reductase but was negative for succinate dehydrogenase, a combination that indicates sarcoplasmic reticulum rather than mitochondria. This matters clinically as well as mechanistically, because it excludes a mitochondrial myopathy from the differential on the biopsy itself, and it is consistent with a disease of proteostasis spreading to membrane-compartment organisation rather than a primary bioenergetic lesion. It is marked PROVISIONAL because the inference rests on a histochemical staining pattern in one study and has not been confirmed by marker immunolocalisation or by any subsequent report.

Cardiomyocyte CL:0000746 skeletal muscle fibre CL:0000188

sarcoplasmic reticulum GO:0016529

Downstream

Ventricular Electrical Instability and Malignant Arrhythmia Disorganisation of the sarcoplasmic reticulum is a plausible contributor to the arrhythmic phenotype through disturbed calcium handling, but this edge is an inference rather than a demonstrated link and no calcium measurements have been made in this disease.

Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling

The myocyte enlarges. The founding heart explant and endomyocardial biopsies showed myocyte hypertrophy, and the HPO annotation set records cardiomyocyte hypertrophy in both individuals examined histologically. At organ level this produces the picture that brings patients to attention: severe septal thickening, a small left ventricular cavity, a reduced left ventricular end-systolic diameter, systolic anterior motion of the mitral valve and dynamic left ventricular outflow tract obstruction, with ejection fraction preserved or supranormal early on. Two things distinguish this hypertrophy from sarcomeric HCM. First, part of the wall thickness is storage rather than contractile mass - accumulated filaments, polysaccharide and membrane occupy the intermyofibrillar space. Second, myofibre disarray, the histological hallmark of sarcomeric HCM, is not what the biopsies show; what they show is intermyofibrillar accumulation. The clinical phenotype is nevertheless indistinguishable at the echocardiogram, which is precisely why the disease is missed.

Cardiomyocyte CL:0000746

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

interventricular septum UBERON:0002094 left ventricle UBERON:0002084

Downstream

Ventricular Electrical Instability and Malignant Arrhythmia Hypertrophied, inclusion-laden myocardium with patchy scar is the substrate on which re-entrant ventricular arrhythmia arises.

Progression to Systolic Failure and Transplantation A subset progress from the hypertrophic, preserved-ejection-fraction phase to ventricular dilatation, akinetic regions and systolic failure.

Show evidence (2 references)

PMID:41823911 SUPPORT Human Clinical

"Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."

Describes the characteristic imaging phenotype - asymmetric septal hypertrophy with preserved systolic function - in an independently reported biallelic KLHL24 case.

PMID:30715372 SUPPORT Human Clinical

"Here, we show that mutations in KLHL24 cause HCM in humans."

Establishes that the organ-level phenotype produced by biallelic KLHL24 loss is hypertrophic cardiomyopathy.

Myocardial Fibrosis and Focal Macrophage Infiltration

The CMH29 heart develops patchy interstitial fibrosis, and the founding explant showed small CD68-positive macrophage infiltrates that were preferentially associated with polyglucosan-containing myocytes. That spatial association suggests the inclusions themselves recruit the infiltrate - an inclusion-triggered innate response rather than a diffuse inflammatory cardiomyopathy - but the observation is from one explanted heart and has not been replicated. The extent of fibrosis is variable: the founding explant showed patchy scar, one independently reported adolescent had minimal fibrosis despite severe hypertrophy, while another young adult had extensive late-gadolinium-enhancement-positive septal scar. Fibrosis burden therefore does not track hypertrophy severity in this disease, which is one reason conventional imaging-based risk scores behave poorly in it.

cardiac fibroblast CL:0002548 CD68-positive macrophage CL:0000235

Show evidence (2 references)

PMID:41823911 SUPPORT Human Clinical

"Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."

Documents the low-fibrosis end of the range in a genetically confirmed biallelic case, which is the observation that decouples fibrosis burden from hypertrophy severity here.

PMID:41348940 SUPPORT Other

"KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature."

Marked PARTIAL because the experimental system carries the gain-of-function allele, not the biallelic loss-of-function genotype of this entity. It establishes that KLHL24 dysfunction in cardiac tissue generates a fibrotic programme, and that cardiac fibroblasts as well as cardiomyocytes are affected cell types, but the direction of substrate change is opposite to this disease's. Tagged OTHER rather than IN_VITRO because this proteomic result is drawn from mixed sources - the abstract states that the authors "integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models" and that the hiPSC-cardiomyocyte mass spectrometry "mirrored the proteomic profile of their corresponding left ventricle tissue samples" - so patient left-ventricle tissue and hiPSC material both contribute and no single evidence_source describes it. The purely hiPSC-derived result from the same paper is cited separately, under Failure of Desmin Intermediate Filament Turnover, and remains tagged IN_VITRO.

Ventricular Electrical Instability and Malignant Arrhythmia

This is the node that determines prognosis, and it is the feature that most distinguishes CMH29 from ordinary hypertrophic cardiomyopathy. Three of the 11 young adults in the founding cohort died suddenly, at ages 20, 26 and 26; several others received implantable cardioverter-defibrillators in their twenties or thirties. Electrocardiography in the founding families showed generalised ST-T change, QRS durations at or above the upper limit of normal (120, 125 and 154 ms in the three individuals with a recorded value), one prolonged PR interval of 210 ms, and frequent episodes of non-sustained ventricular tachycardia in one individual - a pattern of both conduction-system involvement and ventricular ectopy. The other three recorded PR intervals were 186, 188 and 194 ms, so PR prolongation is not a consistent feature and should not be used as a diagnostic pointer. The arrhythmic risk is disproportionate to structural severity and can precede it, which is a genuine departure from the standard HCM risk model. Mechanistically this is attributed to failure of cytoskeletal protein turnover: the desmin network normally couples the sarcolemma, Z-disc and intercalated disc, and its disorganisation disturbs both mechanical coupling and, plausibly, the sarcoplasmic reticulum-dependent calcium handling that underlies the cardiac action potential. That mechanistic account is stated in the literature but has not been tested experimentally in a biallelic loss-of-function system.

Cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ⚠ ABNORMAL cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL

Show evidence (3 references)

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Quantifies the arrhythmic mortality in the founding cohort, which is the primary evidence that this disease is lethally arrhythmogenic in young adulthood.

PMID:41823911 SUPPORT Human Clinical

"KLHL24 (Kelch-like family member 24)-associated hypertrophic cardiomyopathy (HCM) is a recently recognized genetic disorder characterized by early presentation and a disproportionate risk of malignant ventricular arrhythmias due to impaired cytoskeletal protein turnover."

States both the disproportionate arrhythmic risk and the proposed mechanistic attribution to impaired cytoskeletal protein turnover.

PMID:41823911 SUPPORT Human Clinical

"KLHL24-associated HCM is uniquely arrhythmogenic, with malignant ventricular arrhythmias potentially preceding structural severity."

Supports the specific claim that arrhythmic risk in this disease is decoupled from, and may precede, structural severity.

Progression to Systolic Failure and Transplantation

Not every individual stays in the hypertrophic, preserved-ejection-fraction phase. One of the two Iraqi siblings developed a moderately dilated left ventricle with regional akinesia and an ejection fraction of 25 percent, and underwent cardiac transplantation at 26; her brother, whose echocardiogram was recorded at 28, retained an ejection fraction of 50 percent. In the independently reported non-consanguineous sibship of PMID:42158087, the proband's ejection fraction fell progressively from 77 to 55 percent over two years of follow-up with the emergence of definite diastolic dysfunction. A separate exome series describing a consanguineous Middle Eastern family reported the KLHL24 phenotype as a mixture of dilated and hypertrophic features with non-compaction, which suggests that the hypertrophic-to-dilated transition may be part of the natural history of the gene rather than an idiosyncrasy of one family. This is marked PROVISIONAL because the number of individuals followed longitudinally is very small and the reported phenotypes span hypertrophic, dilated and non-compaction morphology without a clear ordering in time.

heart contraction GO:0060047 ↓ DECREASED

Show evidence (3 references)

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Documents progression to transplant-requiring heart failure as one of the two ways this disease kills or disables young adults.

PMID:36672924 SUPPORT Human Clinical

"in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features"

An independent family in which the biallelic KLHL24 phenotype is not purely hypertrophic, supporting a broader morphological spectrum that includes ventricular dilatation.

PMID:42158087 SUPPORT Human Clinical

"Serial clinical evaluations showed progressive left ventricular hypertrophy, diastolic dysfunction, and a gradual decline in left ventricular ejection fraction."

Longitudinal documentation of declining systolic function in a genetically confirmed biallelic case, supporting progression as a feature of the natural history.

Skeletal Muscle Cogwheel Fibre Pathology

KLHL24 is expressed more highly in skeletal muscle than in heart, and skeletal muscle in CMH29 is unambiguously abnormal - yet it is clinically silent. Muscle biopsies from three individuals across both founding families showed focal subsarcolemmal and intermyofibrillar accumulation of glycogen and desmin, distributed so as to give the fibre periphery a jagged outline that the authors named the "cogwheel" fibre and proposed as a diagnostic marker. Both type 1 and type 2 fibres were affected. Against this, no individual had muscle weakness or wasting and nerve conduction studies were normal. This dissociation is one of the two central unexplained features of the disease, alongside the polyglucosan, and it is why this node sits outside the causal chain to the cardiac phenotype rather than upstream of it. Its practical value is diagnostic: a skeletal muscle biopsy in a young adult with unexplained hypertrophic cardiomyopathy is low-morbidity relative to endomyocardial biopsy and, if the cogwheel pattern is present, points directly at this gene.

skeletal muscle fibre CL:0000188

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."

Confirms that skeletal muscle, not only myocardium, carries the desmin accumulation, which is the basis for treating skeletal muscle biopsy as a diagnostic route.

✶

Histopathology

5

Polyglucosan bodies in cardiomyocytes

The finding that names the OMIM entity. Scattered cardiomyocytes contain periodic-acid-Schiff-positive material that persists after alpha-amylase (diastase) digestion, identifying it as polyglucosan rather than ordinary glycogen. Discrete polyglucosan bodies are also found free in the interstitium, where they are associated with small macrophage infiltrates. On electron microscopy the polyglucosan sits within intermyofibrillar regions crowded with glycogen, filaments and tubular structures. The stain pair PAS and PAS-diastase is the entire test, and it is the same pair used to identify PRKAG2 cardiac syndrome - which is why the histology alone does not distinguish the two and the genotype must.

Desmin accumulation in cardiac and skeletal muscle

Immunohistochemistry for desmin shows the accumulated intermyofibrillar and subsarcolemmal material staining strongly, and Western blotting shows desmin markedly upregulated in both heart and skeletal muscle relative to controls. Electron microscopy resolves irregularly arranged intermediate filaments of 8 to 12 nm in the same compartment. This is the finding that ties the histology directly to the molecular mechanism, since desmin is the KLHL24 substrate in striated muscle.

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."

Direct statement that both cardiac and skeletal muscle biopsies show accumulation of desmin intermediate filaments.

Cogwheel skeletal muscle fibres

A pattern proposed as new in the founding report and not previously described in any myopathy: focal subsarcolemmal accumulation of glycogen and desmin distributed around the fibre periphery so as to give the fibre outline a jagged, cogwheel-like appearance on PAS and desmin staining. It affected the majority of both type 1 and type 2 fibres in all three individuals biopsied, across both founding families, and the authors proposed it explicitly as a diagnostic marker. The accumulated material stained for NADH-tetrazolium reductase but not for succinate dehydrogenase, indicating sarcoplasmic reticulum-derived tubules rather than mitochondria.

Interstitial fibrosis with focal CD68-positive macrophage infiltrates

Patchy interstitial fibrosis on van Gieson staining, with small inflammatory infiltrates that stain for CD68 and are preferentially found adjacent to polyglucosan-containing myocytes. The distribution suggests a localised macrophage response to the stored material rather than a diffuse inflammatory process.

Absence of myofibre disarray

A negative finding with diagnostic weight. Myocyte and myofibrillar disarray is the pathognomonic histology of sarcomere-protein hypertrophic cardiomyopathy; what the CMH29 biopsies show instead is myocyte hypertrophy with intermyofibrillar accumulation. The same negative distinguishes PRKAG2 cardiac syndrome from sarcomeric HCM, so this feature separates CMH29 from sarcomeric disease but not from the other storage mimics.

Show evidence (1 reference)

PMID:11827995 SUPPORT Human Clinical

"these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations"

Cited for the general histological principle, established in the PRKAG2 storage mimic, that myofibrillar disarray is pathognomonic of sarcomeric hypertrophic cardiomyopathy and is absent in the storage cardiomyopathies that mimic it. The absence of disarray in CMH29 specifically is described in the full text of PMID:30715372, which is not quotable from its cached abstract.

⬡

Pathograph

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

●

Phenotypes

15

Cardiovascular 6

Hypertrophic cardiomyopathy HP:0001639

Course: PROGRESSIVE Onset: YOUNG ADULT; 16.0-28.0y

No FrequencyEnum band is asserted; see the entry-level notes. The wall thickness figures are from the clinical tables in the full text of PMID:30715372 (PMC6812045, read 2026-08-01) and from the cached full text of PMID:42158087 respectively.

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Here, we show that mutations in KLHL24 cause HCM in humans."

Directly asserts hypertrophic cardiomyopathy as the phenotype produced by KLHL24 mutation in humans.

Syncope HP:0001279

Temporal: RECURRENT

Recurrent syncope is named in the OMIM/MedGen clinical description of CMH29 (MedGen C5774308, retrieved 2026-08-01) and in the founding paper's text, but it is not separately annotated in the HPO annotation file for OMIM:620236, so no fraction is available.

Show evidence (1 reference)

PMID:42158087 SUPPORT Human Clinical

"The proband, a 30-year-old male, initially presented with recurrent syncope at the age of 20, leading to the implantation of a permanent pacemaker."

Documents recurrent syncope as the presenting feature in a genetically confirmed biallelic KLHL24 case, at an age typical for this disease.

Palpitations HP:0001962

The HPO annotation file for OMIM:620236 records HP:0001962 at 5/7, sourced to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached abstract, so no evidence item is attached. No FrequencyEnum band is asserted.

Ventricular arrhythmia HP:0004308

Bound to HP:0004308 (Ventricular arrhythmia) rather than to the parent HP:0011675 (Arrhythmia) or to the more specific HP:0004756 (Ventricular tachycardia): the reported events span non-sustained ventricular tachycardia, defibrillator-treated events and unwitnessed sudden death, so the ventricular-arrhythmia level is the most specific term the evidence supports for the disease as a whole. Both alternatives were checked with OAK. No FrequencyEnum band is asserted; the HPO annotation file for OMIM:620236 carries no ventricular-arrhythmia term.

Show evidence (1 reference)

PMID:41823911 SUPPORT Human Clinical

"KLHL24-associated HCM is uniquely arrhythmogenic, with malignant ventricular arrhythmias potentially preceding structural severity."

Asserts malignant ventricular arrhythmia as a defining feature of this genotype and states that it may precede structural severity.

Sudden cardiac death HP:0001645

The HPO annotation file for OMIM:620236 records HP:0001645 at 3/11, sourced to PMID:30715372 (retrieved 2026-08-01). No FrequencyEnum band is asserted, but note that this denominator of 11 is the largest in the annotation set and refers to all ascertained affected adults rather than to the 8 with tabulated clinical data. The specific ages at death are in the full text (PMC6812045, read 2026-08-01).

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Quantifies sudden death in the founding cohort.

Congestive heart failure HP:0001635

No FrequencyEnum band is asserted; heart failure is not separately annotated in the HPO annotation file for OMIM:620236.

Show evidence (2 references)

PMID:42158087 SUPPORT Human Clinical

"His 20-year-old younger brother, identified through family screening, had no obvious clinical symptoms but exhibited severe biventricular hypertrophy, significantly elevated levels of B-type natriuretic peptide and high-sensitivity troponin T, indicating subclinical myocardial injury and heart failure."

Documents biochemically evident heart failure in an individual who was clinically asymptomatic, which is the basis for the claim that subclinical heart failure precedes symptoms here.

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Documents progression to transplant-requiring heart failure in the founding cohort.

Respiratory 1

Dyspnea HP:0002094

The HPO annotation file for OMIM:620236 records HP:0002094 at 5/7, sourced to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached abstract, so no evidence item is attached. No FrequencyEnum band is asserted.

Other 8

Asymmetric septal hypertrophy HP:0001670

The HPO annotation file for OMIM:620236 records HP:0001670 at 3/8, sourced to PMID:30715372 (retrieved 2026-08-01). No FrequencyEnum band is asserted; the denominator of 8 is the number of individuals with tabulated clinical data, not the number with echocardiography, and three of those eight have "not determined" in one or more echocardiographic fields.

Show evidence (1 reference)

PMID:41823911 SUPPORT Human Clinical

"Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."

Documents asymmetric septal hypertrophy in a genetically confirmed biallelic KLHL24 case.

Left ventricular outflow tract obstruction HP:0032092

The HPO annotation file for OMIM:620236 records HP:0032092 at 3/8, sourced to PMID:30715372 (retrieved 2026-08-01). The gradient values are from the clinical table in the full text (PMC6812045, read 2026-08-01) and are not quotable from the cached abstract. No FrequencyEnum band is asserted, and no evidence item is attached because neither the cached abstract of the founding paper nor any other cached source states this finding.

Systolic anterior motion of the mitral valve HP:0031656

The HPO annotation file for OMIM:620236 records HP:0031656 at 4/8, sourced to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached abstract, so no evidence item is attached. No FrequencyEnum band is asserted.

Mitral regurgitation HP:0001653

The HPO annotation file for OMIM:620236 records HP:0001653 at 3/8, sourced to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached abstract, so no evidence item is attached. No FrequencyEnum band is asserted.

Reduced left ventricular endsystolic diameter HP:0034386

The HPO annotation file for OMIM:620236 records HP:0034386 at 5/7, sourced to PMID:30715372 (retrieved 2026-08-01), which is the highest-frequency structural feature in the annotation set. The volume figures are from the full-text clinical table (PMC6812045, read 2026-08-01). Not mentioned in the cached abstract, so no evidence item is attached.

Cardiomyocyte hypertrophy HP:0031319

The HPO annotation file for OMIM:620236 records HP:0031319 at 2/2, sourced to PMID:30715372 (retrieved 2026-08-01 from https://ontology.jax.org/api/network/annotation/OMIM:620236). The denominator of 2 is the number of individuals with myocardial tissue available, not the number affected. Not mentioned in the cached abstract of PMID:30715372, so no evidence item is attached; the histological description is from the full text (PMC6812045, read 2026-08-01). No FrequencyEnum band is asserted.

Increased myocardial glycogen content HP:0034532

The HPO annotation file for OMIM:620236 records HP:0034532 at 2/2, sourced to PMID:30715372 (retrieved 2026-08-01 from https://ontology.jax.org/api/network/annotation/OMIM:620236), with the same denominator of 2 as HP:0031319 - the individuals with myocardial tissue available. Not mentioned in the cached abstract, so no evidence item is attached; the PAS and PAS-diastase findings are in the full text (PMC6812045, read 2026-08-01) and are also modelled under `histopathology` and in the storage mechanism node. No FrequencyEnum band is asserted.

Cardiac polyglucosan accumulation HP:0034835

HP:0034835 exists in HPO (`runoak -i sqlite:obo:hp info HP:0034835`, checked 2026-08-01) but is NOT among the 13 annotations the HPO annotation file carries for OMIM:620236 (retrieved 2026-08-01 from https://ontology.jax.org/api/network/annotation/OMIM:620236), so it is a curator addition from the primary description rather than an imported annotation, and no frequency is available. The sibling term HP:0034766 Muscle fiber polyglucosan inclusion bodies was considered and deliberately not used: the founding paper reports polyglucosan in cardiomyocytes only, and describes the skeletal muscle accumulation as glycogen, desmin and tubular structures. Not mentioned in the cached abstract, so no evidence item is attached; see the `histopathology` entry for provenance.

🧬

Genetic Associations

1

KLHL24 (Biallelic loss-of-function variants (homozygous or compound heterozygous) in the BACK and Kelch domains)

Gene: KLHL24 hgnc:25947 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:30715372 SUPPORT Human Clinical

"Here, we show that mutations in KLHL24 cause HCM in humans."

The founding gene-disease assertion for this entity.

CGGV:assertion_f1d4ce43-4c2d-41a0-b821-a11ac8eb8fca-2023-09-28T160000.000Z SUPPORT Other

ClinGen expert-panel gene-disease validity classification, recording autosomal recessive inheritance and Moderate strength of evidence under SOP9. Curated against MONDO:0005045, the broad HCM term, not against MONDO:0859372.

PMID:39971408 SUPPORT Human Clinical

"Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive)."

The published form of the ClinGen reappraisal, placing KLHL24 at moderate evidence among newly curated hypertrophic cardiomyopathy genes.

+ 1 more reference

💊

Medical Actions

5

Implantable cardioverter-defibrillator

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

The single intervention with a plausible mortality benefit in this disease, and the one where CMH29 departs from standard hypertrophic cardiomyopathy practice. Because malignant ventricular arrhythmia in this genotype can precede structural severity and can be the first manifestation, conventional HCM risk scores - which weight wall thickness, fibrosis burden, family history of sudden death and syncope - underestimate risk. Several individuals in the founding families received defibrillators in their twenties and thirties, and an independently reported 16-year-old with low conventional risk markers received a prophylactic device on genotype grounds. That decision was made case by case; no guideline addresses this genotype and no comparative data exist.

Show evidence (2 references)

PMID:41823911 SUPPORT Human Clinical

"Despite low conventional risk markers, genotype-directed assessment indicated high arrhythmic risk, prompting prophylactic implantable cardioverter-defibrillator (ICD) placement."

Documents genotype-driven prophylactic defibrillator implantation in a biallelic KLHL24 case whose conventional risk markers were low.

PMID:41823911 SUPPORT Human Clinical

"Early genetic testing enables genotype-guided preventive strategies, including timely prophylactic ICD implantation, even in apparently low-risk phenotypes."

States the management principle that follows from the decoupling of arrhythmic risk from structural severity in this genotype.

Heart transplantation

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

Definitive treatment for the subset who progress to end-stage failure. One of the two Iraqi siblings was transplanted at 26 for heart failure with an ejection fraction of 25 percent. The relevance of transplantation here goes beyond the individual case: because the disease is confined to striated muscle and the skeletal muscle involvement is clinically silent, a transplanted CMH29 patient has no residual systemic disease to limit the outcome, unlike patients transplanted for multisystem storage disorders.

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Documents cardiac transplantation as a management outcome in the founding cohort.

Standard heart failure and hypertrophic cardiomyopathy pharmacotherapy

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: metoprolol CHEBI:6904 spironolactone CHEBI:9241

Management of the haemodynamic phenotype follows standard practice for hypertrophic cardiomyopathy and heart failure and is not disease-specific: beta-blockade for outflow obstruction, symptom control and rate control, with mineralocorticoid receptor antagonism, loop diuretics and vasopressin antagonism added as congestion develops. Reported regimens in genetically confirmed cases have used metoprolol succinate with spironolactone in the less advanced sibling and metoprolol with furosemide and tolvaptan in the more congested one. There is no evidence that any of this modifies the natural history of the underlying proteostatic lesion.

Show evidence (1 reference)

PMID:42158087 SUPPORT Human Clinical

"The proband was on a long-term regimen of metoprolol succinate (47.5 mg daily), spironolactone (10 mg daily), and febuxostat (20 mg daily)."

Documents the actual pharmacological management of a genetically confirmed case; cited as observed practice, not as evidence of efficacy.

Genetic counselling and sibling cascade screening

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling for CMH29 differs from counselling for dominant hypertrophic cardiomyopathy in the direction it points. The recurrence risk that matters is one in four for the proband's siblings, not fifty percent for offspring; the proband's children are obligate heterozygotes and, on present evidence, unaffected unless the other parent is also a carrier, which raises the question of partner testing in consanguineous families. Siblings should be offered targeted testing for the familial alleles and echocardiography without waiting for symptoms, because severe hypertrophy and biochemical heart failure have been documented in an entirely asymptomatic 18-year-old found by screening.

Show evidence (1 reference)

PMID:42158087 SUPPORT Human Clinical

"This case expands the genetic spectrum of HCM and highlights the importance of genetic testing and family screening for KLHL24-related cardiomyopathies."

States the family-screening recommendation that this counselling entry implements.

No disease-modifying therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Nothing addresses the underlying lesion. There is no way to restore CUL3 substrate-adaptor function, and unlike the gain-of-function skin disease - where reducing KLHL24 abundance is at least a coherent therapeutic idea, and has been shown to restore desmin levels and tissue morphology in patient-derived engineered heart tissue - loss of function offers no obvious pharmacological handle. A review of KLHL24-associated cardiomyopathy published in 2025 confirms that no clinical trial of any kind is under way for this gene.

Show evidence (2 references)

PMID:39708934 SUPPORT Other

"currently there are no specific clinical trials going on regarding the therapeutic strategies among patients with KLHL24 mutations"

Directly supports the absence of any disease-specific therapeutic development for KLHL24-associated cardiomyopathy.

PMID:34292882 SUPPORT In Vitro

"KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs."

Marked PARTIAL because it is a proof of principle for the allelic gain-of-function disease, not for this entity. It is cited to make the asymmetry explicit: knocking KLHL24 down rescues the dominant disease and would, if anything, phenocopy this one.

🔬

Diagnosis

4

Exome or genome sequencing with biallelic KLHL24 variant interpretation

Molecular diagnosis rests on identifying biallelic KLHL24 variants against transcript NM_017644.3, with parental testing to confirm that compound heterozygous variants are in trans. Three interpretive points follow from the published genotype-phenotype pattern. First, KLHL24 must actually be on the panel: the founding families were solved only after an 88-gene inherited-cardiac-conditions panel and a 9-gene polyglucosan-storage panel had both come back negative, and the most recent reported sibship was likewise negative across a conventional hypertrophic cardiomyopathy gene panel - MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1, TNNC1, JPH2, PRKAG2, GLA, LAMP2, RYR2, DSP, FLNC, MYPN, CSRP3, TCAP, ZASP and others - before exome sequencing found KLHL24. Second, a single heterozygous KLHL24 variant does not explain a hypertrophic cardiomyopathy phenotype and should not be reported as though it did; the disease is recessive. Third, position matters as much as consequence - an initiation-codon variant is the dominant skin-and-dilated-cardiomyopathy allele, not this disease. For a young adult with severe unexplained hypertrophy, no dominant family history and a negative sarcomere panel, reanalysis or reflex exome sequencing is the appropriate next step.

Show evidence (2 references)

PMID:42158087 SUPPORT Human Clinical

"only compound heterozygous KLHL24 variants segregated with the disease phenotype."

Documents that a conventional hypertrophic cardiomyopathy gene panel was uninformative and that only KLHL24 segregated, which is the argument for including the gene on panels and for reflex exome sequencing.

PMID:42158087 SUPPORT Human Clinical

"KLHL24 could be included in genetic panels, especially for cases with early onset, severe hypertrophy, or non-dominant family histories."

States the panel-inclusion recommendation and the clinical criteria that should trigger consideration of this gene.

Echocardiography with family cascade screening

Echocardiography establishes the structural phenotype - septal thickness, cavity size, systolic anterior motion, outflow gradient, diastolic function - and is the screening test for at-risk relatives. Because inheritance is recessive, cascade screening targets siblings, who carry a one-in-four risk, rather than the parents and offspring who are the focus in dominant hypertrophic cardiomyopathy. The screening yield is high and the finding can be dramatic in someone who reports no symptoms at all: in one reported sibship the asymptomatic younger brother, found on family screening, had interventricular septal thickness of 38 to 42 mm.

Show evidence (2 references)

PMID:42158087 SUPPORT Human Clinical

"His 20-year-old younger brother, identified through family screening, had no obvious clinical symptoms but exhibited severe biventricular hypertrophy, significantly elevated levels of B-type natriuretic peptide and high-sensitivity troponin T, indicating subclinical myocardial injury and heart failure."

Demonstrates the yield of sibling cascade screening in this recessive disease, including severe structural disease in an asymptomatic individual.

PMID:42158087 SUPPORT Human Clinical

"biallelic pathogenic variants can be misleading, as severe structural and subclinical functional heart disease may already be present, necessitating pre-symptomatic diagnosis and management."

States directly that asymptomatic status is unreliable in biallelic individuals, which is the justification for structural screening rather than symptom-triggered assessment.

Skeletal muscle biopsy

An under-used diagnostic route that is specific to this disease. Because KLHL24 is expressed more highly in skeletal muscle than in myocardium and because skeletal muscle carries the same accumulation despite being clinically normal, a quadriceps biopsy can show the desmin and glycogen accumulation and the cogwheel fibre pattern in a patient whose only clinical problem is cardiac. It is substantially less morbid than endomyocardial biopsy. Its limitation is that the pattern has been described in exactly three individuals from two families and its specificity against other desminopathies and glycogen storage myopathies has never been tested.

The skeletal muscle biopsy findings, the proposal of the cogwheel fibre as a diagnostic marker, and the tissue-expression ranking that motivates biopsying muscle rather than heart are all in the full text of PMID:30715372 (PMC6812045, read 2026-08-01). The cached abstract supports only the general statement that skeletal muscle biopsies showed characteristic alterations, which is quoted on the histopathology finding above rather than duplicated here.

Endomyocardial biopsy with PAS and PAS-diastase histochemistry

Where myocardial tissue is available - at endomyocardial biopsy, at transplantation or at autopsy - PAS staining before and after alpha-amylase digestion is the test that reveals the polyglucosan, and desmin immunohistochemistry with electron microscopy reveals the intermediate filament accumulation. In practice this is rarely the route to diagnosis today, since sequencing is faster and non-invasive, but it remains the way the entity was defined and the only way its defining histological feature can be confirmed. It also excludes the principal mimics directly: Danon disease shows autophagic vacuoles with sarcolemmal features, Fabry disease shows lamellar inclusions, and Pompe disease shows lysosomal glycogen.

No evidence item is attached. The histochemical protocol is described in the methods of PMID:30715372 (PMC6812045, read 2026-08-01), which is not quotable from the cached abstract, and the comparative statements about Danon, Fabry and Pompe histology are reasoned differential context rather than quoted findings.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

No prevalence or incidence estimate of any kind has been published for CMH29, and the 2026 case report cited below states that plainly. The total published experience consists of the two founding consanguineous families (11 young affected adults ascertained, of whom 8 are tabulated with clinical detail), plus four subsequent families - a Middle Eastern consanguineous family in a recessive-cardiomyopathy exome series, a Brazilian consanguineous family with two affected sisters, a non-consanguineous sibship of two reported from China, and a single adolescent reported from India. `NOT_YET_DOCUMENTED` is used rather than a qualitative band because there is no source to band, and `rate_per_100000` is deliberately left empty. Ascertainment to date is heavily weighted towards consanguineous populations and towards centres running broad exome-based cardiomyopathy panels, so the geographic distribution of reports reflects how the disease is found rather than where it occurs. Note that the last two reports state only the reporting centre, not the family's ancestry; see the ancestry-versus-reporting-centre note in the entry description.

Show evidence (2 references)

PMID:42158087 SUPPORT Human Clinical

"there is currently no epidemiological data on recessive-inherited hypertrophic cardiomyopathy type 29 caused by KLHL24 variants"

An explicit statement from a 2026 report that no epidemiological data exist for this entity, which is the justification for NOT_YET_DOCUMENTED.

PMID:30715372 SUPPORT Human Clinical

"Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."

Establishes the size of the founding cohort, which is the denominator behind every published clinical statistic about this disease.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from KLHL24-Related Hypertrophic Cardiomyopathy:

Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss Not Yet Curated MONDO:0015006

Overlapping Features The allelic disorder, and the most informative entry in this list. The same gene, mutated at its translation initiation codon rather than in its body, causes a dominant disease of skin fragility with scarring alopecia and DILATED cardiomyopathy. The mechanism is the mirror image of this entity's. Loss of the first 28 amino acids by translation re-initiation at Met29 produces KLHL24-deltaN28, which escapes the autoubiquitination that normally limits KLHL24's own half-life; the stabilised adaptor then hyperdegrades its substrates - keratin 14 and other keratins in basal keratinocytes, desmin, synemin and vimentin in cardiac cells. Where CMH29 accumulates intermediate filament, EBS6 destroys it; where CMH29 gives a thick-walled small-cavity ventricle, EBS6 gives a thin-walled dilated one. A clinician will never confuse the two at the bedside - one has blistering from birth, the other has no skin findings at all - but a laboratory reading a KLHL24 variant absolutely can, and that is why this differential is here.

Distinguishing Features

EBS6 is autosomal dominant and often de novo; CMH29 is autosomal recessive, so zygosity alone separates them in most cases.
EBS6 alleles are confined to the translation initiation codon and to nonsense-inducing changes in c.4_84 that permit re-initiation; CMH29 alleles lie in the BACK and Kelch domains.
EBS6 is a gain-of-function mechanism producing substrate depletion; CMH29 is loss of function producing substrate accumulation.
The cardiomyopathy of EBS6 is dilated; that of CMH29 is hypertrophic with a small cavity.
EBS6 presents at birth with extensive skin denudation and later scarring alopecia; no individual with biallelic KLHL24 variants has had any skin abnormality, and family members of CMH29 probands screened for skin symptoms were normal.

Show evidence (6 references)

PMID:27798626 SUPPORT Human Clinical

"We have identified start-codon mutations in the KLHL24 gene in five patients with EB."

Establishes the start-codon location of the dominant skin alleles, which is the positional contrast with the BACK and Kelch domain alleles of this entity.

PMID:27889062 SUPPORT Human Clinical

"monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes"

Independently establishes that the skin disease alleles are monoallelic and confined to the initiation codon, in direct contrast to the biallelic body-of-gene alleles of CMH29.

PMID:34292882 SUPPORT In Vitro

"The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon."

Defines the truncated protein product that underlies the dominant disease and that has no counterpart in CMH29 genotypes.

+ 3 more references

PRKAG2 cardiac syndrome MONDO:0800484

Overlapping Features The classic glycogen-storage mimic of hypertrophic cardiomyopathy, and the entity that shares CMH29's most distinctive histological feature. Cardiomyocyte polyglucosan bodies, PAS-positive and diastase-resistant, are found in both, so a pathologist reading a PAS-diastase stain cannot tell them apart. Everything upstream and downstream of that stain differs. PRKAG2 encodes the gamma-2 regulatory subunit of AMP-activated protein kinase; dominant missense variants render the kinase constitutively active, which drives glucose uptake and glycogen synthesis and produces bulk non-lysosomal glycogen storage. The stored material is the primary lesion. In CMH29 the primary lesion is failure of intermediate filament turnover, the polyglucosan is secondary and unexplained, and the primary stored species is desmin protein rather than polysaccharide. The clinical separator is electrophysiological. PRKAG2 disease is defined by ventricular pre-excitation - accessory atrioventricular connections producing Wolff-Parkinson-White - with progressive atrioventricular block and pacemaker dependence. CMH29 has conduction-interval prolongation and malignant ventricular arrhythmia but no accessory pathways and no pre-excitation has been reported. An adult with hypertrophy plus a delta wave is PRKAG2 until proven otherwise; an adult with hypertrophy plus non-sustained ventricular tachycardia and unaffected parents who are first cousins is not.

Distinguishing Features

PRKAG2 cardiac syndrome is autosomal dominant with an affected parent in most families; CMH29 is autosomal recessive with unaffected heterozygous parents and frequent parental consanguinity.
Ventricular pre-excitation (Wolff-Parkinson-White) and progressive atrioventricular block define PRKAG2 disease and have not been reported in CMH29.
PRKAG2 is one of the eight canonical muscle polyglucosan storage genes; KLHL24 is not, and was reached in the founding study only after that gene set was sequenced and excluded.
In PRKAG2 disease the stored polysaccharide sits in large isolated cytosolic vacuoles; in CMH29 the polyglucosan is intermyofibrillar and accompanied by accumulated desmin filaments and sarcoplasmic-reticulum-derived tubules.
Desmin accumulation on immunohistochemistry and Western blot is characteristic of CMH29 and is not a feature of PRKAG2 disease.

Show evidence (3 references)

PMID:11827995 SUPPORT Human Clinical

"in which hypertrophy, ventricular pre-excitation and conduction system defects coexist"

Names the triad that defines PRKAG2 disease, of which ventricular pre-excitation is the feature absent from CMH29 and therefore the practical discriminator.

PMID:11827995 SUPPORT Human Clinical

"These vacuoles contained inhomogeneous granular material that stained strongly with PAS"

Establishes the shared PAS-positive storage histology that makes the two diseases indistinguishable on that stain alone.

PMID:26278982 SUPPORT Other

"Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2."

Places PRKAG2 inside, and KLHL24 outside, the canonical polyglucosan storage gene set, which is the genetic basis of the distinction.

Sarcomeric hypertrophic cardiomyopathy Not Yet Curated MONDO:0024573

Overlapping Features The default diagnosis, the parent term of this entity in MONDO, and the label almost every CMH29 patient carries before sequencing. Sarcomeric HCM is dominant, caused by variants in MYH7, MYBPC3 and the other sarcomere-protein genes, and accounts for the large majority of familial hypertrophic cardiomyopathy; the genetic cause of up to 50 percent of clinically diagnosed HCM nevertheless remains unknown, and CMH29 lives in that unexplained fraction. The echocardiographic appearances overlap completely. What separates them is the pedigree, the histology and the gene.

Distinguishing Features

Sarcomeric HCM is autosomal dominant with a vertically transmitted family history; CMH29 is recessive, so unaffected parents and affected siblings are the expected pattern.
Myocyte and myofibrillar disarray is the pathognomonic histology of sarcomeric HCM and is not what CMH29 biopsies show.
Polyglucosan bodies, desmin accumulation and intermyofibrillar glycogen are not features of sarcomeric HCM.
Skeletal muscle histology is normal in sarcomeric HCM and abnormal, though clinically silent, in CMH29.
Arrhythmic risk in sarcomeric HCM tracks conventional risk markers reasonably well; in CMH29 malignant arrhythmia may precede structural severity, so those markers underestimate risk.

Show evidence (1 reference)

PMID:30715372 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown."

Establishes the diagnostic gap in which this entity sits - a large unexplained fraction of clinically diagnosed hypertrophic cardiomyopathy.

Danon disease MONDO:0010281

Overlapping Features An X-linked lysosomal-associated membrane protein 2 defect producing an autophagic vacuolar myopathy with massive left ventricular hypertrophy, skeletal myopathy, pre-excitation and, in males, presentation in adolescence with rapid progression to transplantation. It sits in the same diagnostic slot as CMH29 - a young person with extreme hypertrophy and a non-dominant pedigree - and is a storage cardiomyopathy with a muscle-biopsy diagnosis, so it must be excluded on the same tissue.

Distinguishing Features

Danon disease is X-linked; affected males are severely affected in adolescence and carrier females later and more mildly. CMH29 affects both sexes equally and requires two damaged alleles.
Danon disease combines cardiomyopathy with intellectual disability and a clinically manifest skeletal myopathy with raised creatine kinase; CMH29 has neither.
Ventricular pre-excitation is common in Danon disease and unreported in CMH29.
Danon histology shows autophagic vacuoles with sarcolemmal features and LAMP2 absence on immunostaining; CMH29 shows intermyofibrillar desmin and polyglucosan with preserved LAMP2.

Polyglucosan body myopathy 1 with or without immunodeficiency Not Yet Curated MONDO:0014389

Overlapping Features An RBCK1-related recessive disorder combining polyglucosan storage myopathy with a progressive, often fatal cardiomyopathy, and in some individuals immunodeficiency and autoinflammation. It is the recessive polyglucosan cardiomyopathy that CMH29 most closely resembles by histology and by inheritance, and it is one of the nine genes that the founding study sequenced and excluded before reaching KLHL24. Including it here is the point: the differential for a recessive polyglucosan cardiomyopathy is a short list, and KLHL24 now belongs on it even though its polyglucosan remains unexplained.

Distinguishing Features

RBCK1 disease frequently includes immunodeficiency, recurrent pyogenic infection and systemic autoinflammation; CMH29 is purely cardiac.
RBCK1 disease produces a progressive clinically manifest skeletal myopathy; CMH29 skeletal muscle is abnormal on biopsy but strong.
The RBCK1 cardiomyopathy is typically dilated and progresses to failure in childhood or adolescence; CMH29 is hypertrophic and presents in young adulthood.
RBCK1 is a canonical polyglucosan storage gene with an established mechanism in linear ubiquitin assembly and glycogen handling; the polyglucosan in CMH29 has no established mechanism.

Fabry disease MONDO:0010526

Overlapping Features Included because it is the storage mimic with a disease-modifying therapy, which makes missing it costlier than missing the others. X-linked alpha-galactosidase A deficiency produces concentric left ventricular hypertrophy that is routinely misdiagnosed as hypertrophic cardiomyopathy, and is excluded cheaply by plasma or leukocyte enzyme assay in males and by GLA sequencing in females.

Distinguishing Features

Fabry disease is X-linked with a characteristic multisystem phenotype - acroparaesthesia, angiokeratoma, hypohidrosis, corneal verticillata, proteinuric renal disease and stroke - none of which occurs in CMH29.
Fabry cardiac hypertrophy is typically concentric with a short PR interval; CMH29 hypertrophy is typically asymmetric and septal, and no short PR interval has been reported in it.
Fabry histology shows lamellar myelin-like inclusions of globotriaosylceramide, not polyglucosan or desmin accumulation.
Enzyme replacement and chaperone therapy exist for Fabry disease; no disease-modifying therapy exists for CMH29.

🐁

Animal Models

1

klhl24a splice-blocking antisense morpholino knockdown (morphant; no stable mutant line reported) Danio rerio Transient loss-of-function knockdown model

The only in vivo model of this disorder, and it is a transient morpholino knockdown rather than a germline mutant - a distinction that limits how much weight it can carry. Zebrafish have two KLHL24 orthologues; klhl24a is expressed in the cardiac cone at 22 hours post fertilisation and in the ventricle at 72 hours, whereas klhl24b is not expressed in the developing heart, so the cardiac arm of the gene family is klhl24a. Knockdown produced pericardial oedema, altered heart rate and reduced circulation from 48 hours, progressing to ventricular failure and blocked circulation in about 90 percent of morphants against 4 percent of controls. A second, independently targeted morpholino reproduced the phenotype, and co-injection of wild-type klhl24a mRNA partially rescued it, which are the two standard specificity controls. The experiment that matters most for this entry is the allele test. Zebrafish klhl24a mRNA carrying the residues equivalent to the two human CMH29 alleles failed to rescue, giving heart defects in 71.5 and 77.5 percent of embryos respectively. That is the direct functional evidence that p.Arg306His and p.Glu350* are loss-of-function alleles rather than dominant-negatives or benign variants. Its limitations are substantial and are the reason a knowledge gap is recorded below. The model is a knockdown, not a biallelic point-mutant; it reports on cardiac development in the embryo rather than on adult-onset hypertrophy; desmin protein levels were unchanged in morphants at 52 hours, which the authors attribute to the short experimental window; and it produces ventricular failure rather than the hypertrophy, polyglucosan storage or arrhythmia that define the human disease. Provenance and caveats. The morpholino doses, the second morpholino, the RT-PCR confirmation of exon 3 skipping, the rescue percentages, the allele-specific rescue failure percentages and the unchanged morphant desmin immunoblot are all in the full text and figures of PMID:30715372 (PMC6812045, read 2026-08-01) and not in the cached abstract, so they are described here rather than quoted. Morpholino knockdowns are subject to well-documented off-target and p53-mediated artefacts; the second-morpholino and mRNA-rescue controls reported here mitigate but do not eliminate that concern. No mouse model of KLHL24 loss of function was found during this curation.

Species

Danio rerio

Genotype

klhl24a splice-blocking antisense morpholino knockdown (morphant; no stable mutant line reported)

Show evidence (2 references)

PMID:30715372 SUPPORT Model Organism

"Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene."

Establishes the zebrafish knockdown as the in vivo support for the gene-disease relationship and situates its phenotype alongside other HCM gene knockdowns in the same species.

PMID:30715372 SUPPORT Model Organism

"Our findings reveal a crucial role for KLHL24 in cardiac development and function."

The developmental conclusion drawn from the model, which is also the boundary of what it can show - development rather than adult-onset remodelling.

{ }

Source YAML

click to show

name: KLHL24-Related Hypertrophic Cardiomyopathy
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
  term:
    id: MONDO:0859372
    label: cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
description: >-
  Hypertrophic cardiomyopathy 29 (CMH29) is an autosomal recessive,
  cardiac-restricted cardiomyopathy caused by biallelic loss-of-function
  variants in KLHL24, the gene encoding a BTB-BACK-Kelch substrate adaptor of
  the CUL3-RING E3 ubiquitin ligase. It was defined in 2019 in two unrelated
  consanguineous families, one Iraqi and one Iranian, in whom homozygous KLHL24
  variants segregated with a cardiomyopathy that mimics sarcomeric hypertrophic
  cardiomyopathy clinically but is separable from it pathologically.

  The mechanistic core of the disease is a failure of regulated intermediate
  filament turnover. KLHL24 presents substrates to CUL3 for polyubiquitination
  and proteasomal degradation; in striated muscle its principal known substrate
  is desmin, the muscle-specific intermediate filament and the cardiac
  counterpart of the keratin-14 that the same protein degrades in skin. When
  KLHL24 is inactivated, desmin is no longer cleared. Endomyocardial and
  skeletal muscle biopsies from the founding families showed accumulation of
  desmin intermediate filaments, and immunoblotting showed desmin markedly
  upregulated in both heart and skeletal muscle. Alongside the filaments, the
  intermyofibrillar space fills with glycogen, sarcoplasmic-reticulum-derived
  tubular structures, and discrete polyglucosan bodies - diastase-resistant,
  amylopectin-like polysaccharide inclusions that give the OMIM entity its
  name. No variant was found in any gene on the nine-gene polyglucosan-storage
  panel the authors screened, and they state explicitly that the origin of
  the polyglucosan remains unknown; it is presented as a diagnostic marker
  rather than as an explained step in the causal chain, and this entry does the
  same.

  Clinically the disease presents in young adulthood with recurrent syncope,
  exertional dyspnoea and palpitations, with asymmetric septal hypertrophy, a
  small left ventricular cavity, systolic anterior motion of the mitral valve
  and left ventricular outflow tract obstruction on echocardiography. Its
  defining feature is arrhythmic rather than haemodynamic: of the 11 young
  affected adults in the founding report, 3 died suddenly and 1 required
  cardiac transplantation for heart failure. Skin is not involved, and skeletal
  muscle weakness was absent in every individual examined despite florid
  histological abnormality on muscle biopsy.

  KLHL24 is one of the clearest allelic-contrast genes in cardiology. The same
  gene, mutated at its translation initiation codon, produces the opposite
  molecular lesion - a stabilised N-terminally truncated protein that escapes
  autoubiquitination and hyperdegrades its own substrates - and the opposite
  clinical disease: autosomal dominant epidermolysis bullosa simplex 6 with
  skin fragility, scarring alopecia and dilated, not hypertrophic,
  cardiomyopathy. Too little KLHL24 activity gives desmin accumulation and a
  thick, stiff, small-cavity ventricle; too much gives desmin depletion and a
  thin, dilated one.
parents:
- Cardiovascular Disease
- Genetic Disorder
synonyms:
- CMH29
- cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
- hypertrophic cardiomyopathy 29
- KLHL24-related cardiomyopathy
- autosomal recessive KLHL24 cardiomyopathy
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      The entire reported morbidity is cardiac: hypertrophic remodelling of the
      left ventricle, outflow tract obstruction, ventricular arrhythmia, sudden
      cardiac death and progression to transplantation. Skeletal muscle is
      abnormal on biopsy but clinically silent, and no skin, neurological,
      renal or hepatic involvement has been described in any individual with
      biallelic KLHL24 variants.
    evidence:
    - reference: PMID:30715372
      reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
      explanation: The reported burden of disease is entirely cardiovascular - arrhythmic death and heart failure - which is the basis for the CARDIOVASCULAR chapter assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  ENTITY VERIFICATION AND NEC PREFLIGHT. The target term was verified with OAK
  before any content was written. `runoak -i sqlite:obo:mondo info
  MONDO:0859372 -O obo` returns name "cardiomyopathy, familial hypertrophic,
  29, with polyglucosan bodies", xref OMIM:620236, xrefs GARD:0026721,
  MEDGEN:1824081, UMLS:C5774308, `is_a MONDO:0024573` (familial hypertrophic
  cardiomyopathy) and `relationship: RO:0004003 HGNC:25947 ! KLHL24`.
  `runoak -i sqlite:obo:mondo relationships -p RO:0004003 MONDO:0859372`
  returns the same single gene association. `runoak -i sqlite:obo:hgnc info
  hgnc:25947` returns KLHL24. The causal gene is therefore KLHL24 and not
  PRKAG2, which is the specific confusion this entity has already produced in
  this repository (see the scoping note below).

  Every source used here was gene-checked before use. The founding clinical
  report (PMID:30715372) names KLHL24 throughout and names no other candidate
  gene; it explicitly screened and excluded an 88-gene panel of inherited
  cardiac conditions and a 9-gene polyglucosan-storage panel before reaching
  KLHL24. The corroborating reports (PMID:36672924, PMID:40176835,
  PMID:42158087, PMID:41823911) each report KLHL24 as the segregating gene in
  their own families. No deep-research report was used for this entry; the
  literature was assembled directly from a PubMed query for KLHL24 (71 records
  on 2026-08-01), each record's title and abstract read individually, and the
  cardiac subset separated by hand from the much larger dermatological and
  bioinformatics subsets.

  SCOPING AGAINST PRKAG2. `kb/disorders/PRKAG2_Cardiac_Syndrome.yaml` carries an
  NEC finding recording that a previous curation request named MONDO:0859372
  but described PRKAG2 biology throughout, and that CMH29/KLHL24 therefore
  remained uncurated. This entry is that missing entity. The two diseases are
  genuinely distinct and are deliberately kept split: PRKAG2 cardiac syndrome
  (MONDO:0800484, HGNC:9386, verified with OAK) is a dominant, non-lysosomal
  cardiac glycogenosis in which constitutive AMP-kinase activation drives bulk
  glycogen and polyglucosan storage and the electrophysiological signature is
  ventricular pre-excitation with progressive atrioventricular block; CMH29 is
  a recessive proteostasis defect in which the primary storage species is
  desmin intermediate filament, the polyglucosan is a secondary and
  unexplained finding, and the electrophysiological signature is malignant
  ventricular arrhythmia without accessory pathways. PRKAG2 is one of the eight
  genes canonically associated with muscle polyglucosan storage in
  PMID:26278982; KLHL24 is not, and was reached only after the founding
  study's own nine-gene polyglucosan-storage panel had been excluded. Whether
  that nine-gene panel is exactly the 2015 review's eight genes plus one is
  not stated in the paper and is not asserted here. Nothing in
  `kb/disorders/PRKAG2_Cardiac_Syndrome.yaml` was modified.

  SCOPING AGAINST THE OTHER TWO KLHL24-BEARING FILES.
  `kb/disorders/Hypertrophic_Cardiomyopathy.yaml` carries KLHL24 as one row of
  a gene panel and cites the same ClinGen assertion quoted here; that file
  models sarcomeric HCM as a whole and does not model this entity's mechanism.
  `kb/disorders/Epidermolysis_Bullosa_Simplex.yaml` carries KLHL24 as a
  causative gene for the dominant skin disease and correctly describes the
  gain-of-function start-codon mechanism. Both were read and neither was
  modified. The allelic relationship between the dermatological entity
  (MONDO:0015006, EBS6, OMIM:617294, KLHL24, autosomal dominant - verified with
  OAK) and this one is curated below as a differential diagnosis and as a
  mechanism contrast, because it is the single most informative fact about this
  gene.

  LUMP-VS-SPLIT VERSUS SARCOMERIC HCM. This entity is kept split from
  `kb/disorders/Hypertrophic_Cardiomyopathy.yaml` on the same reasoning applied
  to PRKAG2 in this repository. The two share the gross phenotype of increased
  left ventricular wall thickness and diverge at every modelled level: the
  primary lesion (ubiquitin-ligase substrate adaptor versus contractile
  sarcomere protein), inheritance (recessive versus dominant), the
  histopathology (desmin and polyglucosan accumulation versus myofibre disarray
  with interstitial fibrosis), and the substrate of the hypertrophy
  (proteostatic accumulation versus contractile-protein dysfunction). ClinGen
  nonetheless curated the gene against the broad HCM term MONDO:0005045, which
  is why the ClinGen assertion is quoted here despite the term mismatch; that
  mismatch is stated explicitly wherever the assertion is cited.

  EVIDENCE BASE AND ITS LIMITS. This is a thin, single-founding-cohort disease
  and is curated as such. PMID:30715372 (Hedberg-Oldfors et al., Hum Mol Genet
  2019) is the only publication that describes the histopathology; it is the
  source of the OMIM entry and of every HPO annotation attached to
  OMIM:620236. Only its abstract is cached, so all histological,
  ultrastructural, clinical-table and demographic detail below - including the
  Iraqi and Iranian descent of the two founding families, which the full text
  states as "two families with autosomal recessive cardiomyopathy originating
  from Iraq (family A) and Iran (family B)" and tabulates per individual under
  "Descent" in Table 1 - is derived from the open-access full text
  (PMC6812045, read 2026-08-01) and is attributed to it inline rather than
  asserted with a snippet. Four subsequent independent families have been
  reported (PMID:36672924, PMID:40176835, PMID:42158087, PMID:41823911), which
  is what carries the gene-disease relationship past a single observation, but
  none of them repeats the muscle-biopsy work, so the polyglucosan finding that
  names the OMIM entity has never been independently replicated.

  NO GENEREVIEWS BASELINE EXISTS. No reference here carries `tags:
  [GeneReviews]` because there is no GeneReviews chapter for this entity. A
  PubMed E-utilities search on 2026-08-01 for `KLHL24 AND GeneReviews[book]`
  returns exactly one record, PMID:20301543 - the Epidermolysis Bullosa Simplex
  chapter, which covers the dominant start-codon KLHL24 disease (EBS6,
  MONDO:0015006) and not this recessive cardiomyopathy. That chapter is
  therefore not a baseline for this entry and is not cited as one; the
  dominant/recessive contrast it belongs to is instead curated below as a
  differential diagnosis.

  ANCESTRY VERSUS REPORTING CENTRE. Only two of those four reports state the
  family's descent: PMID:36672924 describes "consanguineous Middle Eastern
  families" and PMID:40176835 a "Brazilian family". PMID:42158087 and
  PMID:41823911 state no ancestry at all - the first describes only "two
  siblings in a non-consanguineous family" and the second only "a 16-year-old
  asymptomatic young man". Those two are therefore referred to throughout this
  entry by the country of the reporting centre (Chengdu, China and
  Thiruvananthapuram, India), which is a statement about where the case was
  published from and not about the patients' ancestry. Author affiliation is
  not an ancestry annotation and is not used as one here.

  DISCORDANT SOURCE, RESOLVED AGAINST THE PRIMARY DATA. The MedGen record for
  this concept (C5774308) lists Muscle weakness (HP:0001324) among its clinical
  features. That is misleading. The HPO annotation file for OMIM:620236
  (retrieved 2026-08-01 from
  https://ontology.jax.org/api/network/annotation/OMIM:620236) records
  HP:0001324 at 0/8 - that is, an explicitly EXCLUDED feature - and the primary
  paper states that no signs of muscular atrophy or weakness were found and
  that nerve conduction studies were normal. Muscle weakness is therefore NOT
  curated as a phenotype of this disease. The dissociation between severe
  skeletal muscle histopathology and absent skeletal muscle symptoms is
  recorded instead as a histopathology finding and as an open question.

  ICIMD CLASSIFICATION DELIBERATELY OMITTED. Despite the polyglucosan storage,
  this entry is not tagged with an inherited-metabolic-disorder category. No
  enzyme or regulator of glycogen metabolism is involved, the founding study's
  nine-gene polyglucosan-storage panel was sequenced and excluded, and the
  authors state that the pathogenesis of the storage is unknown. Classifying it
  as a glycogen-metabolism disorder would assert a mechanism nobody has
  demonstrated. `kb/disorders/PRKAG2_Cardiac_Syndrome.yaml`, where the
  metabolic lesion is established, does carry that tag; the contrast is
  intentional.

  FREQUENCY BANDS DELIBERATELY OMITTED FROM EVERY PHENOTYPE. HPO annotations
  for OMIM:620236 exist and carry exact fractions, but every one of them
  derives from the same two consanguineous families with denominators between 2
  and 11, and the denominators differ per feature because different individuals
  were investigated to different depths. One reclassified individual moves most
  features across a FrequencyEnum boundary. The exact fraction and its
  denominator are recorded in each phenotype's `notes:` instead, per the
  repository's guidance to omit rather than fabricate a band.

  COVERAGE OF THE HPO ANNOTATION SET. The annotation file for OMIM:620236
  (retrieved 2026-08-01 from
  https://ontology.jax.org/api/network/annotation/OMIM:620236) carries 13
  annotations, and every one of them is accounted for: ten are bound as
  phenotypes below, HP:0000007 Autosomal recessive inheritance is carried in
  the `inheritance:` block, HP:0011462 Young adult onset is carried as the
  `onset_category` of the Hypertrophic cardiomyopathy phenotype rather than as
  a separate feature, and HP:0001324 Muscle weakness is annotated at 0/8 - an
  excluded feature - and is therefore deliberately not curated, for the reasons
  set out above. Four further phenotypes below (Hypertrophic cardiomyopathy,
  Syncope, Ventricular arrhythmia, Congestive heart failure) and one
  histopathological phenotype (Cardiac polyglucosan accumulation) are curator
  additions from the primary literature that the annotation file does not
  carry; their `notes:` say so.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    CMH29 requires two damaged KLHL24 alleles. The founding report identified
    homozygous variants in two consanguineous families and showed that the
    parents of affected individuals were heterozygous carriers and unaffected;
    an additional branch of the Iranian family independently produced a
    homozygous affected offspring of heterozygous parents, which is what
    established the recessive pattern rather than assumed it. Subsequent
    families confirm the same architecture in a non-consanguineous setting: a
    Chinese sibship carried compound heterozygous variants inherited one from
    each clinically asymptomatic parent, and an Indian case carried compound
    heterozygous truncating variants with no family history of hypertrophic
    cardiomyopathy.

    This is the point of greatest clinical consequence in the entry. Because
    the disease is recessive and the parents are unaffected, a young adult with
    unexplained septal hypertrophy and no family history is exactly the
    presentation in which a dominant sarcomeric aetiology is assumed and in
    which KLHL24 will be missed unless the panel includes it. Penetrance in
    biallelic individuals appears complete on the evidence available - every
    reported homozygote or compound heterozygote had a demonstrable cardiac
    phenotype - but the total number of biallelic individuals ever described is
    small enough that this should be read as an absence of counterexamples
    rather than as a penetrance estimate. Heterozygous carriers are not
    reported to be affected, and no carrier phenotype has been sought
    systematically.

    Provenance for this assertion. The HPO annotation file for OMIM:620236
    records HP:0000007 sourced to PMID:30715372 (retrieved 2026-08-01), and the
    ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel curated
    the KLHL24 gene-disease relationship specifically under an AR mode of
    inheritance. No dominant mode of inheritance is asserted for this entity;
    the dominant KLHL24 disease is the allelic skin disorder EBS6
    (MONDO:0015006), curated below as a differential.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified homozygous mutations in KLHL24 in two consanguineous families with HCM"
    explanation: Homozygous variants segregating in two consanguineous families is the primary observation establishing autosomal recessive inheritance for this entity.
  - reference: CGGV:assertion_f1d4ce43-4c2d-41a0-b821-a11ac8eb8fca-2023-09-28T160000.000Z
    reference_title: "KLHL24 / hypertrophic cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KLHL24 | HGNC:25947 | hypertrophic cardiomyopathy | MONDO:0005045 | AR | Moderate"
    explanation: >-
      ClinGen's expert panel independently assigned an autosomal recessive mode
      of inheritance to the KLHL24 hypertrophic cardiomyopathy relationship.
      Note the term mismatch - ClinGen curated against the broad HCM term
      MONDO:0005045 rather than against MONDO:0859372 - so this row supports the
      gene, the MOI and the strength of evidence, not the entity boundary.
  - reference: PMID:40176835
    reference_title: "Coexistence of Rare Genetic Disorders in a Consanguineous Family: Case Study of KLHL24-Related Hypertrophic Cardiomyopathy and Char Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two sisters are diagnosed with autosomal recessive KLHL24-related hypertrophic cardiomyopathy"
    explanation: An independent consanguineous family, on a different continent from the founding families, replicates the recessive inheritance pattern.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Family verification revealed a recessive inheritance pattern, with each parent carrying one of the mutations."
    explanation: Compound heterozygosity in trans in a non-consanguineous family demonstrates that the recessive architecture is not an artefact of consanguinity or of a single founder haplotype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence or incidence estimate of any kind has been published for
    CMH29, and the 2026 case report cited below states that plainly. The total
    published experience consists of the two founding consanguineous families
    (11 young affected adults ascertained, of whom 8 are tabulated with clinical
    detail), plus four subsequent families - a Middle Eastern consanguineous
    family in a recessive-cardiomyopathy exome series, a Brazilian
    consanguineous family with two affected sisters, a non-consanguineous
    sibship of two reported from China, and a single adolescent reported from
    India. `NOT_YET_DOCUMENTED` is used rather than a qualitative band because
    there is no source to band, and `rate_per_100000` is deliberately left
    empty. Ascertainment to date is heavily weighted towards consanguineous
    populations and towards centres running broad exome-based cardiomyopathy
    panels, so the geographic distribution of reports reflects how the disease
    is found rather than where it occurs. Note that the last two reports state
    only the reporting centre, not the family's ancestry; see the
    ancestry-versus-reporting-centre note in the entry description.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is currently no epidemiological data on recessive-inherited hypertrophic cardiomyopathy type 29 caused by KLHL24 variants"
    explanation: An explicit statement from a 2026 report that no epidemiological data exist for this entity, which is the justification for NOT_YET_DOCUMENTED.
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Establishes the size of the founding cohort, which is the denominator behind every published clinical statistic about this disease.
pathophysiology:
- name: Biallelic Loss-of-Function KLHL24 Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The primary lesion is biallelic damage to KLHL24 at 3q27.1, reported against
    transcript NM_017644.3. The founding alleles are a homozygous nonsense
    variant c.1048G>T (p.Glu350*) in the Kelch-repeat region and a homozygous
    missense variant c.917G>A (p.Arg306His) at a residue conserved both across
    vertebrates and across the KLHL protein family. Later families add a
    frameshift in the BACK domain and a missense in the Kelch domain in trans,
    and compound heterozygous truncating alleles. All reported CMH29 genotypes
    therefore damage the BACK or Kelch portions of the protein - the substrate
    adaptor machinery - and none of them affects the translation initiation
    codon, which is the region mutated in the dominant skin disease. That
    positional separation is the structural basis of the allelic contrast that
    runs through this entry.

    The alleles behave as true loss of function rather than as
    dominant-negatives: heterozygous parents are unaffected, and both founding
    alleles failed to rescue zebrafish klhl24a knockdown when the equivalent
    substitutions were engineered into the fish transcript, whereas wild-type
    klhl24a mRNA did rescue.
  genes:
  - preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that mutations in KLHL24 cause HCM in humans."
    explanation: Establishes KLHL24 as the causal gene for this hypertrophic cardiomyopathy entity.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.532del frameshift variant truncates the BACK domain, resulting in complete loss of function (LOF) of the mutant allele."
    explanation: Assigns a reported CMH29 allele to a specific functional domain and classifies its consequence as complete loss of function, which is the variant class that defines this entity.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case demonstrates that biallelic, loss-of-function KLHL24 mutations can cause severe, early-onset recessive HCM, even in the absence of the cutaneous features typically associated with dominant gain-of-function variants."
    explanation: States the loss-of-function versus gain-of-function contrast directly and ties the cardiac-only presentation to the loss-of-function allele class.
  notes: >-
    Allelic detail. The variant coordinates, the 8.7 Mb and 3.4 Mb runs of
    homozygosity, the LOD score of 3.6 in the Iranian family, the absence of
    both alleles from the Greater Middle Eastern Variome and from 500
    ancestry-matched in-house exomes, and the KLHL24 Residual Variation
    Intolerance Score of -0.78 (13.22nd percentile) are all in the full text of
    PMID:30715372 (PMC6812045, read 2026-08-01) and not in the cached abstract,
    so they are recorded here rather than quoted.
  downstream:
  - target: Loss of CUL3-KLHL24 Substrate Adaptor Function
    description: >-
      Nonsense and frameshift alleles remove the substrate-binding apparatus
      outright; the p.Arg306His and p.Tyr505Cys missense alleles sit in
      conserved Kelch-repeat positions and are predicted to disrupt the
      substrate-binding pocket of the beta-propeller. Either way the CUL3
      complex loses its ability to select this adaptor's substrates.
- name: Loss of CUL3-KLHL24 Substrate Adaptor Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    KLHL24 is a BTB-BACK-Kelch protein. Its BTB and BACK domains dock onto
    CUL3, and its C-terminal six-bladed Kelch beta-propeller selects
    substrates; the assembled CUL3-RBX1-KLHL24 complex then transfers ubiquitin
    onto those substrates and commits them to the 26S proteasome. KLHL24 is not
    a housekeeping component of that machinery but a specificity module: which
    proteins are degraded depends on which Kelch adaptor is loaded. Losing
    KLHL24 therefore does not impair ubiquitination in general - it removes one
    branch of substrate selection, which is why the disease is
    tissue-restricted despite the ubiquity of the proteasome. KLHL24 is most
    highly expressed in skeletal muscle, then lung, then left ventricle, so the
    branch that is lost is the one that operates in striated muscle.
  genes:
  - preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  protein_complexes:
  - preferred_term: CUL3-RBX1-KLHL24 E3 ubiquitin ligase
    modifier: DECREASED
    term:
      id: GO:0031463
      label: Cul3-RING ubiquitin ligase complex
  molecular_functions:
  - preferred_term: ubiquitin-protein transferase activity
    modifier: DECREASED
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
  biological_processes:
  - preferred_term: substrate polyubiquitination by the CUL3-KLHL24 ligase
    modifier: DECREASED
    term:
      id: GO:0000209
      label: protein polyubiquitination
  - preferred_term: proteasomal degradation of KLHL24 substrates
    modifier: DECREASED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases."
    explanation: Establishes the molecular function of the gene product as a substrate-selecting adaptor for a Cullin-RING E3 ubiquitin ligase.
  - reference: PMID:41348940
    reference_title: "KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase."
    explanation: >-
      Independent statement of the substrate-adaptor function from a cardiac
      rather than a dermatological group. Tagged OTHER rather than IN_VITRO
      because this sentence sits in the paper's AIMS section and is background
      framing of established biology, not a result generated by the study's own
      hiPSC experiments.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24 encodes a substrate adaptor of the Cullin3 (CUL3) E3 ubiquitin ligase complex, with two core functional domains: the N-terminal BACK domain and the C-terminal KELCH repeat domain"
    explanation: Names the two functional domains that CMH29 alleles disrupt and identifies CUL3 as the cullin scaffold, which is the structural basis for treating these variants as adaptor-function loss.
  notes: >-
    The tissue-expression ranking (skeletal muscle > lung > left ventricle,
    GTEx v6p) is reported in the full text of PMID:30715372 (PMC6812045, read
    2026-08-01) and is not in the cached abstract, so it is recorded here
    rather than quoted. Note that this expression pattern is itself part of
    the disease's unexplained anatomy: the tissue with the highest expression,
    skeletal muscle, is the one that is histologically abnormal but clinically
    silent.
  downstream:
  - target: Failure of Desmin Intermediate Filament Turnover
    description: >-
      The only KLHL24 substrate identified in striated muscle is desmin. With
      the adaptor gone, desmin escapes ubiquitin-dependent clearance and
      accumulates.
  - target: Intermyofibrillar Glycogen and Polyglucosan Storage
    description: >-
      An unexplained parallel consequence. The stored polysaccharide appears in
      the same intermyofibrillar compartment as the accumulated filaments, but
      no mechanistic link between adaptor loss and polysaccharide handling has
      been demonstrated, and this edge is asserted only as temporal and spatial
      co-occurrence.
- name: Failure of Desmin Intermediate Filament Turnover
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Desmin is the muscle-specific type III intermediate filament that links
    adjacent Z-discs to each other, to the sarcolemma at costameres, and to
    mitochondria and nuclei, transmitting force laterally and maintaining
    myofibrillar register. It is a dynamic polymer whose subunits are
    continuously exchanged, and that exchange requires a route for disposal of
    displaced subunits. KLHL24 supplies that route in muscle: it is the cardiac
    and skeletal-muscle counterpart of the KLHL24-keratin-14 relationship
    characterised in basal keratinocytes, desmin standing to the myocyte as
    keratin-14 stands to the keratinocyte.

    In KLHL24-null myocytes the polymer is not disposed of. Immunohistochemistry
    on heart and skeletal muscle from the founding families showed desmin
    accumulating in the intermyofibrillar and subsarcolemmal spaces, electron
    microscopy resolved irregularly arranged 8-12 nm filaments in the same
    compartment, and Western blotting showed desmin markedly upregulated in
    both tissues relative to controls. This is the inverse of the lesion in
    KLHL24 gain-of-function disease, in which desmin is depleted roughly
    tenfold in patient-derived engineered heart tissue and in explanted
    myocardium. The same protein pair therefore produces two cardiomyopathies
    of opposite morphology depending on the direction in which turnover fails.
  genes:
  - preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: desmin intermediate filament
    modifier: INCREASED
    term:
      id: GO:0005882
      label: intermediate filament
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  biological_processes:
  - preferred_term: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."
    explanation: Direct human tissue evidence that loss of KLHL24 results in accumulation rather than clearance of desmin intermediate filaments in both affected striated muscles.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including desmin—the cardiac homolog of keratin-14"
    explanation: States the substrate correspondence that makes desmin the expected cardiac substrate of KLHL24, by analogy with the keratin-14 relationship established in skin.
  - reference: PMID:34292882
    reference_title: "Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients' explanted heart."
    explanation: >-
      Establishes the opposite pole of the same axis. Excess KLHL24 activity
      depletes cardiac desmin; this entity's loss of KLHL24 activity is
      accompanied by desmin accumulation. Marked as supporting because it
      demonstrates that desmin abundance in cardiomyocytes is set by KLHL24
      activity, which is the premise of this node.
  - reference: PMID:41348940
    reference_title: "KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts."
    explanation: >-
      Extends the KLHL24 cardiac substrate set beyond desmin to synemin and
      vimentin. Cited here because it identifies which proteins are under
      KLHL24 control in the heart; the direction of change in that system is
      the gain-of-function direction, not this entity's.
  notes: >-
    The immunohistochemistry, the 8-12 nm filament measurement, and the
    desmin immunoblot are in the full text and figures of PMID:30715372
    (PMC6812045, read 2026-08-01) and not in the cached abstract, so they are
    described here rather than quoted. The immunoblot comparison carries a
    caveat the paper itself states in the Figure 5 legend: control 3 is a
    normal heart, whereas control 4 is a heart explant from a patient with a
    different cardiomyopathy "with an expected moderate upregulation of
    desmin". The assay therefore reads against both a normal and a
    failing-myocardium baseline, and the second of those is not a
    desmin-normal comparator.
  downstream:
  - target: Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling
    description: >-
      Accumulated intermediate filament protein contributes to the increase in
      myocyte size and to the mechanical stiffening that produces a
      small-cavity, thick-walled ventricle.
  - target: Myocardial Fibrosis and Focal Macrophage Infiltration
    description: >-
      Myocytes burdened with filamentous and polysaccharide inclusions attract
      focal macrophage infiltration and are replaced by patchy scar.
  - target: Skeletal Muscle Cogwheel Fibre Pathology
    description: >-
      The same substrate failure occurs in skeletal muscle, where KLHL24
      expression is highest, producing striking histological change without
      clinical weakness.
- name: Intermyofibrillar Glycogen and Polyglucosan Storage
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Alongside the accumulated filaments, the intermyofibrillar space of CMH29
    cardiomyocytes fills with glycogen and with discrete polyglucosan bodies -
    periodic-acid-Schiff-positive material that resists alpha-amylase
    digestion, identifying it as the amylopectin-like, poorly branched,
    poorly soluble polysaccharide called polyglucosan rather than as ordinary
    glycogen. Skeletal muscle shows the same focal subsarcolemmal and
    intermyofibrillar glycogen accumulation.

    This node is deliberately marked HYPOTHETICAL, because its mechanism is
    genuinely unknown and the founding authors say so. Cardiomyopathies with
    polyglucosan accumulation are otherwise essentially confined to disorders
    of glycogen metabolism, and eight genes are canonically associated with
    muscle polyglucosan storage - GYG1, GBE1, RBCK1, PFKM, EPM2A, EPM2B,
    PRDM8 and PRKAG2. None of those was mutated in the founding families; a
    dedicated nine-gene polyglucosan-storage panel was screened and excluded
    before KLHL24 was reached. KLHL24 has no known role in glycogen metabolism,
    and no experiment has connected loss of its ligase-adaptor function to
    polysaccharide handling. Three explanations remain open and are set out in
    the knowledge-gap discussion below. Until one is demonstrated, the
    polyglucosan is curated as a reproducible diagnostic marker of the disease
    and as an unexplained co-occurrence, not as a step in the causal chain.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  chemical_entities:
  - preferred_term: polyglucosan (amylopectin-like polysaccharide)
    modifier: INCREASED
    term:
      id: CHEBI:28057
      label: amylopectin
  - preferred_term: glycogen
    modifier: INCREASED
    term:
      id: CHEBI:28087
      label: glycogen
  biological_processes:
  - preferred_term: glycogen metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0005977
      label: glycogen metabolic process
  evidence:
  - reference: PMID:26278982
    reference_title: "Polyglucosan storage myopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2."
    explanation: >-
      Enumerates the canonical polyglucosan-storage gene set, written by the
      same group that later described CMH29. KLHL24 is absent from it, which is
      what makes the polyglucosan in this disease anomalous rather than
      expected.
  - reference: PMID:26278982
    reference_title: "Polyglucosan storage myopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Polyglucosan is an amylopectin-like polysaccharide associated with defective glycogen metabolism and, unlike normal glycogen, it is to some extent resistant to"
    explanation: Defines the stored material and the biochemical property - resistance to amylase digestion - on which its histological identification depends.
  - reference: PMID:26278982
    reference_title: "Polyglucosan storage myopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These diseases frequently involve both skeletal and cardiac muscle tissue, causing myopathy with muscle weakness and wasting, and cardiomyopathy with arrhythmia, conduction block, and cardiac failure."
    explanation: >-
      Marked PARTIAL. The cardiac half of this description - arrhythmia and
      cardiac failure with skeletal muscle involvement - matches CMH29 closely,
      but the skeletal muscle weakness and wasting that characterise the
      classical polyglucosan storage myopathies were explicitly absent in the
      CMH29 families, so the analogy holds only in part.
  notes: >-
    The PAS and PAS-diastase histochemistry, the electron microscopy, the
    exclusion of the nine-gene polyglucosan panel, and the authors' statement
    that "the pathogenesis of the polyglucosan storage in our patients remains
    unknown but may serve as a diagnostic marker" are all in the full text of
    PMID:30715372 (PMC6812045, read 2026-08-01). Only the abstract of that
    paper is cached, and the abstract does not mention polyglucosan at all, so
    none of this is quotable and all of it is recorded as notes. A PubMed
    search for `KLHL24 AND polyglucosan` on 2026-08-01 returned zero records,
    which is a direct measure of how little attention this feature has had
    since 2019 despite naming the OMIM entity.
  downstream:
  - target: Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling
    description: >-
      Stored polysaccharide adds mass and volume to the myocyte independently
      of contractile-protein content, contributing to wall thickening that is
      partly storage rather than partly true hypertrophy.
- name: Sarcoplasmic Reticulum-Derived Tubular Aggregation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A third species accumulates in the same intermyofibrillar compartment:
    arrays of tubular membranous structures. Their origin was inferred
    histochemically in the founding study - the accumulated material stained
    for NADH-tetrazolium reductase but was negative for succinate
    dehydrogenase, a combination that indicates sarcoplasmic reticulum rather
    than mitochondria. This matters clinically as well as mechanistically,
    because it excludes a mitochondrial myopathy from the differential on the
    biopsy itself, and it is consistent with a disease of proteostasis
    spreading to membrane-compartment organisation rather than a primary
    bioenergetic lesion. It is marked PROVISIONAL because the inference rests
    on a histochemical staining pattern in one study and has not been confirmed
    by marker immunolocalisation or by any subsequent report.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  cellular_components:
  - preferred_term: sarcoplasmic reticulum
    modifier: ABNORMAL
    term:
      id: GO:0016529
      label: sarcoplasmic reticulum
  notes: >-
    No evidence item is attached. The NADH-TR-positive, SDH-negative staining
    pattern and the electron-microscopic description of tubular structures are
    in the full text and figures of PMID:30715372 (PMC6812045, read
    2026-08-01); the cached abstract says only "characteristic alterations" and
    does not mention tubules or sarcoplasmic reticulum, so quoting it here
    would be a claim/snippet mismatch.
  downstream:
  - target: Ventricular Electrical Instability and Malignant Arrhythmia
    description: >-
      Disorganisation of the sarcoplasmic reticulum is a plausible contributor
      to the arrhythmic phenotype through disturbed calcium handling, but this
      edge is an inference rather than a demonstrated link and no calcium
      measurements have been made in this disease.
- name: Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The myocyte enlarges. The founding heart explant and endomyocardial
    biopsies showed myocyte hypertrophy, and the HPO annotation set records
    cardiomyocyte hypertrophy in both individuals examined histologically. At
    organ level this produces the picture that brings patients to attention:
    severe septal thickening, a small left ventricular cavity, a reduced left
    ventricular end-systolic diameter, systolic anterior motion of the mitral
    valve and dynamic left ventricular outflow tract obstruction, with ejection
    fraction preserved or supranormal early on.

    Two things distinguish this hypertrophy from sarcomeric HCM. First, part of
    the wall thickness is storage rather than contractile mass - accumulated
    filaments, polysaccharide and membrane occupy the intermyofibrillar space.
    Second, myofibre disarray, the histological hallmark of sarcomeric HCM, is
    not what the biopsies show; what they show is intermyofibrillar
    accumulation. The clinical phenotype is nevertheless indistinguishable at
    the echocardiogram, which is precisely why the disease is missed.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    modifier: INCREASED
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."
    explanation: Describes the characteristic imaging phenotype - asymmetric septal hypertrophy with preserved systolic function - in an independently reported biallelic KLHL24 case.
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that mutations in KLHL24 cause HCM in humans."
    explanation: Establishes that the organ-level phenotype produced by biallelic KLHL24 loss is hypertrophic cardiomyopathy.
  notes: >-
    The per-individual echocardiographic measurements - septal wall thickness
    from 0.9 to 4.0 cm, left ventricular end-diastolic volumes as low as 30 mL,
    outflow gradients of 48 and 112 mmHg - are tabulated in the full text of
    PMID:30715372 (PMC6812045, read 2026-08-01) and are not quotable from the
    cached abstract. They are cited here as the source of the "small cavity,
    thick wall" description rather than reproduced as asserted figures.
  downstream:
  - target: Ventricular Electrical Instability and Malignant Arrhythmia
    description: >-
      Hypertrophied, inclusion-laden myocardium with patchy scar is the
      substrate on which re-entrant ventricular arrhythmia arises.
  - target: Progression to Systolic Failure and Transplantation
    description: >-
      A subset progress from the hypertrophic, preserved-ejection-fraction
      phase to ventricular dilatation, akinetic regions and systolic failure.
- name: Myocardial Fibrosis and Focal Macrophage Infiltration
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The CMH29 heart develops patchy interstitial fibrosis, and the founding
    explant showed small CD68-positive macrophage infiltrates that were
    preferentially associated with polyglucosan-containing myocytes. That
    spatial association suggests the inclusions themselves recruit the
    infiltrate - an inclusion-triggered innate response rather than a diffuse
    inflammatory cardiomyopathy - but the observation is from one explanted
    heart and has not been replicated. The extent of fibrosis is variable: the
    founding explant showed patchy scar, one independently reported adolescent
    had minimal fibrosis despite severe hypertrophy, while another young adult
    had extensive late-gadolinium-enhancement-positive septal scar. Fibrosis
    burden therefore does not track hypertrophy severity in this disease, which
    is one reason conventional imaging-based risk scores behave poorly in it.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: CD68-positive macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."
    explanation: Documents the low-fibrosis end of the range in a genetically confirmed biallelic case, which is the observation that decouples fibrosis burden from hypertrophy severity here.
  - reference: PMID:41348940
    reference_title: "KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature."
    explanation: >-
      Marked PARTIAL because the experimental system carries the
      gain-of-function allele, not the biallelic loss-of-function genotype of
      this entity. It establishes that KLHL24 dysfunction in cardiac tissue
      generates a fibrotic programme, and that cardiac fibroblasts as well as
      cardiomyocytes are affected cell types, but the direction of substrate
      change is opposite to this disease's. Tagged OTHER rather than IN_VITRO
      because this proteomic result is drawn from mixed sources - the abstract
      states that the authors "integrated clinical data with proteomic analyses
      of heart tissue as well as human induced pluripotent stem cell (hiPSC)
      models" and that the hiPSC-cardiomyocyte mass spectrometry "mirrored the
      proteomic profile of their corresponding left ventricle tissue samples" -
      so patient left-ventricle tissue and hiPSC material both contribute and
      no single evidence_source describes it. The purely hiPSC-derived result
      from the same paper is cited separately, under Failure of Desmin
      Intermediate Filament Turnover, and remains tagged IN_VITRO.
  notes: >-
    The CD68 immunostaining, the van Gieson-stained patchy fibrosis and the
    association of macrophage infiltrates with polyglucosan-containing myocytes
    are in the full text and figures of PMID:30715372 (PMC6812045, read
    2026-08-01), not in the cached abstract. The contrasting
    extensive-scar case is in the cached full text of PMID:42158087, which
    reports multifocal mid-wall late gadolinium enhancement in the septum of
    the younger sibling; the exact wording there contains PDF ligature
    artefacts, so it is described rather than quoted.
- name: Ventricular Electrical Instability and Malignant Arrhythmia
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    This is the node that determines prognosis, and it is the feature that most
    distinguishes CMH29 from ordinary hypertrophic cardiomyopathy. Three of the
    11 young adults in the founding cohort died suddenly, at ages 20, 26 and
    26; several others received implantable cardioverter-defibrillators in
    their twenties or thirties. Electrocardiography in the founding families
    showed generalised ST-T change, QRS durations at or above the upper limit
    of normal (120, 125 and 154 ms in the three individuals with a recorded
    value), one prolonged PR interval of 210 ms, and frequent episodes of
    non-sustained ventricular tachycardia in one individual - a pattern of both
    conduction-system involvement and ventricular ectopy. The other three
    recorded PR intervals were 186, 188 and 194 ms, so PR prolongation is not a
    consistent feature and should not be used as a diagnostic pointer. The arrhythmic risk is disproportionate to structural
    severity and can precede it, which is a genuine departure from the standard
    HCM risk model.

    Mechanistically this is attributed to failure of cytoskeletal protein
    turnover: the desmin network normally couples the sarcolemma, Z-disc and
    intercalated disc, and its disorganisation disturbs both mechanical
    coupling and, plausibly, the sarcoplasmic reticulum-dependent calcium
    handling that underlies the cardiac action potential. That mechanistic
    account is stated in the literature but has not been tested experimentally
    in a biallelic loss-of-function system.
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: ABNORMAL
    term:
      id: GO:0061337
      label: cardiac conduction
  - preferred_term: cardiac muscle cell action potential
    modifier: ABNORMAL
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Quantifies the arrhythmic mortality in the founding cohort, which is the primary evidence that this disease is lethally arrhythmogenic in young adulthood.
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24 (Kelch-like family member 24)-associated hypertrophic cardiomyopathy (HCM) is a recently recognized genetic disorder characterized by early presentation and a disproportionate risk of malignant ventricular arrhythmias due to impaired cytoskeletal protein turnover."
    explanation: States both the disproportionate arrhythmic risk and the proposed mechanistic attribution to impaired cytoskeletal protein turnover.
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24-associated HCM is uniquely arrhythmogenic, with malignant ventricular arrhythmias potentially preceding structural severity."
    explanation: Supports the specific claim that arrhythmic risk in this disease is decoupled from, and may precede, structural severity.
- name: Progression to Systolic Failure and Transplantation
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Not every individual stays in the hypertrophic, preserved-ejection-fraction
    phase. One of the two Iraqi siblings developed a moderately dilated left
    ventricle with regional akinesia and an ejection fraction of 25 percent,
    and underwent cardiac transplantation at 26; her brother, whose
    echocardiogram was recorded at 28, retained an ejection fraction of 50
    percent. In the independently reported non-consanguineous sibship of
    PMID:42158087, the proband's ejection fraction fell progressively from 77
    to 55 percent over two years of follow-up with the emergence of definite
    diastolic dysfunction. A separate exome series describing a consanguineous
    Middle Eastern family reported the KLHL24 phenotype as a mixture of dilated
    and hypertrophic features with non-compaction, which suggests that the
    hypertrophic-to-dilated transition may be part of the natural history of
    the gene rather than an idiosyncrasy of one family.

    This is marked PROVISIONAL because the number of individuals followed
    longitudinally is very small and the reported phenotypes span hypertrophic,
    dilated and non-compaction morphology without a clear ordering in time.
  biological_processes:
  - preferred_term: heart contraction
    modifier: DECREASED
    term:
      id: GO:0060047
      label: heart contraction
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Documents progression to transplant-requiring heart failure as one of the two ways this disease kills or disables young adults.
  - reference: PMID:36672924
    reference_title: "Genetic Insights from Consanguineous Cardiomyopathy Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features"
    explanation: An independent family in which the biallelic KLHL24 phenotype is not purely hypertrophic, supporting a broader morphological spectrum that includes ventricular dilatation.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serial clinical evaluations showed progressive left ventricular hypertrophy, diastolic dysfunction, and a gradual decline in left ventricular ejection fraction."
    explanation: Longitudinal documentation of declining systolic function in a genetically confirmed biallelic case, supporting progression as a feature of the natural history.
- name: Skeletal Muscle Cogwheel Fibre Pathology
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    KLHL24 is expressed more highly in skeletal muscle than in heart, and
    skeletal muscle in CMH29 is unambiguously abnormal - yet it is clinically
    silent. Muscle biopsies from three individuals across both founding
    families showed focal subsarcolemmal and intermyofibrillar accumulation of
    glycogen and desmin, distributed so as to give the fibre periphery a jagged
    outline that the authors named the "cogwheel" fibre and proposed as a
    diagnostic marker. Both type 1 and type 2 fibres were affected. Against
    this, no individual had muscle weakness or wasting and nerve conduction
    studies were normal.

    This dissociation is one of the two central unexplained features of the
    disease, alongside the polyglucosan, and it is why this node sits outside
    the causal chain to the cardiac phenotype rather than upstream of it. Its
    practical value is diagnostic: a skeletal muscle biopsy in a young adult
    with unexplained hypertrophic cardiomyopathy is low-morbidity relative to
    endomyocardial biopsy and, if the cogwheel pattern is present, points
    directly at this gene.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."
    explanation: Confirms that skeletal muscle, not only myocardium, carries the desmin accumulation, which is the basis for treating skeletal muscle biopsy as a diagnostic route.
  notes: >-
    The term "cogwheel" fibre, the type 1 and type 2 fibre involvement, the
    proposal of the pattern as a diagnostic marker, and the explicit statement
    that no muscular atrophy or weakness was found and nerve conduction studies
    were normal are all in the full text of PMID:30715372 (PMC6812045, read
    2026-08-01). None is in the cached abstract. The HPO annotation file for
    OMIM:620236 independently records Muscle weakness (HP:0001324) at 0/8,
    corroborating the absence of weakness.
genetic:
- name: KLHL24
  association: Biallelic loss-of-function variants (homozygous or compound heterozygous) in the BACK and Kelch domains
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  notes: >-
    Nomenclature and locus. hgnc:25947 is symbol KLHL24, kelch-like family
    member 24, at 3q27.1 (verified with `runoak -i sqlite:obo:hgnc info
    hgnc:25947` and against the MONDO gene association for MONDO:0859372,
    2026-08-01). Reference transcript in both the founding report and the most
    recent case report is NM_017644.3.

    Allelic architecture, and the positional rule that separates the two KLHL24
    diseases. The recessive cardiac alleles reported to date are the homozygous
    nonsense c.1048G>T (p.Glu350*) and homozygous missense c.917G>A
    (p.Arg306His) of the founding families, and the compound heterozygous
    frameshift c.532del (p.His178Ilefs*66) in the BACK domain with missense
    c.1514A>G (p.Tyr505Cys) in the Kelch domain reported in the
    non-consanguineous sibship of PMID:42158087.
    Every one of these lies well downstream of the start codon, in the domains
    that dock CUL3 and select substrates. The dominant skin alleles, by
    contrast, are confined to the translation initiation codon and its
    immediate vicinity - c.1A>G, c.1A>T, c.2T>C, c.2T>G, c.3G>A, c.3G>C,
    c.3G>T - plus, as later shown, any nonsense-inducing change in c.4_84 that
    permits translation re-initiation at Met29. The rule is therefore
    positional as well as functional: variants that abolish the normal start
    codon and allow re-initiation produce a stabilised, hyperactive
    KLHL24-deltaN28 and dominant disease; variants that damage the body of the
    protein produce a dead adaptor and recessive disease. A diagnostic
    laboratory reporting a KLHL24 variant cannot assign a phenotype from the
    gene alone, and must read the position and the zygosity.

    Gene-disease validity. ClinGen's Hereditary Cardiovascular Disease Gene
    Curation Expert Panel classified KLHL24 as MODERATE for hypertrophic
    cardiomyopathy under autosomal recessive inheritance in September 2023, and
    the panel's 2025 reappraisal publication lists KLHL24 among the newly
    curated genes reaching moderate evidence. Moderate, not definitive or
    strong, is the honest state of this gene: the human genetic evidence is
    several small families and the experimental evidence is a zebrafish
    morpholino knockdown with allele-specific rescue failure. That is enough to
    justify including KLHL24 on a hypertrophic cardiomyopathy panel and
    reporting biallelic loss-of-function variants, and not enough to treat a
    single biallelic finding as diagnostic without phenotype correlation.

    Not asserted, deliberately. No gnomAD constraint metric (pLI, o/e LoF,
    missense Z) is recorded anywhere in this entry, because none was retrieved
    from a primary source during this curation. The founding paper's Residual
    Variation Intolerance Score is recorded in the pathophysiology notes with
    its source rather than restated as a constraint claim. No founder allele,
    modifier locus, methylation episignature, digenic contribution or somatic
    mechanism has been described for this disease and none is asserted.
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that mutations in KLHL24 cause HCM in humans."
    explanation: The founding gene-disease assertion for this entity.
  - reference: CGGV:assertion_f1d4ce43-4c2d-41a0-b821-a11ac8eb8fca-2023-09-28T160000.000Z
    reference_title: "KLHL24 / hypertrophic cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KLHL24 | HGNC:25947 | hypertrophic cardiomyopathy | MONDO:0005045 | AR | Moderate"
    explanation: >-
      ClinGen expert-panel gene-disease validity classification, recording
      autosomal recessive inheritance and Moderate strength of evidence under
      SOP9. Curated against MONDO:0005045, the broad HCM term, not against
      MONDO:0859372.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive)."
    explanation: The published form of the ClinGen reappraisal, placing KLHL24 at moderate evidence among newly curated hypertrophic cardiomyopathy genes.
  - reference: PMID:34526680
    reference_title: "Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients"
    explanation: Places KLHL24 in the class of non-sarcomeric hypertrophic cardiomyopathy genes, each accounting for a small number of patients, which is the correct framing of its contribution to the HCM genetic spectrum.
phenotypes:
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  diagnostic: true
  description: >-
    Unexplained left ventricular hypertrophy is the presenting and defining
    phenotype. The morphology is that of classical hypertrophic cardiomyopathy
    - a thick-walled, small-cavity ventricle with preserved or supranormal
    ejection fraction early on - which is why the disease is diagnosed as
    sarcomeric HCM until sequencing says otherwise. Reported wall thicknesses
    reach extremes: septal thickness of 4.0 cm in one founding-family
    individual and interventricular septal thickness of 38 to 42 mm in an
    independently reported adolescent.

    Onset is characteristically in the late teens to late twenties. Recorded
    ages of onset in the founding families were 16, 19, 21, 24 and 28 years,
    and independently reported probands presented at 16, 18 and 20. The
    combination of a young age at presentation, severe hypertrophy and no
    dominant family history is the clinical signature that should prompt
    consideration of a recessive non-sarcomeric gene.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
    clinical_course: PROGRESSIVE
    onset:
      onset_category: YOUNG_ADULT
      min_age_years: 16.0
      max_age_years: 28.0
      notes: >-
        The HPO annotation file for OMIM:620236 records Young adult onset
        (HP:0011462) at 5/5, sourced to PMID:30715372 (retrieved 2026-08-01) -
        that is, in every individual for whom an age of onset was determinable.
        The 16 to 28 year range comes from the founding cohort's clinical table
        (PMC6812045, read 2026-08-01) together with the more recent reports,
        two of which describe presentations at 16 and 18 years. Those are
        adolescent rather than young adult, so the HPO category may narrow the
        true onset window.
  notes: >-
    No FrequencyEnum band is asserted; see the entry-level notes. The wall
    thickness figures are from the clinical tables in the full text of
    PMID:30715372 (PMC6812045, read 2026-08-01) and from the cached full text
    of PMID:42158087 respectively.
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that mutations in KLHL24 cause HCM in humans."
    explanation: Directly asserts hypertrophic cardiomyopathy as the phenotype produced by KLHL24 mutation in humans.
- name: Asymmetric septal hypertrophy
  category: Cardiovascular
  diagnostic: true
  description: >-
    The hypertrophy is predominantly septal and asymmetric in most reported
    individuals, which is the pattern that generates dynamic outflow tract
    obstruction and systolic anterior motion of the mitral valve. It is present
    in adolescents who are entirely asymptomatic, and is often the finding that
    triggers investigation after an incidental murmur or a family screening
    echocardiogram.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0001670 at 3/8, sourced
    to PMID:30715372 (retrieved 2026-08-01). No FrequencyEnum band is asserted;
    the denominator of 8 is the number of individuals with tabulated clinical
    data, not the number with echocardiography, and three of those eight have
    "not determined" in one or more echocardiographic fields.
  evidence:
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging revealed asymmetric septal hypertrophy with minimal fibrosis and preserved systolic function."
    explanation: Documents asymmetric septal hypertrophy in a genetically confirmed biallelic KLHL24 case.
- name: Left ventricular outflow tract obstruction
  category: Cardiovascular
  description: >-
    Dynamic obstruction of the left ventricular outflow tract follows from the
    combination of septal hypertrophy, a small cavity and systolic anterior
    motion of the mitral valve. Measured resting gradients in the founding
    families were substantial - 48 mmHg in one individual and 112 mmHg in
    another - and obstruction is the main determinant of exertional symptoms.
    It is not universal: several individuals with severe hypertrophy had no
    outflow gradient.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0032092 at 3/8, sourced
    to PMID:30715372 (retrieved 2026-08-01). The gradient values are from the
    clinical table in the full text (PMC6812045, read 2026-08-01) and are not
    quotable from the cached abstract. No FrequencyEnum band is asserted, and
    no evidence item is attached because neither the cached abstract of the
    founding paper nor any other cached source states this finding.
- name: Systolic anterior motion of the mitral valve
  category: Cardiovascular
  description: >-
    Systolic anterior motion of the mitral valve leaflet into the outflow tract
    is the mechanical basis of the dynamic obstruction and, with it, of the
    associated mitral regurgitation. It was described as moderate to severe in
    the affected individuals in whom it was present.
  phenotype_term:
    preferred_term: Systolic anterior motion of the mitral valve
    term:
      id: HP:0031656
      label: Systolic anterior motion of the mitral valve
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0031656 at 4/8, sourced
    to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached
    abstract, so no evidence item is attached. No FrequencyEnum band is
    asserted.
- name: Mitral regurgitation
  category: Cardiovascular
  description: >-
    Mitral regurgitation in this disease is secondary rather than primary -
    the valve is structurally normal and the leak follows from systolic
    anterior motion and outflow obstruction. It ranged from mild to moderate in
    the reported individuals. Its importance is chiefly that it is one more
    feature indistinguishable from sarcomeric hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0001653 at 3/8, sourced
    to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached
    abstract, so no evidence item is attached. No FrequencyEnum band is
    asserted.
- name: Reduced left ventricular endsystolic diameter
  category: Cardiovascular
  description: >-
    A small, obliterating left ventricular cavity is a consistent and
    under-appreciated feature. Left ventricular end-diastolic volumes as low as
    30 to 47 mL were recorded in the Iranian family, and in an independently
    reported case the cavity was described as severely obliterated. It
    contributes to diastolic dysfunction and to the low stroke volume that
    underlies exertional symptoms even when ejection fraction is normal or
    high.
  phenotype_term:
    preferred_term: Reduced left ventricular endsystolic diameter
    term:
      id: HP:0034386
      label: Reduced left ventricular endsystolic diameter
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0034386 at 5/7, sourced
    to PMID:30715372 (retrieved 2026-08-01), which is the highest-frequency
    structural feature in the annotation set. The volume figures are from the
    full-text clinical table (PMC6812045, read 2026-08-01). Not mentioned in
    the cached abstract, so no evidence item is attached.
- name: Syncope
  category: Cardiovascular
  diagnostic: true
  description: >-
    Recurrent syncope is one of the two commonest presenting symptoms and, in a
    young adult with hypertrophic remodelling, is the symptom that should
    trigger urgent arrhythmic risk assessment rather than reassurance. In one
    independently reported proband it was the presenting complaint at age 20
    and led directly to pacemaker implantation.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
    temporality: RECURRENT
  notes: >-
    Recurrent syncope is named in the OMIM/MedGen clinical description of
    CMH29 (MedGen C5774308, retrieved 2026-08-01) and in the founding paper's
    text, but it is not separately annotated in the HPO annotation file for
    OMIM:620236, so no fraction is available.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband, a 30-year-old male, initially presented with recurrent syncope at the age of 20, leading to the implantation of a permanent pacemaker."
    explanation: Documents recurrent syncope as the presenting feature in a genetically confirmed biallelic KLHL24 case, at an age typical for this disease.
- name: Palpitations
  category: Cardiovascular
  description: >-
    Palpitations were among the initial symptoms in most affected individuals
    in the founding families and are the subjective correlate of the ventricular
    ectopy and non-sustained ventricular tachycardia documented on monitoring.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0001962 at 5/7, sourced
    to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached
    abstract, so no evidence item is attached. No FrequencyEnum band is
    asserted.
- name: Dyspnea
  category: Cardiovascular
  description: >-
    Exertional dyspnoea reflects diastolic dysfunction in a small, stiff
    ventricle and, where present, dynamic outflow obstruction. One founding
    individual was in NYHA class III at presentation.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0002094 at 5/7, sourced
    to PMID:30715372 (retrieved 2026-08-01). Not mentioned in the cached
    abstract, so no evidence item is attached. No FrequencyEnum band is
    asserted.
- name: Ventricular arrhythmia
  category: Cardiovascular
  diagnostic: true
  description: >-
    Malignant ventricular arrhythmia is the phenotype that makes this disease
    dangerous, and the literature is explicit that its risk is out of
    proportion to structural severity. Frequent episodes of non-sustained
    ventricular tachycardia were documented in a founding-family individual who
    later required transplantation, and an independently reported adolescent
    with low conventional risk markers received a prophylactic implantable
    cardioverter-defibrillator on genotype grounds alone.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  notes: >-
    Bound to HP:0004308 (Ventricular arrhythmia) rather than to the parent
    HP:0011675 (Arrhythmia) or to the more specific HP:0004756 (Ventricular
    tachycardia): the reported events span non-sustained ventricular
    tachycardia, defibrillator-treated events and unwitnessed sudden death, so
    the ventricular-arrhythmia level is the most specific term the evidence
    supports for the disease as a whole. Both alternatives were checked with
    OAK. No FrequencyEnum band is asserted; the HPO annotation file for
    OMIM:620236 carries no ventricular-arrhythmia term.
  evidence:
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24-associated HCM is uniquely arrhythmogenic, with malignant ventricular arrhythmias potentially preceding structural severity."
    explanation: Asserts malignant ventricular arrhythmia as a defining feature of this genotype and states that it may precede structural severity.
- name: Sudden cardiac death
  category: Cardiovascular
  diagnostic: true
  description: >-
    Sudden cardiac death in the third decade is the single most consequential
    outcome of this disease. In the founding cohort three of eleven affected
    young adults died suddenly, at ages 20, 26 and 26. Because inheritance is
    recessive, an affected individual's siblings carry a one-in-four risk and
    may be entirely asymptomatic with severe hypertrophy already present, which
    is what makes cascade screening urgent rather than routine.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0001645 at 3/11, sourced
    to PMID:30715372 (retrieved 2026-08-01). No FrequencyEnum band is asserted,
    but note that this denominator of 11 is the largest in the annotation set
    and refers to all ascertained affected adults rather than to the 8 with
    tabulated clinical data. The specific ages at death are in the full text
    (PMC6812045, read 2026-08-01).
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Quantifies sudden death in the founding cohort.
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    A minority progress to overt heart failure. One founding-family individual
    was transplanted at 26 with an ejection fraction of 25 percent and regional
    akinesia; in an independently reported sibship, both siblings had markedly
    elevated B-type natriuretic peptide and high-sensitivity troponin T, the
    younger one while still describing himself as asymptomatic. Subclinical
    biochemical heart failure therefore precedes symptomatic heart failure in
    this disease and is detectable by simple blood tests.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    No FrequencyEnum band is asserted; heart failure is not separately
    annotated in the HPO annotation file for OMIM:620236.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His 20-year-old younger brother, identified through family screening, had no obvious clinical symptoms but exhibited severe biventricular hypertrophy, significantly elevated levels of B-type natriuretic peptide and high-sensitivity troponin T, indicating subclinical myocardial injury and heart failure."
    explanation: Documents biochemically evident heart failure in an individual who was clinically asymptomatic, which is the basis for the claim that subclinical heart failure precedes symptoms here.
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Documents progression to transplant-requiring heart failure in the founding cohort.
- name: Cardiomyocyte hypertrophy
  category: Cardiovascular
  description: >-
    The cellular substrate of the wall thickening. Both individuals from the
    founding families whose myocardium was examined - the cardiac explant of
    one and the endomyocardial biopsy of the other - showed hypertrophied
    cardiomyocytes. It is curated separately from the organ-level phenotype
    because in this disease part of the increase in cell size is occupied by
    stored desmin filaments, glycogen and tubular membrane rather than by added
    contractile apparatus.
  phenotype_term:
    preferred_term: Cardiomyocyte hypertrophy
    term:
      id: HP:0031319
      label: Cardiomyocyte hypertrophy
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0031319 at 2/2, sourced
    to PMID:30715372 (retrieved 2026-08-01 from
    https://ontology.jax.org/api/network/annotation/OMIM:620236). The
    denominator of 2 is the number of individuals with myocardial tissue
    available, not the number affected. Not mentioned in the cached abstract of
    PMID:30715372, so no evidence item is attached; the histological
    description is from the full text (PMC6812045, read 2026-08-01). No
    FrequencyEnum band is asserted.
- name: Increased myocardial glycogen content
  category: Cardiovascular
  description: >-
    PAS staining of the myocardium shows accumulation of glycogen in
    cardiomyocytes, filling the intermyofibrillar space alongside the
    diastase-resistant polyglucosan and the desmin filaments. The glycogen
    itself is ordinary - it is digested by alpha-amylase, which is what
    separates it from the polyglucosan in the same cells - and the same
    accumulation is present in skeletal muscle.
  phenotype_term:
    preferred_term: Increased myocardial glycogen content
    term:
      id: HP:0034532
      label: Increased myocardial glycogen content
  notes: >-
    The HPO annotation file for OMIM:620236 records HP:0034532 at 2/2, sourced
    to PMID:30715372 (retrieved 2026-08-01 from
    https://ontology.jax.org/api/network/annotation/OMIM:620236), with the same
    denominator of 2 as HP:0031319 - the individuals with myocardial tissue
    available. Not mentioned in the cached abstract, so no evidence item is
    attached; the PAS and PAS-diastase findings are in the full text
    (PMC6812045, read 2026-08-01) and are also modelled under `histopathology`
    and in the storage mechanism node. No FrequencyEnum band is asserted.
- name: Cardiac polyglucosan accumulation
  category: Cardiovascular
  diagnostic: true
  description: >-
    The feature that names the OMIM entity. Scattered cardiomyocytes contain
    PAS-positive material that survives alpha-amylase digestion, and discrete
    polyglucosan bodies are also found in the interstitium associated with
    macrophage infiltrates. It is bound as a phenotype as well as being
    described under `histopathology` because it is the entity-defining feature
    and the reason the disease sits alongside the glycogen-storage
    cardiomyopathies in differential diagnosis, even though its pathogenesis
    here is unexplained.
  phenotype_term:
    preferred_term: Cardiac polyglucosan accumulation
    term:
      id: HP:0034835
      label: Cardiac polyglucosan accumulation
  notes: >-
    HP:0034835 exists in HPO (`runoak -i sqlite:obo:hp info HP:0034835`,
    checked 2026-08-01) but is NOT among the 13 annotations the HPO annotation
    file carries for OMIM:620236 (retrieved 2026-08-01 from
    https://ontology.jax.org/api/network/annotation/OMIM:620236), so it is a
    curator addition from the primary description rather than an imported
    annotation, and no frequency is available. The sibling term HP:0034766
    Muscle fiber polyglucosan inclusion bodies was considered and deliberately
    not used: the founding paper reports polyglucosan in cardiomyocytes only,
    and describes the skeletal muscle accumulation as glycogen, desmin and
    tubular structures. Not mentioned in the cached abstract, so no evidence
    item is attached; see the `histopathology` entry for provenance.
histopathology:
- name: Polyglucosan bodies in cardiomyocytes
  diagnostic: true
  description: >-
    The finding that names the OMIM entity. Scattered cardiomyocytes contain
    periodic-acid-Schiff-positive material that persists after alpha-amylase
    (diastase) digestion, identifying it as polyglucosan rather than ordinary
    glycogen. Discrete polyglucosan bodies are also found free in the
    interstitium, where they are associated with small macrophage infiltrates.
    On electron microscopy the polyglucosan sits within intermyofibrillar
    regions crowded with glycogen, filaments and tubular structures. The stain
    pair PAS and PAS-diastase is the entire test, and it is the same pair used
    to identify PRKAG2 cardiac syndrome - which is why the histology alone does
    not distinguish the two and the genotype must.
  finding_term:
    preferred_term: PAS-positive diastase-resistant polyglucosan inclusion
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  notes: >-
    Described from the full text and figures of PMID:30715372 (PMC6812045, read
    2026-08-01), which report PAS and PAS-diastase staining of the cardiac
    explant of one individual and of endomyocardial biopsy material from
    another, plus electron microscopy. The cached abstract of that paper does
    not mention polyglucosan, so no snippet from it can support this finding
    and none is attached. This finding has never been reported by an
    independent group; every subsequent KLHL24 cardiomyopathy report has been
    genotype-plus-imaging without myocardial histology.
- name: Desmin accumulation in cardiac and skeletal muscle
  diagnostic: true
  description: >-
    Immunohistochemistry for desmin shows the accumulated intermyofibrillar and
    subsarcolemmal material staining strongly, and Western blotting shows
    desmin markedly upregulated in both heart and skeletal muscle relative to
    controls. Electron microscopy resolves irregularly arranged intermediate
    filaments of 8 to 12 nm in the same compartment. This is the finding that
    ties the histology directly to the molecular mechanism, since desmin is the
    KLHL24 substrate in striated muscle.
  finding_term:
    preferred_term: intermediate filament (desmin) accumulation
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments."
    explanation: Direct statement that both cardiac and skeletal muscle biopsies show accumulation of desmin intermediate filaments.
- name: Cogwheel skeletal muscle fibres
  diagnostic: true
  description: >-
    A pattern proposed as new in the founding report and not previously
    described in any myopathy: focal subsarcolemmal accumulation of glycogen
    and desmin distributed around the fibre periphery so as to give the fibre
    outline a jagged, cogwheel-like appearance on PAS and desmin staining. It
    affected the majority of both type 1 and type 2 fibres in all three
    individuals biopsied, across both founding families, and the authors
    proposed it explicitly as a diagnostic marker. The accumulated material
    stained for NADH-tetrazolium reductase but not for succinate dehydrogenase,
    indicating sarcoplasmic reticulum-derived tubules rather than mitochondria.
  finding_term:
    preferred_term: cogwheel fibre
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  notes: >-
    Described from the full text and figures of PMID:30715372 (PMC6812045, read
    2026-08-01). The cached abstract says only "characteristic alterations", so
    no snippet supports the cogwheel description specifically and none is
    attached. Because it has appeared in exactly one paper and has not been
    sought in any subsequent case, its sensitivity and specificity are entirely
    unknown; it is recorded here as a described marker, not a validated one.
- name: Interstitial fibrosis with focal CD68-positive macrophage infiltrates
  description: >-
    Patchy interstitial fibrosis on van Gieson staining, with small
    inflammatory infiltrates that stain for CD68 and are preferentially found
    adjacent to polyglucosan-containing myocytes. The distribution suggests a
    localised macrophage response to the stored material rather than a diffuse
    inflammatory process.
  finding_term:
    preferred_term: interstitial fibrosis with macrophage infiltration
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  notes: >-
    Described from the full text and figures of the cardiac explant analysis in
    PMID:30715372 (PMC6812045, read 2026-08-01). One heart, one patient; not
    replicated. No snippet is available from the cached abstract.
- name: Absence of myofibre disarray
  description: >-
    A negative finding with diagnostic weight. Myocyte and myofibrillar
    disarray is the pathognomonic histology of sarcomere-protein hypertrophic
    cardiomyopathy; what the CMH29 biopsies show instead is myocyte hypertrophy
    with intermyofibrillar accumulation. The same negative distinguishes
    PRKAG2 cardiac syndrome from sarcomeric HCM, so this feature separates
    CMH29 from sarcomeric disease but not from the other storage mimics.
  finding_term:
    preferred_term: absence of myofibre disarray
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations"
    explanation: >-
      Cited for the general histological principle, established in the PRKAG2
      storage mimic, that myofibrillar disarray is pathognomonic of sarcomeric
      hypertrophic cardiomyopathy and is absent in the storage cardiomyopathies
      that mimic it. The absence of disarray in CMH29 specifically is described
      in the full text of PMID:30715372, which is not quotable from its cached
      abstract.
diagnosis:
- name: Exome or genome sequencing with biallelic KLHL24 variant interpretation
  description: >-
    Molecular diagnosis rests on identifying biallelic KLHL24 variants against
    transcript NM_017644.3, with parental testing to confirm that compound
    heterozygous variants are in trans. Three interpretive points follow from
    the published genotype-phenotype pattern. First, KLHL24 must actually be on
    the panel: the founding families were solved only after an 88-gene
    inherited-cardiac-conditions panel and a 9-gene polyglucosan-storage panel
    had both come back negative, and the most recent reported sibship was
    likewise negative across a conventional hypertrophic cardiomyopathy gene
    panel - MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1, TNNC1, JPH2,
    PRKAG2, GLA, LAMP2, RYR2, DSP, FLNC, MYPN, CSRP3, TCAP, ZASP and others -
    before exome sequencing found KLHL24. Second, a single heterozygous
    KLHL24 variant does not explain a hypertrophic cardiomyopathy phenotype and
    should not be reported as though it did; the disease is recessive. Third,
    position matters as much as consequence - an initiation-codon variant is
    the dominant skin-and-dilated-cardiomyopathy allele, not this disease. For a
    young adult with severe unexplained hypertrophy, no dominant family history
    and a negative sarcomere panel, reanalysis or reflex exome sequencing is
    the appropriate next step.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only compound heterozygous KLHL24 variants segregated with the disease phenotype."
    explanation: Documents that a conventional hypertrophic cardiomyopathy gene panel was uninformative and that only KLHL24 segregated, which is the argument for including the gene on panels and for reflex exome sequencing.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLHL24 could be included in genetic panels, especially for cases with early onset, severe hypertrophy, or non-dominant family histories."
    explanation: States the panel-inclusion recommendation and the clinical criteria that should trigger consideration of this gene.
- name: Echocardiography with family cascade screening
  description: >-
    Echocardiography establishes the structural phenotype - septal thickness,
    cavity size, systolic anterior motion, outflow gradient, diastolic function
    - and is the screening test for at-risk relatives. Because inheritance is
    recessive, cascade screening targets siblings, who carry a one-in-four
    risk, rather than the parents and offspring who are the focus in dominant
    hypertrophic cardiomyopathy. The screening yield is high and the finding
    can be dramatic in someone who reports no symptoms at all: in one reported
    sibship the asymptomatic younger brother, found on family screening, had
    interventricular septal thickness of 38 to 42 mm.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His 20-year-old younger brother, identified through family screening, had no obvious clinical symptoms but exhibited severe biventricular hypertrophy, significantly elevated levels of B-type natriuretic peptide and high-sensitivity troponin T, indicating subclinical myocardial injury and heart failure."
    explanation: Demonstrates the yield of sibling cascade screening in this recessive disease, including severe structural disease in an asymptomatic individual.
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants can be misleading, as severe structural and subclinical functional heart disease may already be present, necessitating pre-symptomatic diagnosis and management."
    explanation: States directly that asymptomatic status is unreliable in biallelic individuals, which is the justification for structural screening rather than symptom-triggered assessment.
- name: Skeletal muscle biopsy
  description: >-
    An under-used diagnostic route that is specific to this disease. Because
    KLHL24 is expressed more highly in skeletal muscle than in myocardium and
    because skeletal muscle carries the same accumulation despite being
    clinically normal, a quadriceps biopsy can show the desmin and glycogen
    accumulation and the cogwheel fibre pattern in a patient whose only
    clinical problem is cardiac. It is substantially less morbid than
    endomyocardial biopsy. Its limitation is that the pattern has been
    described in exactly three individuals from two families and its
    specificity against other desminopathies and glycogen storage myopathies
    has never been tested.
  notes: >-
    The skeletal muscle biopsy findings, the proposal of the cogwheel fibre as
    a diagnostic marker, and the tissue-expression ranking that motivates
    biopsying muscle rather than heart are all in the full text of
    PMID:30715372 (PMC6812045, read 2026-08-01). The cached abstract supports
    only the general statement that skeletal muscle biopsies showed
    characteristic alterations, which is quoted on the histopathology finding
    above rather than duplicated here.
- name: Endomyocardial biopsy with PAS and PAS-diastase histochemistry
  description: >-
    Where myocardial tissue is available - at endomyocardial biopsy, at
    transplantation or at autopsy - PAS staining before and after alpha-amylase
    digestion is the test that reveals the polyglucosan, and desmin
    immunohistochemistry with electron microscopy reveals the intermediate
    filament accumulation. In practice this is rarely the route to diagnosis
    today, since sequencing is faster and non-invasive, but it remains the way
    the entity was defined and the only way its defining histological feature
    can be confirmed. It also excludes the principal mimics directly: Danon
    disease shows autophagic vacuoles with sarcolemmal features, Fabry disease
    shows lamellar inclusions, and Pompe disease shows lysosomal glycogen.
  notes: >-
    No evidence item is attached. The histochemical protocol is described in
    the methods of PMID:30715372 (PMC6812045, read 2026-08-01), which is not
    quotable from the cached abstract, and the comparative statements about
    Danon, Fabry and Pompe histology are reasoned differential context rather
    than quoted findings.
differential_diagnoses:
- name: Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
  disease_term:
    preferred_term: epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
    term:
      id: MONDO:0015006
      label: epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
  description: >-
    The allelic disorder, and the most informative entry in this list. The same
    gene, mutated at its translation initiation codon rather than in its body,
    causes a dominant disease of skin fragility with scarring alopecia and
    DILATED cardiomyopathy. The mechanism is the mirror image of this entity's.
    Loss of the first 28 amino acids by translation re-initiation at Met29
    produces KLHL24-deltaN28, which escapes the autoubiquitination that
    normally limits KLHL24's own half-life; the stabilised adaptor then
    hyperdegrades its substrates - keratin 14 and other keratins in basal
    keratinocytes, desmin, synemin and vimentin in cardiac cells. Where CMH29
    accumulates intermediate filament, EBS6 destroys it; where CMH29 gives a
    thick-walled small-cavity ventricle, EBS6 gives a thin-walled dilated one.
    A clinician will never confuse the two at the bedside - one has blistering
    from birth, the other has no skin findings at all - but a laboratory
    reading a KLHL24 variant absolutely can, and that is why this differential
    is here.
  distinguishing_features:
  - EBS6 is autosomal dominant and often de novo; CMH29 is autosomal recessive, so zygosity alone separates them in most cases.
  - EBS6 alleles are confined to the translation initiation codon and to nonsense-inducing changes in c.4_84 that permit re-initiation; CMH29 alleles lie in the BACK and Kelch domains.
  - EBS6 is a gain-of-function mechanism producing substrate depletion; CMH29 is loss of function producing substrate accumulation.
  - The cardiomyopathy of EBS6 is dilated; that of CMH29 is hypertrophic with a small cavity.
  - EBS6 presents at birth with extensive skin denudation and later scarring alopecia; no individual with biallelic KLHL24 variants has had any skin abnormality, and family members of CMH29 probands screened for skin symptoms were normal.
  notes: >-
    MONDO:0015006 was verified with OAK: `runoak -i sqlite:obo:mondo info
    MONDO:0015006 -O obo` returns xref OMIM:617294, `is_a MONDO:0000426`
    (autosomal dominant disease), `is_a MONDO:0017610` (epidermolysis bullosa
    simplex) and `relationship: RO:0004003 HGNC:25947 ! KLHL24` - the same gene
    as this entry, which is what makes it allelic. The dismech entry
    `kb/disorders/Epidermolysis_Bullosa_Simplex.yaml` covers this disease as
    part of the broader EBS entity and was not modified.
  evidence:
  - reference: PMID:27798626
    reference_title: "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified start-codon mutations in the KLHL24 gene in five patients with EB."
    explanation: Establishes the start-codon location of the dominant skin alleles, which is the positional contrast with the BACK and Kelch domain alleles of this entity.
  - reference: PMID:27889062
    reference_title: "Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes"
    explanation: Independently establishes that the skin disease alleles are monoallelic and confined to the initiation codon, in direct contrast to the biallelic body-of-gene alleles of CMH29.
  - reference: PMID:34292882
    reference_title: "Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon."
    explanation: Defines the truncated protein product that underlies the dominant disease and that has no counterpart in CMH29 genotypes.
  - reference: PMID:34292882
    reference_title: "Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function"
    explanation: Establishes the opposite direction of the desmin lesion in the allelic dominant disease, which is the core of the mechanistic contrast.
  - reference: PMID:34740256
    reference_title: "Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation."
    explanation: States the dominant, gain-of-function character of the allelic disease explicitly.
  - reference: PMID:35975634
    reference_title: "A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study shows that gain-of-function variants in KLHL24 causing EBS and DCM, do not only originate in the start-codon"
    explanation: Extends the dominant allele class beyond the initiation codon itself to any nonsense-inducing change permitting re-initiation, which sharpens the positional rule a laboratory must apply.
- name: PRKAG2 cardiac syndrome
  disease_term:
    preferred_term: PRKAG2 cardiac syndrome
    term:
      id: MONDO:0800484
      label: PRKAG2-related cardiomyopathy
  description: >-
    The classic glycogen-storage mimic of hypertrophic cardiomyopathy, and the
    entity that shares CMH29's most distinctive histological feature.
    Cardiomyocyte polyglucosan bodies, PAS-positive and diastase-resistant, are
    found in both, so a pathologist reading a PAS-diastase stain cannot tell
    them apart. Everything upstream and downstream of that stain differs.
    PRKAG2 encodes the gamma-2 regulatory subunit of AMP-activated protein
    kinase; dominant missense variants render the kinase constitutively active,
    which drives glucose uptake and glycogen synthesis and produces bulk
    non-lysosomal glycogen storage. The stored material is the primary lesion.
    In CMH29 the primary lesion is failure of intermediate filament turnover,
    the polyglucosan is secondary and unexplained, and the primary stored
    species is desmin protein rather than polysaccharide.

    The clinical separator is electrophysiological. PRKAG2 disease is defined by
    ventricular pre-excitation - accessory atrioventricular connections
    producing Wolff-Parkinson-White - with progressive atrioventricular block
    and pacemaker dependence. CMH29 has conduction-interval prolongation and
    malignant ventricular arrhythmia but no accessory pathways and no
    pre-excitation has been reported. An adult with hypertrophy plus a delta
    wave is PRKAG2 until proven otherwise; an adult with hypertrophy plus
    non-sustained ventricular tachycardia and unaffected parents who are first
    cousins is not.
  distinguishing_features:
  - PRKAG2 cardiac syndrome is autosomal dominant with an affected parent in most families; CMH29 is autosomal recessive with unaffected heterozygous parents and frequent parental consanguinity.
  - Ventricular pre-excitation (Wolff-Parkinson-White) and progressive atrioventricular block define PRKAG2 disease and have not been reported in CMH29.
  - PRKAG2 is one of the eight canonical muscle polyglucosan storage genes; KLHL24 is not, and was reached in the founding study only after that gene set was sequenced and excluded.
  - In PRKAG2 disease the stored polysaccharide sits in large isolated cytosolic vacuoles; in CMH29 the polyglucosan is intermyofibrillar and accompanied by accumulated desmin filaments and sarcoplasmic-reticulum-derived tubules.
  - Desmin accumulation on immunohistochemistry and Western blot is characteristic of CMH29 and is not a feature of PRKAG2 disease.
  notes: >-
    MONDO:0800484 was verified with OAK: it carries `relationship: RO:0004003
    HGNC:9386 ! PRKAG2` and the synonym "PRKAG2 cardiac syndrome", and matches
    the disease_term already bound in
    `kb/disorders/PRKAG2_Cardiac_Syndrome.yaml`. That file was read for scoping
    and was not modified. Its NEC note records that MONDO:0859372 was
    incorrectly proposed as its target; this entry is the correct home for that
    identifier.
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in which hypertrophy, ventricular pre-excitation and conduction system defects coexist"
    explanation: Names the triad that defines PRKAG2 disease, of which ventricular pre-excitation is the feature absent from CMH29 and therefore the practical discriminator.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These vacuoles contained inhomogeneous granular material that stained strongly with PAS"
    explanation: Establishes the shared PAS-positive storage histology that makes the two diseases indistinguishable on that stain alone.
  - reference: PMID:26278982
    reference_title: "Polyglucosan storage myopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2."
    explanation: Places PRKAG2 inside, and KLHL24 outside, the canonical polyglucosan storage gene set, which is the genetic basis of the distinction.
- name: Sarcomeric hypertrophic cardiomyopathy
  disease_term:
    preferred_term: familial hypertrophic cardiomyopathy
    term:
      id: MONDO:0024573
      label: familial hypertrophic cardiomyopathy
  description: >-
    The default diagnosis, the parent term of this entity in MONDO, and the
    label almost every CMH29 patient carries before sequencing. Sarcomeric HCM
    is dominant, caused by variants in MYH7, MYBPC3 and the other
    sarcomere-protein genes, and accounts for the large majority of familial
    hypertrophic cardiomyopathy; the genetic cause of up to 50 percent of
    clinically diagnosed HCM nevertheless remains unknown, and CMH29 lives in
    that unexplained fraction. The
    echocardiographic appearances overlap completely. What separates them is
    the pedigree, the histology and the gene.
  distinguishing_features:
  - Sarcomeric HCM is autosomal dominant with a vertically transmitted family history; CMH29 is recessive, so unaffected parents and affected siblings are the expected pattern.
  - Myocyte and myofibrillar disarray is the pathognomonic histology of sarcomeric HCM and is not what CMH29 biopsies show.
  - Polyglucosan bodies, desmin accumulation and intermyofibrillar glycogen are not features of sarcomeric HCM.
  - Skeletal muscle histology is normal in sarcomeric HCM and abnormal, though clinically silent, in CMH29.
  - Arrhythmic risk in sarcomeric HCM tracks conventional risk markers reasonably well; in CMH29 malignant arrhythmia may precede structural severity, so those markers underestimate risk.
  notes: >-
    MONDO:0024573 was verified with OAK and is the asserted MONDO parent of
    MONDO:0859372. `kb/disorders/Hypertrophic_Cardiomyopathy.yaml` is the
    dismech entry covering sarcomeric HCM; it lists KLHL24 as a panel gene and
    quotes the same ClinGen assertion cited here, and it was not modified.
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown."
    explanation: Establishes the diagnostic gap in which this entity sits - a large unexplained fraction of clinically diagnosed hypertrophic cardiomyopathy.
- name: Danon disease
  disease_term:
    preferred_term: Danon disease
    term:
      id: MONDO:0010281
      label: Danon disease
  description: >-
    An X-linked lysosomal-associated membrane protein 2 defect producing an
    autophagic vacuolar myopathy with massive left ventricular hypertrophy,
    skeletal myopathy, pre-excitation and, in males, presentation in
    adolescence with rapid progression to transplantation. It sits in the same
    diagnostic slot as CMH29 - a young person with extreme hypertrophy and a
    non-dominant pedigree - and is a storage cardiomyopathy with a
    muscle-biopsy diagnosis, so it must be excluded on the same tissue.
  distinguishing_features:
  - Danon disease is X-linked; affected males are severely affected in adolescence and carrier females later and more mildly. CMH29 affects both sexes equally and requires two damaged alleles.
  - Danon disease combines cardiomyopathy with intellectual disability and a clinically manifest skeletal myopathy with raised creatine kinase; CMH29 has neither.
  - Ventricular pre-excitation is common in Danon disease and unreported in CMH29.
  - Danon histology shows autophagic vacuoles with sarcolemmal features and LAMP2 absence on immunostaining; CMH29 shows intermyofibrillar desmin and polyglucosan with preserved LAMP2.
  notes: >-
    MONDO:0010281 was verified with OAK and carries `RO:0004003 HGNC:6501 !
    LAMP2`. `kb/disorders/Danon_disease.yaml` is the dismech entry for this
    disease. The LAMP2 immunostaining contrast is grounded in the founding
    CMH29 study having included LAMP2 as a lysosomal marker in its
    immunohistochemistry panel (methods of PMID:30715372, PMC6812045, read
    2026-08-01); no snippet is available for it, so no evidence item is
    attached to this differential.
- name: Desminopathy and desmin-related myofibrillar myopathy
  disease_term:
    preferred_term: qualitative or quantitative defects of desmin
    term:
      id: MONDO:0016187
      label: qualitative or quantitative defects of desmin
  description: >-
    The mechanistically closest disease outside the KLHL24 locus. Dominant DES
    variants produce desmin aggregation in cardiac and skeletal muscle with
    cardiomyopathy, conduction disease and arrhythmia - the same end state that
    CMH29 reaches by removing the ligase that clears desmin rather than by
    damaging desmin itself. The pair makes the point that the desmin network
    can be broken from either side, and it is the reason desmin
    immunohistochemistry does not by itself distinguish them.
  distinguishing_features:
  - Desminopathy is usually autosomal dominant and caused by variants in DES itself; CMH29 is recessive and DES is normal.
  - Desminopathy typically produces a clinically manifest skeletal myopathy with distal-onset weakness progressing proximally; in CMH29 skeletal muscle is histologically abnormal but strength is normal.
  - The cardiac phenotype of desminopathy is most often dilated or arrhythmogenic-right-ventricular rather than hypertrophic with a small cavity.
  - Polyglucosan bodies and intermyofibrillar glycogen are not features of desminopathy.
  notes: >-
    MONDO:0016187 was verified with OAK; `runoak -i sqlite:obo:mondo
    relationships --direction down -p RO:0004003 HGNC:2770` returns it as the
    only MONDO term carrying a DES gene association in this build, which is why
    the grouping term is used here rather than a numbered myofibrillar myopathy
    term whose gene association is not asserted in the ontology. This
    differential is mechanistic; no evidence item is attached because the
    comparison is reasoned rather than quoted.
- name: Polyglucosan body myopathy 1 with or without immunodeficiency
  disease_term:
    preferred_term: polyglucosan body myopathy 1 with or without immunodeficiency
    term:
      id: MONDO:0014389
      label: polyglucosan body myopathy 1 with or without immunodeficiency
  description: >-
    An RBCK1-related recessive disorder combining polyglucosan storage myopathy
    with a progressive, often fatal cardiomyopathy, and in some individuals
    immunodeficiency and autoinflammation. It is the recessive polyglucosan
    cardiomyopathy that CMH29 most closely resembles by histology and by
    inheritance, and it is one of the nine genes that the founding study
    sequenced and excluded before reaching KLHL24. Including it here is the
    point: the differential for a recessive polyglucosan cardiomyopathy is a
    short list, and KLHL24 now belongs on it even though its polyglucosan
    remains unexplained.
  distinguishing_features:
  - RBCK1 disease frequently includes immunodeficiency, recurrent pyogenic infection and systemic autoinflammation; CMH29 is purely cardiac.
  - RBCK1 disease produces a progressive clinically manifest skeletal myopathy; CMH29 skeletal muscle is abnormal on biopsy but strong.
  - The RBCK1 cardiomyopathy is typically dilated and progresses to failure in childhood or adolescence; CMH29 is hypertrophic and presents in young adulthood.
  - RBCK1 is a canonical polyglucosan storage gene with an established mechanism in linear ubiquitin assembly and glycogen handling; the polyglucosan in CMH29 has no established mechanism.
  notes: >-
    MONDO:0014389 was verified with OAK and carries `RO:0004003 HGNC:15864 !
    RBCK1`. No evidence item is attached; the contrast is reasoned from the
    polyglucosan storage myopathy review cited elsewhere in this entry and from
    the founding study's exclusion of the polyglucosan gene panel.
- name: Fabry disease
  disease_term:
    preferred_term: Fabry disease
    term:
      id: MONDO:0010526
      label: Fabry disease
  description: >-
    Included because it is the storage mimic with a disease-modifying therapy,
    which makes missing it costlier than missing the others. X-linked
    alpha-galactosidase A deficiency produces concentric left ventricular
    hypertrophy that is routinely misdiagnosed as hypertrophic cardiomyopathy,
    and is excluded cheaply by plasma or leukocyte enzyme assay in males and by
    GLA sequencing in females.
  distinguishing_features:
  - Fabry disease is X-linked with a characteristic multisystem phenotype - acroparaesthesia, angiokeratoma, hypohidrosis, corneal verticillata, proteinuric renal disease and stroke - none of which occurs in CMH29.
  - Fabry cardiac hypertrophy is typically concentric with a short PR interval; CMH29 hypertrophy is typically asymmetric and septal, and no short PR interval has been reported in it.
  - Fabry histology shows lamellar myelin-like inclusions of globotriaosylceramide, not polyglucosan or desmin accumulation.
  - Enzyme replacement and chaperone therapy exist for Fabry disease; no disease-modifying therapy exists for CMH29.
  notes: >-
    MONDO:0010526 was verified with OAK and carries `RO:0004003 HGNC:4296 !
    GLA`. `kb/disorders/Fabry_Disease.yaml` is the dismech entry for this
    disease. No evidence item is attached; the contrast is reasoned clinical
    comparison rather than a quoted finding.
treatments:
- name: Implantable cardioverter-defibrillator
  description: >-
    The single intervention with a plausible mortality benefit in this disease,
    and the one where CMH29 departs from standard hypertrophic cardiomyopathy
    practice. Because malignant ventricular arrhythmia in this genotype can
    precede structural severity and can be the first manifestation, conventional
    HCM risk scores - which weight wall thickness, fibrosis burden, family
    history of sudden death and syncope - underestimate risk. Several
    individuals in the founding families received defibrillators in their
    twenties and thirties, and an independently reported 16-year-old with low
    conventional risk markers received a prophylactic device on genotype
    grounds. That decision was made case by case; no guideline addresses this
    genotype and no comparative data exist.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  notes: >-
    `runoak -i sqlite:obo:ncit search 't~defibrillator'` returns NCIT:C80435
    Implantable Cardioverter-Defibrillator Placement, which matches the
    preferred term exactly and is the identifier already used for this
    intervention elsewhere in the repository (for example
    `kb/disorders/Brugada_Syndrome.yaml` and
    `kb/disorders/Paroxysmal_Familial_Ventricular_Fibrillation.yaml`).
    `runoak -i sqlite:obo:ncit ancestors -p i NCIT:C80435` places it under
    NCIT:C80430 Cardiac Therapeutic Procedure and NCIT:C49236 Therapeutic
    Procedure, so this binding is the specific term rather than the branch
    root.
  evidence:
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite low conventional risk markers, genotype-directed assessment indicated high arrhythmic risk, prompting prophylactic implantable cardioverter-defibrillator (ICD) placement."
    explanation: Documents genotype-driven prophylactic defibrillator implantation in a biallelic KLHL24 case whose conventional risk markers were low.
  - reference: PMID:41823911
    reference_title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early genetic testing enables genotype-guided preventive strategies, including timely prophylactic ICD implantation, even in apparently low-risk phenotypes."
    explanation: States the management principle that follows from the decoupling of arrhythmic risk from structural severity in this genotype.
- name: Heart transplantation
  description: >-
    Definitive treatment for the subset who progress to end-stage failure. One
    of the two Iraqi siblings was transplanted at 26 for heart failure with an
    ejection fraction of 25 percent. The relevance of transplantation here goes
    beyond the individual case: because the disease is confined to striated
    muscle and the skeletal muscle involvement is clinically silent, a
    transplanted CMH29 patient has no residual systemic disease to limit the
    outcome, unlike patients transplanted for multisystem storage disorders.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  notes: >-
    `runoak -i sqlite:obo:ncit search "Heart Transplantation"` returns
    NCIT:C15246 as an exact match, so the organ-specific term is used rather
    than its parent NCIT:C15289 Organ Transplantation.
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure."
    explanation: Documents cardiac transplantation as a management outcome in the founding cohort.
- name: Standard heart failure and hypertrophic cardiomyopathy pharmacotherapy
  description: >-
    Management of the haemodynamic phenotype follows standard practice for
    hypertrophic cardiomyopathy and heart failure and is not disease-specific:
    beta-blockade for outflow obstruction, symptom control and rate control,
    with mineralocorticoid receptor antagonism, loop diuretics and vasopressin
    antagonism added as congestion develops. Reported regimens in genetically
    confirmed cases have used metoprolol succinate with spironolactone in the
    less advanced sibling and metoprolol with furosemide and tolvaptan in the
    more congested one. There is no evidence that any of this modifies the
    natural history of the underlying proteostatic lesion.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  notes: >-
    These are the agents actually used in a reported case, not a recommended
    regimen; no trial, guideline or cohort study addresses pharmacotherapy in
    KLHL24 cardiomyopathy specifically.
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband was on a long-term regimen of metoprolol succinate (47.5 mg daily), spironolactone (10 mg daily), and febuxostat (20 mg daily)."
    explanation: Documents the actual pharmacological management of a genetically confirmed case; cited as observed practice, not as evidence of efficacy.
- name: Genetic counselling and sibling cascade screening
  description: >-
    Counselling for CMH29 differs from counselling for dominant hypertrophic
    cardiomyopathy in the direction it points. The recurrence risk that matters
    is one in four for the proband's siblings, not fifty percent for offspring;
    the proband's children are obligate heterozygotes and, on present evidence,
    unaffected unless the other parent is also a carrier, which raises the
    question of partner testing in consanguineous families. Siblings should be
    offered targeted testing for the familial alleles and echocardiography
    without waiting for symptoms, because severe hypertrophy and biochemical
    heart failure have been documented in an entirely asymptomatic 18-year-old
    found by screening.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42158087
    reference_title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case expands the genetic spectrum of HCM and highlights the importance of genetic testing and family screening for KLHL24-related cardiomyopathies."
    explanation: States the family-screening recommendation that this counselling entry implements.
- name: No disease-modifying therapy
  description: >-
    Nothing addresses the underlying lesion. There is no way to restore CUL3
    substrate-adaptor function, and unlike the gain-of-function skin disease -
    where reducing KLHL24 abundance is at least a coherent therapeutic idea,
    and has been shown to restore desmin levels and tissue morphology in
    patient-derived engineered heart tissue - loss of function offers no
    obvious pharmacological handle. A review of KLHL24-associated cardiomyopathy
    published in 2025 confirms that no clinical trial of any kind is under way
    for this gene.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39708934
    reference_title: "KLHL24 associated cardiomyopathy: Gene function to clinical management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "currently there are no specific clinical trials going on regarding the therapeutic strategies among patients with KLHL24 mutations"
    explanation: Directly supports the absence of any disease-specific therapeutic development for KLHL24-associated cardiomyopathy.
  - reference: PMID:34292882
    reference_title: "Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs."
    explanation: >-
      Marked PARTIAL because it is a proof of principle for the allelic
      gain-of-function disease, not for this entity. It is cited to make the
      asymmetry explicit: knocking KLHL24 down rescues the dominant disease and
      would, if anything, phenocopy this one.
animal_models:
- species: Danio rerio
  genotype: klhl24a splice-blocking antisense morpholino knockdown (morphant; no stable mutant line reported)
  category: Transient loss-of-function knockdown model
  description: >-
    The only in vivo model of this disorder, and it is a transient morpholino
    knockdown rather than a germline mutant - a distinction that limits how
    much weight it can carry. Zebrafish have two KLHL24 orthologues; klhl24a is
    expressed in the cardiac cone at 22 hours post fertilisation and in the
    ventricle at 72 hours, whereas klhl24b is not expressed in the developing
    heart, so the cardiac arm of the gene family is klhl24a. Knockdown produced
    pericardial oedema, altered heart rate and reduced circulation from 48
    hours, progressing to ventricular failure and blocked circulation in about
    90 percent of morphants against 4 percent of controls. A second,
    independently targeted morpholino reproduced the phenotype, and co-injection
    of wild-type klhl24a mRNA partially rescued it, which are the two standard
    specificity controls.

    The experiment that matters most for this entry is the allele test.
    Zebrafish klhl24a mRNA carrying the residues equivalent to the two human
    CMH29 alleles failed to rescue, giving heart defects in 71.5 and 77.5
    percent of embryos respectively. That is the direct functional evidence
    that p.Arg306His and p.Glu350* are loss-of-function alleles rather than
    dominant-negatives or benign variants.

    Its limitations are substantial and are the reason a knowledge gap is
    recorded below. The model is a knockdown, not a biallelic point-mutant; it
    reports on cardiac development in the embryo rather than on adult-onset
    hypertrophy; desmin protein levels were unchanged in morphants at 52 hours,
    which the authors attribute to the short experimental window; and it
    produces ventricular failure rather than the hypertrophy, polyglucosan
    storage or arrhythmia that define the human disease.

    Provenance and caveats. The morpholino doses, the second morpholino, the
    RT-PCR confirmation of exon 3 skipping, the rescue percentages, the
    allele-specific rescue failure percentages and the unchanged morphant
    desmin immunoblot are all in the full text and figures of PMID:30715372
    (PMC6812045, read 2026-08-01) and not in the cached abstract, so they are
    described here rather than quoted. Morpholino knockdowns are subject to
    well-documented off-target and p53-mediated artefacts; the
    second-morpholino and mRNA-rescue controls reported here mitigate but do
    not eliminate that concern. No mouse model of KLHL24 loss of function was
    found during this curation.
  associated_phenotypes:
  - Pericardial oedema
  - Altered heart rate
  - Ventricular failure with blocked circulation
  - Failure of rescue by mRNA carrying human CMH29 alleles
  evidence:
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene."
    explanation: Establishes the zebrafish knockdown as the in vivo support for the gene-disease relationship and situates its phenotype alongside other HCM gene knockdowns in the same species.
  - reference: PMID:30715372
    reference_title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings reveal a crucial role for KLHL24 in cardiac development and function."
    explanation: The developmental conclusion drawn from the model, which is also the boundary of what it can show - development rather than adult-onset remodelling.
discussions:
- discussion_id: klhl24-polyglucosan-pathogenesis-unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does loss of a CUL3 substrate adaptor produce polyglucosan bodies in
    cardiomyocytes, when KLHL24 has no known role in glycogen metabolism and no
    canonical polyglucosan storage gene is involved?
  rationale: >-
    This is the central unexplained fact about the disease, and it is the
    feature that OMIM chose to put in its name. The founding authors sequenced
    a dedicated nine-gene polyglucosan storage panel, found nothing, and stated
    plainly that the pathogenesis of the storage remains unknown and that it may
    serve as a diagnostic marker. Seven years later a PubMed search for
    `KLHL24 AND polyglucosan` returns zero records, so nobody has taken the
    question up. Three explanations are live and they have different
    consequences. First, the polyglucosan may be a secondary consequence of
    proteostatic failure - stalled autophagic or proteasomal flux is known to
    permit abnormal polysaccharide to accumulate, in which case the storage is
    epiphenomenal and the diagnostic marker is real but mechanistically empty.
    Second, KLHL24 may have an unidentified substrate in glycogen handling,
    which would make it a bona fide, if unconventional, glycogen-metabolism
    gene. Third, the polysaccharide may simply be trapped by the disorganised
    intermediate filament and tubular meshwork, a physical rather than
    metabolic explanation. Resolving this determines whether CMH29 should be
    classified among the inherited metabolic disorders at all - a classification
    this entry currently withholds for exactly this reason.
  attaches_to:
  - "pathophysiology#Intermyofibrillar Glycogen and Polyglucosan Storage"
  proposed_experiments:
  - experiment_id: klhl24-cardiac-glycogen-biochemistry
    name: Biochemical characterisation of the stored polysaccharide in KLHL24-null myocardium
    description: >-
      Determine chain-length distribution, branching ratio and phosphate
      content of the polysaccharide isolated from KLHL24-deficient cardiac
      tissue, and compare directly against material from PRKAG2 and GBE1
      hearts. If the material is biochemically identical to classical
      polyglucosan the metabolic hypothesis gains ground; if it differs, the
      trapping hypothesis does.
  - experiment_id: klhl24-substrate-proteomics-glycogen-enzymes
    name: Unbiased ubiquitylome and interactome of KLHL24 in cardiomyocytes
    description: >-
      Perform diGly proteomics and proximity labelling in wild-type versus
      KLHL24-null human iPSC-derived cardiomyocytes to ask whether any enzyme
      of glycogen synthesis, branching or degradation is a KLHL24 substrate.
      A comparable proteomic approach has already been applied to the
      gain-of-function allele and yielded a candidate substrate list, so the
      method is established for this gene.
  notes: >-
    The authors' statement of ignorance is in the discussion section of the
    full text of PMID:30715372 (PMC6812045, read 2026-08-01) and is not in the
    cached abstract, so this discussion carries no evidence item.
- discussion_id: klhl24-bidirectional-desmin-proteostasis
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do opposite perturbations of the same KLHL24-desmin axis produce
    opposite cardiac morphologies - hypertrophic with a small cavity when the
    ligase is dead, dilated when it is hyperactive - and is there a therapeutic
    window between them?
  rationale: >-
    KLHL24 is an unusually clean natural experiment: one gene, two directions,
    two cardiomyopathies. Excess adaptor activity depletes desmin, synemin and
    vimentin and gives dilated cardiomyopathy with mitochondrial mislocalisation
    and sarcomere shortening; absent adaptor activity lets desmin accumulate and
    gives hypertrophic cardiomyopathy with intermyofibrillar storage. The two
    have never been studied side by side in the same experimental system, and
    the intermediate states have never been probed at all. The question has
    direct therapeutic relevance in both directions: reducing KLHL24 abundance
    rescues the gain-of-function phenotype in engineered heart tissue, which
    implies a dose-response curve with an optimum somewhere between the two
    diseases, and mapping that curve is what would show whether a partial
    modulator is conceivable. It also bears on whether desmin abundance itself,
    rather than KLHL24 activity, is the proximate determinant of ventricular
    geometry.
  attaches_to:
  - "pathophysiology#Failure of Desmin Intermediate Filament Turnover"
  - "pathophysiology#Loss of CUL3-KLHL24 Substrate Adaptor Function"
  proposed_experiments:
  - experiment_id: klhl24-allelic-series-eht
    name: Isogenic KLHL24 allelic series in engineered heart tissue
    description: >-
      Build an isogenic iPSC panel spanning KLHL24 null, biallelic CMH29
      missense, heterozygous, wild-type, and deltaN28 gain-of-function, and
      measure desmin abundance, tissue geometry, force generation and calcium
      handling in dynamically loaded engineered heart tissues across the whole
      series. The gain-of-function end of this panel already exists and has
      been characterised, so only the loss-of-function arm is new.
  - experiment_id: klhl24-desmin-dose-titration
    name: Direct titration of cardiomyocyte desmin abundance
    description: >-
      Independently of KLHL24, titrate desmin levels up and down in
      cardiomyocytes and engineered tissues to test whether desmin abundance
      alone is sufficient to move tissue geometry between the hypertrophic and
      dilated poles, or whether other KLHL24 substrates are required.
- discussion_id: klhl24-silent-skeletal-muscle
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is skeletal muscle histologically severely abnormal but clinically
    normal in CMH29, when KLHL24 is expressed more highly in skeletal muscle
    than in heart?
  rationale: >-
    Every individual biopsied showed cogwheel fibres with desmin and glycogen
    accumulation affecting the majority of both fibre types, yet none had
    weakness or wasting and nerve conduction studies were normal. The HPO
    annotation set records muscle weakness at 0 of 8. This is not a minor
    curiosity: it is a counterexample to the assumption that intermediate
    filament accumulation causes muscle dysfunction, and it means the tissue
    with the highest KLHL24 expression is the tissue that tolerates its loss
    best. Candidate explanations include redundancy from another KLHL family
    adaptor in skeletal muscle, a lower mechanical demand for continuous desmin
    turnover in skeletal than in cardiac muscle, or subclinical dysfunction
    that nobody has looked for because no one has performed quantitative
    myometry, creatine kinase measurement or exercise testing in these
    individuals. It also has a practical consequence, which is that the
    absence of weakness must not be used to exclude the diagnosis.
  attaches_to:
  - "pathophysiology#Skeletal Muscle Cogwheel Fibre Pathology"
  proposed_experiments:
  - experiment_id: klhl24-skeletal-muscle-deep-phenotyping
    name: Quantitative skeletal muscle phenotyping of biallelic KLHL24 individuals
    description: >-
      Quantitative myometry, serum creatine kinase, muscle MRI and
      cardiopulmonary exercise testing in living biallelic individuals, to
      establish whether the skeletal muscle is genuinely unaffected
      functionally or merely unassessed.
  - experiment_id: klhl24-paralogue-redundancy-screen
    name: Test for KLHL paralogue redundancy in skeletal muscle
    description: >-
      Ask whether another KLHL family adaptor substitutes for KLHL24 in
      skeletal but not cardiac muscle, by comparing KLHL family expression
      between the two tissues and by testing whether co-depletion of a
      candidate paralogue unmasks a skeletal phenotype in a model system.
  notes: >-
    The absence of weakness and the normal nerve conduction studies are stated
    in the full text of PMID:30715372 (PMC6812045, read 2026-08-01) and are
    corroborated by the HPO annotation file for OMIM:620236, which records
    HP:0001324 at 0/8 (retrieved 2026-08-01). Neither source is quotable as a
    snippet from the cached abstract, so this discussion carries no evidence
    item.
- discussion_id: klhl24-no-model-of-the-human-genotype
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any model system represent the genotype that defines this disorder,
    given that the only in vivo work is an embryonic zebrafish morpholino
    knockdown and every cardiac cell model carries the gain-of-function allele
    instead?
  rationale: >-
    This is a model-fidelity problem rather than an absence of evidence, which
    is why it is recorded as HUMAN_MODEL_MISMATCH. Informative in vivo and in
    vitro work on KLHL24 in the heart exists, but none of it models CMH29. The
    zebrafish experiment is a transient knockdown assayed at 48 to 72 hours
    post fertilisation; it reports ventricular developmental failure, not
    adult-onset hypertrophy, and morphant desmin was unchanged over that
    window. Every human cardiac cell model published - the dynamically loaded
    engineered heart tissues, the patient iPSC lines, the proteomic
    characterisation of failing myocardium - carries the dominant
    KLHL24-deltaN28 gain-of-function allele, which produces the opposite
    molecular lesion. No mouse model of KLHL24 loss of function was identified
    during this curation. Consequently there is no system in which the
    polyglucosan storage, the desmin accumulation, the hypertrophy or the
    arrhythmia of this disease has ever been reproduced, and every mechanistic
    claim in this entry beyond the substrate identity rests on human
    histopathology from two families.
  attaches_to:
  - "pathophysiology#Intermyofibrillar Glycogen and Polyglucosan Storage"
  - "pathophysiology#Ventricular Electrical Instability and Malignant Arrhythmia"
  proposed_experiments:
  - experiment_id: klhl24-knockin-mouse-cmh29
    name: Knock-in mouse carrying a CMH29-equivalent biallelic genotype
    description: >-
      Generate homozygous p.Arg306His and null mice and phenotype the heart
      longitudinally with echocardiography, telemetry for arrhythmia, and
      PAS-diastase and desmin histology, to ask whether the polyglucosan and
      the arrhythmic phenotype are reproducible outside humans.
  - experiment_id: klhl24-null-ipsc-eht
    name: KLHL24-null human engineered heart tissue
    description: >-
      Build the loss-of-function counterpart of the existing gain-of-function
      engineered heart tissue system and measure desmin accumulation, tissue
      geometry, contractile force, calcium handling and arrhythmic propensity,
      to give the disease its first cardiac cell model.
- discussion_id: klhl24-arrhythmic-risk-stratification
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How should sudden death risk be stratified in biallelic KLHL24 individuals,
    given that malignant arrhythmia may precede structural severity and
    conventional hypertrophic cardiomyopathy risk models therefore underestimate
    it?
  rationale: >-
    Three of eleven young adults in the founding cohort died suddenly, and an
    independently reported adolescent received a prophylactic defibrillator on
    genotype grounds despite low conventional risk markers. Neither observation
    amounts to a risk model. The established HCM sudden-death calculators weight
    maximal wall thickness, left atrial size, outflow gradient, unexplained
    syncope, non-sustained ventricular tachycardia and family history of sudden
    death - and the last of those behaves differently in a recessive disease,
    where affected relatives are siblings rather than ancestors, and where a
    family with a single affected child has no family history to weight at all.
    The reported fibrosis burden also varies from minimal to extensive
    independently of hypertrophy, so late gadolinium enhancement may not carry
    its usual weight either. Whether every biallelic individual warrants a
    primary-prevention defibrillator is an open and consequential question,
    currently answered case by case.
  attaches_to:
  - "pathophysiology#Ventricular Electrical Instability and Malignant Arrhythmia"
  - "phenotypes#Sudden cardiac death"
  proposed_experiments:
  - experiment_id: klhl24-international-registry
    name: International registry of biallelic KLHL24 individuals
    description: >-
      Pool the small number of reported and unreported families into a
      genotype-defined registry with systematic prospective collection of
      arrhythmic events, device therapies, imaging and outcomes, which is the
      only realistic route to a risk model for a disease this rare.
  - experiment_id: klhl24-electrophysiological-phenotyping
    name: Systematic electrophysiological phenotyping
    description: >-
      Prospective ambulatory monitoring, signal-averaged electrocardiography
      and, where devices are implanted, interrogation-derived arrhythmia burden
      in biallelic individuals, to establish whether the arrhythmic substrate
      is detectable before structural disease.
- discussion_id: klhl24-gene-disease-validity-moderate
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What evidence would move KLHL24 from moderate to strong or definitive
    gene-disease validity for hypertrophic cardiomyopathy, and is the disease
    entity being curated the same one ClinGen assessed?
  rationale: >-
    ClinGen's Hereditary Cardiovascular Disease expert panel classified KLHL24
    as moderate for hypertrophic cardiomyopathy with autosomal recessive
    inheritance in 2023, and the 2025 reappraisal publication confirms that
    placement. Moderate is the correct level and it constrains how this entry
    should be read: the human genetic evidence is a handful of small families
    and the functional evidence is a morpholino knockdown. Two things would move
    it - additional unrelated probands with segregating biallelic variants,
    which are accumulating steadily, and a cardiac functional model of the
    loss-of-function genotype, which does not yet exist. There is also a term
    mismatch worth flagging for anyone reusing this entry computationally:
    ClinGen curated against MONDO:0005045, the broad hypertrophic cardiomyopathy
    term, whereas the entity curated here is MONDO:0859372, a much narrower
    descendant two is_a steps below it (MONDO:0859372 is_a MONDO:0024573 is_a
    MONDO:0005045, per `runoak -i sqlite:obo:mondo paths -p i --target
    MONDO:0005045 MONDO:0859372`). The classification supports the gene and the mode of
    inheritance; it does not adjudicate the entity boundary, and nothing in this
    entry should be read as claiming that it does.
  attaches_to:
  - "genetic#KLHL24"
  proposed_experiments:
  - experiment_id: klhl24-reappraisal-with-new-probands
    name: ClinGen re-curation incorporating post-2023 probands
    description: >-
      Re-run the gene-disease validity curation including the Brazilian family
      and the two families reported from China and India after the 2023
      assessment, and the cardiac functional data that has appeared since, to
      test whether the classification now supports an upgrade.
references:
- reference: PMID:30715372
  title: "Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24."
- reference: PMID:39971408
  title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
- reference: CGGV:assertion_f1d4ce43-4c2d-41a0-b821-a11ac8eb8fca-2023-09-28T160000.000Z
  title: "KLHL24 / hypertrophic cardiomyopathy (Moderate)"
- reference: PMID:42158087
  title: "Novel compound heterozygous mutations in KLHL24-induced recessive inherited hypertrophic cardiomyopathy: a case report."
- reference: PMID:41823911
  title: "KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype."
- reference: PMID:40176835
  title: "Coexistence of Rare Genetic Disorders in a Consanguineous Family: Case Study of KLHL24-Related Hypertrophic Cardiomyopathy and Char Syndrome."
- reference: PMID:36672924
  title: "Genetic Insights from Consanguineous Cardiomyopathy Families."
- reference: PMID:34526680
  title: "Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies."
- reference: PMID:26278982
  title: "Polyglucosan storage myopathies."
- reference: PMID:11827995
  title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
- reference: PMID:34292882
  title: "Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues."
- reference: PMID:41348940
  title: "KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients."
- reference: PMID:27798626
  title: "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility."
- reference: PMID:27889062
  title: "Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility."
- reference: PMID:34740256
  title: "Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy."
- reference: PMID:35975634
  title: "A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation."
- reference: PMID:39708934
  title: "KLHL24 associated cardiomyopathy: Gene function to clinical management."

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References & Deep Research