Hypertrophic Cardiomyopathy 28

Mendelian MONDO:0030317 Pathograph 27 Show in embeddings browser Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy 28 (CMH28) is the FHOD3-attributed member of the numbered familial hypertrophic cardiomyopathy series. FHOD3 encodes a formin, an actin-assembly protein; its heart-enriched long isoform is recruited to the sarcomere C-zone by cardiac myosin-binding protein C and is required to build and maintain the thin-filament array of the cardiac sarcomere. FHOD3 is therefore a sarcomere-associated rather than a core sarcomeric gene, and it is now one of the main non-sarcomeric causes of HCM, accounting for roughly 1-2% of probands in the founding Spanish/UK cohort of 3,189 patients. ClinGen classifies FHOD3 as Definitive for autosomal dominant hypertrophic cardiomyopathy. The disease is autosomal dominant with incomplete penetrance and variable expressivity. Diagnosis is typically in mid-adulthood (mean 46 years in the founding cohort), most patients have asymmetric septal hypertrophy, and a minority show left ventricular hypertrabeculation, reduced ejection fraction or, in one reported family, a predominantly noncompaction phenotype. Pathogenic alleles are mostly non-truncating (missense, in-frame indels, splice-site and exon deletions) and cluster in a conserved coiled-coil / diaphanous inhibitory region and in the cardiac-specific exon 12. How these alleles change FHOD3 function has not been shown biochemically; the pathophysiology below is built from knockdown, knockout and overexpression models and is labelled accordingly. One recurrent coiled-coil allele, p.Arg637Gln, behaves as a low-penetrance intermediate-effect risk allele in heterozygotes and causes a severe early phenotype in homozygotes.

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Inheritance
7
Pathophys.
12
Phenotypes
1
Hypotheses
3
Gaps
27
Pathograph
3
Genes
7
Medical Actions
6
Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous FHOD3 variants segregate with HCM as an autosomal dominant trait, with very strong combined cosegregation across 17 families in the founding cohort. Penetrance is incomplete and expressivity is variable: age at onset in the Balkan founder families ranged from 4 to 63 years. The recurrent p.Arg637Gln allele is the exception to simple dominance - an intermediate-effect allele with penetrance of about 1% in heterozygotes and a severe early phenotype in most homozygotes - and is curated as a separate risk-factor genetic record rather than as recessive inheritance.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (4 references)
PMID:30442288 SUPPORT Human Clinical
"FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
Family cosegregation of heterozygous variants with HCM establishes dominant transmission.
CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z SUPPORT Other
"FHOD3 | HGNC:26178 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen curates the FHOD3-HCM relationship with autosomal dominant mode of inheritance.
PMID:38051749 SUPPORT BACKGROUND Human Clinical
"Disease-causing variants in FHOD3 are most commonly associated with the phenotype of HCM, with penetrance being incomplete"
The introduction summarises prior cohorts as showing incomplete penetrance of FHOD3 disease variants.
+ 1 more reference
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Mechanistic Hypotheses

1
Non-truncating FHOD3 alleles act through an altered (interfering) protein rather than haploinsufficiency
fhod3_allele_mechanism EMERGING
Evidence balance 2 support
Three observations point away from simple haploinsufficiency: the disease alleles are overwhelmingly non-truncating and clustered in regulatory and sarcomere-targeting regions; all known splice alleles are predicted to skip in-frame cardiac exons; and Fhod3 heterozygous mice are normal. An overexpressed actin-assembly-dead FHOD3 causes cardiomyopathic changes in mice despite a wild-type allele, which shows that a defective FHOD3 can interfere in vivo. None of this tests a patient allele, so the hypothesis remains open; it is not encoded as DOMINANT_NEGATIVE on the pathway.
Show evidence (2 references)
PMID:35205353 SUPPORT INDIRECT Computational
"Along with the predominance of missense variants in previous FHOD3 studies, this allows us to speculate that the mechanism of FHOD3 malfunctioning is dominant-negative rather than haploinsufficiency, although there are still not enough data to make that assertion with confidence."
The explicit, self-qualified statement of the hypothesis.
PMID:23213483 SUPPORT INDIRECT Model Organism
"Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
Halving Fhod3 dosage in mice produces no overt phenotype, which argues against haploinsufficiency as the disease mechanism (with the caveat of species difference).
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Discussions and Knowledge Gaps

3
What do heterozygous non-truncating FHOD3 patient alleles actually do to FHOD3 activity and localisation in adult cardiomyocytes?
HUMAN MODEL MISMATCH OPEN fhod3_patient_allele_mechanism
Attached to
pathophysiology#Heterozygous FHOD3 Non-Truncating Variant pathophysiology#Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere animal_models#Fhod3 constitutive knockout mouse
Every functional system used so far removes FHOD3 (knockdown, knockout, conditional deletion) or overexpresses an engineered mutant, whereas patients are heterozygous for mostly non-truncating alleles clustered in the coiled-coil/DID region and exon 12. Null mice die as embryos and heterozygous nulls are normal, so neither reproduces adult-onset HCM, and ClinGen explicitly notes that no study has demonstrated a clear HCM phenotype in a model. The mechanism chain in this entry is therefore built from loss-of-function systems, and the allele-to-protein step is UNKNOWN. A patient-allele knock-in (for example a coiled-coil missense, p.Arg637Gln, or the exon 15-16 deletion) in mice or isogenic iPSC-derived cardiomyocytes would test whether these alleles reduce actin assembly, mislocalise FHOD3 away from the C-zone, or interfere with the wild-type protein.
Show evidence (2 references)
PMID:39132495 SUPPORT REVIEW SYNTHESIS Other
"However, it should be noted that while experimental studies have shown an important role for FHOD3 in heart and sarcomeric development, no studies have demonstrated a clear HCM phenotype."
Expert-panel statement of the model gap.
PMID:23213483 SUPPORT Model Organism
"Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
The dosage-matched null mouse has no phenotype.
Is FHOD3 expression increased or decreased in diseased human myocardium, and does mislocalised FHOD3 contribute to hypertrophy?
CONTROVERSY OPEN fhod3_expression_direction_in_cardiomyopathy
Attached to
pathophysiology#Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
One group found FHOD3 expression increased in HCM myectomy tissue; another found reduced FHOD3 with an isoform switch in murine and human cardiomyopathy. In cMyBP-C-null mice, where FHOD3 is mislocalised, overexpressing FHOD3 worsened and reducing it partially relieved the cardiomyopathy, which suggests mislocalised FHOD3 can be harmful rather than merely insufficient. These observations come from different disease contexts (not FHOD3-variant hearts) and are not reconciled, which is why the pathway does not commit to a single direction of FHOD3 dysfunction.
Show evidence (3 references)
PMID:23255317 SUPPORT Human Clinical
"FHOD3 expression is increased in the setting of HCM, and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue."
Increased FHOD3 expression in human HCM tissue.
PMID:21149568 REFUTE Human Clinical
"In murine and human cardiomyopathy, we observe reduced FHOD3 expression with a concomitant isoform switch and change of subcellular targeting."
Reduced FHOD3 expression in cardiomyopathic myocardium, the opposite direction. The sentence pools mouse and human tissue; HUMAN_CLINICAL is kept because the human samples are the part relevant here, but the observation is not human-only.
PMID:29686099 SUPPORT Model Organism
"The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under..."
Mislocalised FHOD3 is deleterious in a mouse HCM model, supporting a toxic-mislocalisation branch.
Do FHOD3 variants also cause dilated cardiomyopathy?
OPEN QUESTION OPEN fhod3_dcm_association
Attached to
genetic#FHOD3
A single FHOD3 missense variant (p.Tyr1249Asn) was reported in a Japanese adult-onset DCM case with in vitro functional impairment, and the noncompaction family showed moderate dilatation late in its course, but the DCM association is regarded as unproven. DCM is therefore not curated as a CMH28 phenotype.
Show evidence (2 references)
PMID:24088304 SUPPORT In Vitro
"Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant..."
The single-case functional evidence for a DCM association.
PMID:38051749 REFUTE BACKGROUND Human Clinical
"while the role of rare FHOD3 variants in dilated cardiomyopathy remains as yet unproven"
States that the DCM association is unproven.
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Pathophysiology

7
Heterozygous FHOD3 Non-Truncating Variant
Mechanism confidence: Established
The initiating lesion is a heterozygous germline FHOD3 variant. Most reported disease alleles are non-truncating - missense, in-frame indels, canonical splice-site variants predicted to skip in-frame cardiac exons, and in-frame deletions of exons 15-16 - and they cluster in a conserved coiled-coil segment (amino acids 622-655), the diaphanous inhibitory domain and the cardiac-specific exon 12. The genetic association itself is established; what the alleles do to the protein is not. The clustering and the absence of a phenotype in Fhod3 heterozygous mice argue against simple haploinsufficiency, but no patient allele has been tested biochemically, so the functional impact is recorded as UNKNOWN rather than as dominant negative.
FHOD3 hgnc:26178 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context FHOD3 hgnc:26178 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Predominantly missense, in-frame indel, splice-site and in-frame exon 15-16 deletion alleles. Recorded as UNKNOWN because the consequence for FHOD3 activity has not been measured for any patient allele; the dominant-negative reading is an inference from variant class and clustering (see discussions).
Animal models
Fhod3 constitutive knockout mouse Mouse fails to recapitulate Halving Fhod3 dosage produces no overt phenotype.
Downstream
Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere Assumed, not demonstrated. The step from a patient allele to altered FHOD3 actin-assembly activity has not been measured; the edge is drawn because the variants fall in regulatory and sarcomere-targeting regions of a protein whose actin-assembly activity is required for sarcomere integrity.
Show evidence (4 references)
PMID:30442288 SUPPORT Human Clinical
"One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects"
Establishes the coiled-coil hotspot and its strong enrichment in HCM.
PMID:32335906 SUPPORT Human Clinical
"We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group)."
In-frame exon 15-16 deletions in three HCM families extend the allele spectrum to copy-number variants affecting the same region.
PMID:38051749 SUPPORT BACKGROUND Human Clinical
"Most pathogenic FHOD3 variants associated with HCM so far seem to be restricted to non-truncating variants (missense, splice-site, and in-frame deletions/insertions variants) and cluster to two DID regions, to exon 12 and to the coiled-coil domain encoded by exons 15 and 16"
Summarises the non-truncating, clustered allele spectrum across prior FHOD3 HCM studies.
+ 1 more reference
Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
Mechanism confidence: Provisional
The heart-enriched long isoform FHOD3L nucleates actin and elongates filaments, and its elongation activity specifically is required for sarcomere formation and contraction. Its sarcomeric position depends on the cardiac-specific N-terminal region, which binds cardiac myosin-binding protein C and directs FHOD3 to the C-zone of the A-band; myofibril targeting is also regulated by CK2 phosphorylation of a muscle-specific exon. Disease alleles are predicted to disturb this localised actin assembly, either by reducing activity or by mislocalising it, but which of these happens for patient alleles is unknown. All evidence for this node is from cell-culture and animal systems.
FHOD3 hgnc:26178 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee.
actin filament polymerization GO:0030041 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin filament polymerization (GO:0030041). GO:0030041 is a biological process from the Gene Ontology.
actin filament binding GO:0051015 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology.
A band GO:0031672 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves A band (GO:0031672). GO:0031672 is a cellular component from the Gene Ontology. actin filament GO:0005884 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves actin filament (GO:0005884). GO:0005884 is a cellular component from the Gene Ontology.
Experimental models
Neonatal rat ventricular myocytes with function-separating FHOD3L mutants PRIMARY CELL CULTURE Selectively removes FHOD3L elongation activity and reads out sarcomere formation and contraction.
Downstream
Sarcomere Disorganization and Impaired Myofibril Maintenance Loss of FHOD3 actin-assembly activity disorganises the sarcomere, and the defect is rescued by wild-type FHOD3 but not by actin-assembly-dead mutants, which ties the structural defect to the actin-assembly activity itself.
Show evidence (4 references)
PMID:40663059 SUPPORT In Vitro
"We found that FHOD3L's elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes."
Function-separating mutants identify actin elongation as the FHOD3L activity the sarcomere depends on.
PMID:29686099 SUPPORT Model Organism
"The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone."
Shows in mouse that sarcomeric positioning of FHOD3 depends on its cardiac-specific cMyBP-C-binding region. That this region is encoded by exon 12 comes from the background statement below, not from this sentence.
PMID:38051749 SUPPORT BACKGROUND Model Organism
"Cardiac-specific exon 12 of the FHOD3 encodes a region that is required for the localisation of the long FHOD3 isoform to sarcomeric C-zone, a process mediated through interaction between FHOD3 and cardiac myosin-binding protein C."
Introduction statement (summarising prior experimental work) that ties exon 12, one of the human variant clusters, to C-zone targeting via cMyBP-C. Whether exon-12 patient variants actually mislocalise FHOD3 has not been tested.
+ 1 more reference
Sarcomere Disorganization and Impaired Myofibril Maintenance
Mechanism confidence: Provisional
Without adequate FHOD3 activity, thin filaments are lost and the sarcomere is disorganised and degraded; in human stem-cell-derived cardiomyocytes this is accompanied by impaired calcium handling and mitochondrial function. This is the primary cardiomyocyte insult from which the hypertrophic and contractile consequences follow. The evidence is from knockdown and knockout systems, which remove FHOD3 rather than express a patient allele.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
sarcomere organization GO:0045214 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. cardiac myofibril assembly GO:0055003 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac myofibril assembly (GO:0055003). GO:0055003 is a biological process from the Gene Ontology.
sarcomere GO:0030017 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcomere (GO:0030017). GO:0030017 is a cellular component from the Gene Ontology.
Experimental models
FHOD3-knockout hESC-derived cardiomyocytes OTHER Marked sarcomere disorganisation and degradation in human cardiomyocytes.
Animal models
Cardiac Fhod3 I1127A transgenic mouse Mouse recapitulates A defective FHOD3 disturbs myofibrils in the presence of the wild-type protein.
Downstream
Reduced Cardiomyocyte Contractility Disorganised sarcomeres generate less force.
CaMKII Activation FHOD3 loss is followed by CaMKII autophosphorylation; the intermediate steps (for example, the calcium-handling defect) are not resolved.
Show evidence (4 references)
PMID:19706596 SUPPORT In Vitro
"RNA interference-mediated depletion of Fhod3 results in a marked reduction in filamentous actin and disruption of the sarcomeric structure."
FHOD3 depletion in cardiomyocytes reduces filamentous actin and disrupts sarcomeres.
PMID:21149568 SUPPORT In Vitro
"Furthermore, we show that muscle FHOD3 efficiently promotes the polymerization of actin filaments in cardiomyocytes and that the down-regulation of its expression severely affects myofibril integrity."
Independent group showing that reduced FHOD3 compromises myofibril integrity.
PMID:29158260 SUPPORT Model Organism
"Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development."
In vivo cardiac deletion produces severely impaired myofibrils in enlarged hearts.
+ 1 more reference
Reduced Cardiomyocyte Contractility
Mechanism confidence: Provisional
Reduced force generation by FHOD3-deficient cardiomyocytes. Shown in human stem-cell-derived cardiomyocytes, rat ventricular myocytes, adult conditional-knockout mice (mild) and the fly heart; in patients the corresponding finding is the minority with reduced ejection fraction. How contractility of FHOD3 variant hearts compares with the hypercontractile state typical of sarcomeric HCM has not been measured.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle contraction GO:0060048 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology.
Experimental models
FHOD3-knockout hESC-derived cardiomyocytes OTHER Reduced contractility, partially rescued by omecamtiv mecarbil.
Animal models
Cardiac Fhod3 conditional knockout mouse (perinatal and adult inducible) Mouse partially recapitulates Mild, sustained impairment of cardiac function after adult deletion.
Drosophila fhos heart model Fruit fly recapitulates The fly orthologue is needed for normal adult systolic contraction.
Downstream
Reduced left ventricular ejection fraction Inferred: reduced cardiomyocyte force is the plausible cellular basis of the reduced ejection fraction seen in 14% of carriers, but this has not been shown in patient myocardium.
Left ventricular thrombus Inferred: thrombus formed in a poorly contracting, noncompacted left ventricle in the one reported family; stasis is the presumed but unmeasured intermediate.
Show evidence (2 references)
PMID:23255317 SUPPORT Model Organism
"Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction."
Invertebrate evidence that the FHOD3 orthologue is needed for normal systolic contraction.
PMID:29158260 SUPPORT Model Organism
"However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
Adult-onset deletion in mouse heart produces a mild, sustained functional impairment.
CaMKII Activation
Mechanism confidence: Hypothetical
Autophosphorylation of CaMKII at Thr286 in FHOD3-null human cardiomyocytes. CaMKII is an established driver of cardiac hypertrophic and maladaptive remodelling, so this is a candidate link from the sarcomeric lesion to the hypertrophic response; it is shown in one knockout cell model and is not yet demonstrated in patient tissue or with patient alleles.
calcium/calmodulin-dependent protein kinase activity GO:0004683 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased calcium/calmodulin-dependent protein kinase activity (GO:0004683). GO:0004683 is a molecular function from the Gene Ontology.
Experimental models
FHOD3-knockout hESC-derived cardiomyocytes OTHER CaMKII Thr286 phosphorylation rises in FHOD3-null cardiomyocytes.
Downstream
Maladaptive Hypertrophic Remodeling Proposed by the authors of the knockout study on the basis of CaMKII's known role; not tested by CaMKII inhibition in an FHOD3 model.
Congestive heart failure The knockout study attributes its heart-failure-like phenotype in part to CaMKII activation.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
Reports CaMKII activation in FHOD3-knockout human cardiomyocytes.
Maladaptive Hypertrophic Remodeling
Mechanism confidence: Provisional
The ventricular myocardium responds with cardiomyocyte hypertrophy and a fetal gene programme, producing the asymmetric, septum-predominant wall thickening that defines the clinical disease. In adult Fhod3-deleted mice the hypertrophic gene response to a pressor stimulus is exaggerated, suggesting FHOD3 restrains hypertrophic remodelling; whether patient alleles act the same way is inferred. Fibrosis and, in a minority, systolic dysfunction follow.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. cardiac fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy in response to stress GO:0014898 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy in response to stress (GO:0014898). GO:0014898 is a biological process from the Gene Ontology.
interventricular septum UBERON:0002094 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interventricular septum (UBERON:0002094). UBERON:0002094 is an anatomical location from the Uberon multi-species anatomy ontology. heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cardiac Fhod3 conditional knockout mouse (perinatal and adult inducible) Mouse partially recapitulates Adult deletion yields slight cardiomegaly and an exaggerated hypertrophic gene response to stress.
Downstream
Arrhythmia Arrhythmia arises in the remodelled myocardium of FHOD3 carriers; the electrophysiological intermediates have not been studied.
Hypertrophic cardiomyopathy The remodelled, thickened ventricle is the clinical hypertrophic cardiomyopathy.
Asymmetric septal hypertrophy Cardiomyocyte hypertrophy summed across the septum is the clinical septal hypertrophy.
Myocardial fibrosis Fibroblast activation and matrix deposition within the remodelling ventricle; documented in the FHOD3 noncompaction family, with no FHOD3-specific fibrosis mechanism study.
Congestive heart failure Progression to heart failure occurs in a minority; reported mainly from the noncompaction family.
Show evidence (2 references)
PMID:29158260 SUPPORT Model Organism
"In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the..."
Loss of FHOD3 in the adult mouse heart exaggerates the hypertrophic gene response to stress.
PMID:30442288 SUPPORT Human Clinical
"Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
The human tissue-level outcome of the remodelling node in 70 carriers of (likely) pathogenic variants.
Impaired Ventricular Trabecular Compaction
Mechanism confidence: Hypothetical
A minority of carriers have left ventricular hypertrabeculation, and one family presented with predominant noncompaction. Fhod3-null mouse embryos fail to form trabeculae, so a developmental myocardial-architecture defect is a candidate explanation. This node is HYPOTHETICAL: it rests on a complete embryonic knockout, whereas patients are heterozygous and hypertrabeculation may be under-ascertained without cardiac MRI.
cardiac muscle tissue development GO:0048738 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac muscle tissue development (GO:0048738). GO:0048738 is a biological process from the Gene Ontology.
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fhod3 constitutive knockout mouse Mouse partially recapitulates Trabecular myocardial development aborts in null embryos.
Downstream
Left ventricular noncompaction Inferred link from an embryonic trabeculation defect in null mice to adult hypertrabeculation in heterozygous patients; not demonstrated.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
Complete loss of FHOD3 in mouse embryos aborts trabecular myocardial development.
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Pathograph

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Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 28 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Blood 1
Left ventricular thrombus HP:0040412 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular thrombus (HP:0040412). HP:0040412 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
Thrombotic complications in an FHOD3 family; the full text specifies left ventricular apical thrombosis.
Cardiovascular 9
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30442288 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males."
Defines the clinical HCM phenotype and adult age at diagnosis in FHOD3 carriers.
PMID:33586461 SUPPORT Human Clinical
"On the basis of familial segregation, we identified one truncating variant (c.1286+2delT) as a causal variant in 4 patients."
Replication of FHOD3 HCM in a Chinese cohort with a segregating splice allele.
PMID:31742804 SUPPORT Human Clinical
"A non-frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member."
Family segregation of an exon-12 in-frame deletion with HCM, including an unaffected young carrier consistent with age-dependent penetrance.
Asymmetric septal hypertrophy VERY_FREQUENT HP:0001670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asymmetric septal hypertrophy (HP:0001670). HP:0001670 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30442288 SUPPORT Human Clinical
"Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
82% frequency maps to VERY_FREQUENT.
Left ventricular noncompaction OCCASIONAL HP:0030682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction (HP:0030682). HP:0030682 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30442288 SUPPORT Human Clinical
"Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
Hypertrabeculation in 16% maps to OCCASIONAL.
PMID:35205353 SUPPORT Human Clinical
"We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
A family in which noncompaction was the principal phenotype, cosegregating with an FHOD3 splice variant.
Reduced left ventricular ejection fraction OCCASIONAL HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30442288 SUPPORT Human Clinical
"Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
14% with LVEF below 50% maps to OCCASIONAL.
Myocardial fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
Reports myocardial fibrosis in FHOD3 carriers (single family).
Arrhythmia HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"The HM-ECG showed atrial fibrillation and nonsustained ventricular tachycardia."
Documents atrial and ventricular arrhythmia in the proband of an FHOD3 family.
Palpitations HP:0001962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palpitations (HP:0001962). HP:0001962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38051749 SUPPORT Human Clinical
"Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
Reports palpitations among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38051749 SUPPORT Human Clinical
"Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
Reports syncope among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"In this study, we observed a remarkable phenotype of noncompaction progressing to heart failure, moderate dilatation and fibrosis in siblings with burdened family history harboring the FHOD3 splicing variant."
Heart failure in two affected FHOD3 carriers.
Respiratory 1
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38051749 SUPPORT Human Clinical
"Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
Reports dyspnea among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
Constitutional 1
Chest pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38051749 SUPPORT Human Clinical
"Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
Reports chest pain among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
🧬

Genetic Associations

3
FHOD3 (Pathogenic Variants)
Gene: FHOD3 hgnc:26178 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (7 references)
PMID:30442288 SUPPORT Human Clinical
"The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001)."
Case-control burden evidence for FHOD3 in HCM.
PMID:30442288 SUPPORT Human Clinical
"FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
Segregation evidence for causation.
CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z SUPPORT Other
"FHOD3 | HGNC:26178 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen Definitive classification for FHOD3 in (generic) autosomal dominant HCM.
+ 4 more references
FHOD3 p.Arg637Gln (Intermediate-effect risk allele)
Gene: FHOD3 hgnc:26178 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (4 references)
PMID:38160043 SUPPORT Human Clinical
"The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%."
Establishes low heterozygous penetrance and the risk-factor character of the allele.
PMID:38160043 SUPPORT Human Clinical
"Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype."
Homozygosity produces a more severe, earlier phenotype.
PMID:40879562 SUPPORT INDIRECT Human Clinical
"IEVs also modified disease expression in individuals with monogenic variants, causing a more aggressive phenotype than in individuals from the monogenic-only group with HCM onset at younger age and a higher left ventricular maximum wall thickness (all P<0.0001), with major adverse cardiac..."
Pooled across genes (FHOD3 is one of five non-sarcomeric genes analysed), intermediate-effect variants act as modifiers of monogenic disease; the sentence does not name FHOD3, hence INDIRECT.
+ 1 more reference
FHOD3 rs516514 / p.Val1151Ile common variants (Common-variant association)
Gene: FHOD3 hgnc:26178 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FHOD3 (hgnc:26178). hgnc:26178 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:23255317 SUPPORT Human Clinical
"We identified an intronic FHOD3 variant (rs516514) associated with HCM (odds ratio, 2.45; 95% confidence interval, 1.76-3.41; P=1.25×10(-7)) and validated this finding in an independent cohort."
Genome-wide association of a common FHOD3 variant with HCM.
💊

Medical Actions

7
Cascade Screening and Cardiac Surveillance of At-Risk Relatives
Action: cascade genetic and cardiac screening of at-risk relativesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cascade genetic and cardiac screening of at-risk relatives, annotated with Cardiac Disease Screening (NCIT:C168126). NCIT:C168126 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Disease Screening NCIT:C168126
Platform: Other
Predictive testing of first-degree relatives for the familial FHOD3 variant, followed by serial cardiac evaluation of carriers. Strong cosegregation makes a relative's genotype informative; incomplete penetrance and adult onset mean an unaffected young carrier is not discharged. The intermediate-effect p.Arg637Gln allele is a special case: with about 1% heterozygous penetrance, a positive cascade result conveys only modest risk.
Show evidence (2 references)
PMID:30442288 SUPPORT Human Clinical
"FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
Cosegregation is what makes cascade genotyping of relatives informative.
PMID:31742804 SUPPORT Human Clinical
"The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies."
Identifying the familial allele enables family-based counselling and testing.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Counselling should convey autosomal dominant transmission, incomplete penetrance with onset from childhood to late adulthood, and the distinct low-penetrance, dosage-sensitive behaviour of p.Arg637Gln, whose homozygotes are at risk of early severe disease.
Show evidence (1 reference)
PMID:38160043 SUPPORT Human Clinical
"All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers."
Supplies the allele-specific penetrance and dosage information counselling must convey.
Pharmacotherapy for Symptomatic Hypertrophic Cardiomyopathy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metoprolol CHEBI:6904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metoprolol (CHEBI:6904). CHEBI:6904 is a therapeutic agent from Chemical Entities of Biological Interest. verapamil CHEBI:9948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses verapamil (CHEBI:9948). CHEBI:9948 is a therapeutic agent from Chemical Entities of Biological Interest. disopyramide CHEBI:4657 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses disopyramide (CHEBI:4657). CHEBI:4657 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Standard HCM pharmacotherapy (beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide) for symptoms and outflow obstruction.
Cardiac Myosin Inhibitor Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mavacamten CHEBI:756998 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mavacamten (CHEBI:756998). CHEBI:756998 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Mavacamten improves exercise capacity and outflow obstruction in symptomatic obstructive HCM. The pivotal trial was not genotype stratified, no FHOD3 carriers are reported separately, and FHOD3 knockout cardiomyocytes are hypocontractile, so whether myosin inhibition suits FHOD3 disease is untested; it is listed as general obstructive-HCM therapy, not as an FHOD3-directed one. Outflow obstruction, the indication, was not observed among the Balkan founder carriers, so it may be relevant to a minority of FHOD3 patients only.
Show evidence (2 references)
PMID:32871100 SUPPORT INDIRECT Human Clinical
"Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."
Efficacy in obstructive HCM generally; applying it to FHOD3 carriers is an inference.
PMID:38051749 SUPPORT Human Clinical
"Left outflow obstruction, severely impaired left ventricular filling pattern, apical aneurysm, reduced left ventricular ejection fraction, and atrial fibrillation were not observed."
Outflow obstruction, the indication for myosin inhibition, was absent in the Balkan founder carriers.
Implantable Cardioverter-Defibrillator
Action: Implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
Primary or secondary prevention of sudden death on standard HCM risk criteria. Annual cardiovascular mortality of about 1% in the founding cohort, and nonsustained ventricular tachycardia in the noncompaction family, keep arrhythmic risk stratification in scope.
Target Phenotypes: Arrhythmia HP:0011675 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Guideline-Directed Heart Failure Therapy
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Small molecule
Standard medical therapy for systolic dysfunction and heart failure, with anticoagulation for ventricular thrombus; in the noncompaction family this stabilised the proband for a time.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"The patient refused immunosuppressive therapy for myocarditis; he received the standard therapy for heart failure, due to which his condition stabilized."
Single-patient report of stabilisation on standard heart-failure therapy.
Omecamtiv Mecarbil (Preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: omecamtiv mecarbil CHEBI:188664 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses omecamtiv mecarbil (CHEBI:188664). CHEBI:188664 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The cardiac myosin activator omecamtiv mecarbil partially restored contractility in FHOD3-knockout human stem-cell-derived cardiomyocytes without correcting calcium handling. This is a single in vitro result in a loss-of-function model, not in patients or with patient alleles, and is recorded as a hypothesis-generating preclinical finding only.
Mechanism Target:
INHIBITS Reduced Cardiomyocyte Contractility — Myosin activation counteracts the contractile deficit downstream of sarcomere loss, without addressing the sarcomeric lesion itself.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy."
Partial rescue of contractility in FHOD3-knockout human cardiomyocytes.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy."
In vitro only; no clinical use in CMH28 is reported.
🔬

Diagnosis

3
Echocardiography
Imaging for unexplained left ventricular wall thickening, most often asymmetric septal hypertrophy, and for systolic function.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42291545 SUPPORT Human Clinical
"Here, we report a young male patient with asymmetric myocardial hypertrophy assessed by echocardiography, who was asymptomatic."
Echocardiography detected asymmetric hypertrophy in an asymptomatic FHOD3 carrier.
Cardiac Magnetic Resonance Imaging
Cardiac MRI characterises hypertrabeculation or noncompaction and myocardial fibrosis. In the reported noncompaction family, both affected siblings were first diagnosed with HCM and reclassified only after MRI.
cardiac MRI NCIT:C137915 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35205353 SUPPORT Human Clinical
"It should be noted that, in the present case, the proband and his sister were initially diagnosed with HCM, and the diagnosis of LVNC was clarified after the cMRI analysis was performed."
MRI changed the diagnosis from HCM to noncompaction in FHOD3 carriers.
Molecular Genetic Testing Including FHOD3 and CNV Analysis
Multigene HCM panel or exome sequencing that includes FHOD3, with copy-number analysis so that in-frame exon 15-16 deletions are not missed. Interpretation should distinguish Mendelian alleles from the intermediate-effect p.Arg637Gln allele.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30442288 SUPPORT Human Clinical
"The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels."
Recommendation to include FHOD3 in HCM gene panels.
PMID:32335906 SUPPORT Human Clinical
"This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease."
Supports routine CNV analysis to detect FHOD3 exon deletions.
📈

Progression

2
Genotype-positive relative before age 30
Clinical events are rare before age 30 and mean age at diagnosis is in the mid-forties, but onset as early as 4 years is reported for the Balkan founder allele, so carriers need longitudinal surveillance from childhood.
Show evidence (2 references)
PMID:30442288 SUPPORT Human Clinical
"Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up."
Low event rate before 30 defines the early pre-event phase.
PMID:38051749 SUPPORT Human Clinical
"Individuals with this variant had a wide range of ages at onset of the disease (4-63 years)."
Onset can occur in childhood.
Established hypertrophic cardiomyopathy
Course and event rate resemble unselected HCM in the founding cohort, with annual cardiovascular death about 1%. Outcome data conflict: Balkan founder carriers had no adverse cardiac events, while a Chinese cohort associated candidate variants with higher mortality. A minority progress to systolic dysfunction and heart failure.
Show evidence (2 references)
PMID:30442288 SUPPORT Human Clinical
"The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts."
Overall prognosis is that of unselected HCM.
PMID:38051749 SUPPORT Human Clinical
"No adverse cardiac events were observed."
Benign course among founder-allele carriers, one side of the conflicting outcome data.
🧫

Experimental Models

2
FHOD3-knockout hESC-derived cardiomyocytes OTHER
CRISPR/Cas9 FHOD3-null human embryonic stem cell line differentiated to cardiomyocytes. Models complete loss of FHOD3 in human cells, not a heterozygous patient allele, and the cells are developmentally immature.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:41540467
Pathograph links
Sarcomere Disorganization and Impaired Myofibril Maintenance recapitulates fidelity: moderate observes: cellular Marked sarcomere disorganisation and degradation in human cardiomyocytes.
Limitations: Homozygous null in immature stem-cell-derived cardiomyocytes; patients are heterozygous for mostly non-truncating alleles.
Readouts
Sarcomere organisation
Direction: DECREASED
Interpretation: Sarcomeres disorganise and degrade without FHOD3.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
Reports the sarcomere readout.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Transcriptomic analysis revealed significant downregulation of sarcomere-related genes and calcium-handling genes, with enrichment in pathways associated with cardiomyopathy and calcium signaling."
Transcriptomic support that the model engages sarcomeric and cardiomyopathy pathways.
CaMKII Activation recapitulates fidelity: low observes: cellular CaMKII Thr286 phosphorylation rises in FHOD3-null cardiomyocytes.
Limitations: Only system in which this has been shown; not tested in patient tissue or with patient alleles.
Readouts
CaMKII Thr286 phosphorylation
Direction: INCREASED
Interpretation: CaMKII is activated by FHOD3 loss.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
Reports the phosphorylation readout.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
Supports the model as the source of the CaMKII node.
Reduced Cardiomyocyte Contractility recapitulates fidelity: moderate observes: cellular Reduced contractility, partially rescued by omecamtiv mecarbil.
Limitations: Immature cardiomyocytes and a null genotype.
Show evidence (1 reference)
PMID:41540467 SUPPORT In Vitro
"FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
Reports reduced contractility.
Neonatal rat ventricular myocytes with function-separating FHOD3L mutants PRIMARY_CELL_CULTURE
Knockdown-and-replacement of FHOD3L in neonatal rat ventricular myocytes with mutants that separate nucleation, elongation, capping and bundling, used to identify which biochemical activity the sarcomere requires.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
rat NCBITaxon:10116 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in rat, annotated with Rattus norvegicus (NCBITaxon:10116). NCBITaxon:10116 is an organism from the NCBI Taxonomy.
Publication
PMID:40663059
Pathograph links
Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere perturbs fidelity: moderate observes: molecular Selectively removes FHOD3L elongation activity and reads out sarcomere formation and contraction.
Limitations: Engineered mutants, not patient alleles; neonatal rat cells.
Show evidence (1 reference)
PMID:40663059 SUPPORT In Vitro
"We found that FHOD3L's elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes."
Identifies elongation as the required FHOD3L activity.
🐁

Animal Models

4
Fhod3 constitutive knockout mouse
Germline Fhod3 nulls die by E11.5 because premyofibrils fail to mature and chamber formation and trabeculation abort. Heterozygotes, the genotype closest to the human dosage, are phenotypically normal. Transgenic cardiac re-expression of wild-type Fhod3 rescues the embryos.
Species
Mouse
Genotype
Fhod3-/- (germline null); Fhod3+/- heterozygotes
Publication
PMID:23213483
Pathograph links
Impaired Ventricular Trabecular Compaction partially recapitulates fidelity: low observes: tissue Trabecular myocardial development aborts in null embryos.
Limitations: A complete embryonic-lethal null; patients are heterozygous for mostly non-truncating alleles and present with adult hypertrabeculation, and heterozygous mice are normal.
Readouts
Embryonic trabecular development
Direction: DECREASED
Interpretation: Trabeculation fails in the absence of FHOD3.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
Reports the trabeculation measurement.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
Supports the model as informative for the trabeculation node.
Heterozygous FHOD3 Non-Truncating Variant fails to recapitulate fidelity: low observes: organism Halving Fhod3 dosage produces no overt phenotype.
Limitations: A null allele, not a patient non-truncating allele, and mouse lifespan and haemodynamics differ; it rules out haploinsufficiency only for the mouse.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
The heterozygous null does not model the dominant human disease.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"However, these premyofibrils fail to mature and myocardial development does not continue, leading to embryonic lethality by E11.5."
Establishes the embryonic lethal null phenotype.
Cardiac Fhod3 I1127A transgenic mouse
Overexpression of an actin-assembly-defective FHOD3 in the heart causes cardiomyopathic changes with immature myofibrils despite wild-type Fhod3.
Species
Mouse
Genotype
alpha-MHC-driven Fhod3 I1127A (actin-assembly-defective) transgene on a wild-type background
Publication
PMID:23213483
Pathograph links
Sarcomere Disorganization and Impaired Myofibril Maintenance recapitulates fidelity: moderate observes: tissue A defective FHOD3 disturbs myofibrils in the presence of the wild-type protein.
Limitations: Engineered point mutant in the FH2 domain, expressed from a transgene at non-physiological levels; it is not a patient allele or a hotspot region.
Show evidence (1 reference)
PMID:23213483 SUPPORT Model Organism
"Moreover, cardiomyopathic changes with immature myofibrils are caused in mice overexpressing a mutant Fhod3, defective in binding to actin."
Reports the myofibrillar and cardiomyopathic phenotype of the mutant transgene.
Cardiac Fhod3 conditional knockout mouse (perinatal and adult inducible)
Perinatal cardiac deletion causes juvenile death with enlarged hearts and severely impaired myofibrils; adult deletion causes slight cardiomegaly, mild dysfunction and an exaggerated fetal-gene response to phenylephrine, without sarcomere disruption.
Species
Mouse
Genotype
floxed Fhod3 with cardiac Cre (perinatal) or tamoxifen-inducible cardiac Cre (adult)
Publication
PMID:29158260
Pathograph links
Maladaptive Hypertrophic Remodeling partially recapitulates fidelity: low observes: organism Adult deletion yields slight cardiomegaly and an exaggerated hypertrophic gene response to stress.
Limitations: Complete cardiac deletion rather than a heterozygous patient allele; the adult hearts show slight cardiomegaly, not asymmetric septal hypertrophy, and ClinGen notes that no model has shown a clear HCM phenotype.
Readouts
Fetal cardiac gene expression after phenylephrine
Direction: INCREASED
Interpretation: The hypertrophic gene programme is exaggerated without FHOD3.
Show evidence (1 reference)
PMID:29158260 SUPPORT Model Organism
"In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the..."
Reports the fetal-gene readout.
Show evidence (1 reference)
PMID:29158260 SUPPORT Model Organism
"However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
Adult deletion produces a mild cardiomyopathy, partially modelling remodelling.
Reduced Cardiomyocyte Contractility partially recapitulates fidelity: low observes: organism Mild, sustained impairment of cardiac function after adult deletion.
Limitations: Whole-heart function after complete deletion; magnitude is mild and the allele is not a patient allele.
Show evidence (1 reference)
PMID:29158260 SUPPORT Model Organism
"However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
Reports reduced cardiac function in the adult deletion model.
Drosophila fhos heart model
Species
Fruit fly
Genotype
reduced fhos (FHOD3 orthologue) in the heart
Publication
PMID:23255317
Pathograph links
Reduced Cardiomyocyte Contractility recapitulates fidelity: low observes: organism The fly orthologue is needed for normal adult systolic contraction.
Limitations: Invertebrate tubular heart without a ventricular septum; models contractile requirement, not hypertrophy.
Show evidence (1 reference)
PMID:23255317 SUPPORT Model Organism
"Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction."
Reports the systolic contraction defect in the fly model.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 28
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- CMH28
- cardiomyopathy, familial hypertrophic, 28
- familial hypertrophic cardiomyopathy 28
- FHOD3-related hypertrophic cardiomyopathy
description: >-
  Hypertrophic cardiomyopathy 28 (CMH28) is the FHOD3-attributed member of the
  numbered familial hypertrophic cardiomyopathy series. FHOD3 encodes a formin,
  an actin-assembly protein; its heart-enriched long isoform is recruited to the
  sarcomere C-zone by cardiac myosin-binding protein C and is required to build
  and maintain the thin-filament array of the cardiac sarcomere. FHOD3 is
  therefore a sarcomere-associated rather than a core sarcomeric gene, and it is
  now one of the main non-sarcomeric causes of HCM, accounting for roughly 1-2%
  of probands in the founding Spanish/UK cohort of 3,189 patients. ClinGen
  classifies FHOD3 as Definitive for autosomal dominant hypertrophic
  cardiomyopathy.

  The disease is autosomal dominant with incomplete penetrance and variable
  expressivity. Diagnosis is typically in mid-adulthood (mean 46 years in the
  founding cohort), most patients have asymmetric septal hypertrophy, and a
  minority show left ventricular hypertrabeculation, reduced ejection fraction
  or, in one reported family, a predominantly noncompaction phenotype.
  Pathogenic alleles are mostly non-truncating (missense, in-frame indels,
  splice-site and exon deletions) and cluster in a conserved coiled-coil /
  diaphanous inhibitory region and in the cardiac-specific exon 12. How these
  alleles change FHOD3 function has not been shown biochemically; the
  pathophysiology below is built from knockdown, knockout and overexpression
  models and is labelled accordingly. One recurrent coiled-coil allele,
  p.Arg637Gln, behaves as a low-penetrance intermediate-effect risk allele in
  heterozygotes and causes a severe early phenotype in homozygotes.
disease_term:
  preferred_term: cardiomyopathy, familial hypertrophic, 28
  term:
    id: MONDO:0030317
    label: cardiomyopathy, familial hypertrophic, 28
parents:
- Hypertrophic Cardiomyopathy
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: PMID:30442288
  title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
- reference: PMID:39971408
  title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
- reference: PMID:38160043
  title: "Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers."
- reference: PMID:38051749
  title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous FHOD3 variants segregate with HCM as an autosomal dominant
    trait, with very strong combined cosegregation across 17 families in the
    founding cohort. Penetrance is incomplete and expressivity is variable: age
    at onset in the Balkan founder families ranged from 4 to 63 years. The
    recurrent p.Arg637Gln allele is the exception to simple dominance - an
    intermediate-effect allele with penetrance of about 1% in heterozygotes and
    a severe early phenotype in most homozygotes - and is curated as a separate
    risk-factor genetic record rather than as recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
    explanation: Family cosegregation of heterozygous variants with HCM establishes dominant transmission.
  - reference: CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z
    reference_title: "FHOD3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FHOD3 | HGNC:26178 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: ClinGen curates the FHOD3-HCM relationship with autosomal dominant mode of inheritance.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Disease-causing variants in FHOD3 are most commonly associated with the phenotype of HCM, with penetrance being incomplete"
    explanation: The introduction summarises prior cohorts as showing incomplete penetrance of FHOD3 disease variants.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with this variant had a wide range of ages at onset of the disease (4-63 years)."
    explanation: The wide age range at onset among carriers of one allele documents variable expressivity.
pathophysiology:
- name: Heterozygous FHOD3 Non-Truncating Variant
  description: >-
    The initiating lesion is a heterozygous germline FHOD3 variant. Most
    reported disease alleles are non-truncating - missense, in-frame indels,
    canonical splice-site variants predicted to skip in-frame cardiac exons,
    and in-frame deletions of exons 15-16 - and they cluster in a conserved
    coiled-coil segment (amino acids 622-655), the diaphanous inhibitory domain
    and the cardiac-specific exon 12. The genetic association itself is
    established; what the alleles do to the protein is not. The clustering and
    the absence of a phenotype in Fhod3 heterozygous mice argue against simple
    haploinsufficiency, but no patient allele has been tested biochemically, so
    the functional impact is recorded as UNKNOWN rather than as dominant
    negative.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genetic_context:
    gene:
      preferred_term: FHOD3
      term:
        id: hgnc:26178
        label: FHOD3
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Predominantly missense, in-frame indel, splice-site and in-frame exon
      15-16 deletion alleles. Recorded as UNKNOWN because the consequence for
      FHOD3 activity has not been measured for any patient allele; the
      dominant-negative reading is an inference from variant class and
      clustering (see discussions).
  genes:
  - preferred_term: FHOD3
    term:
      id: hgnc:26178
      label: FHOD3
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects"
    explanation: Establishes the coiled-coil hotspot and its strong enrichment in HCM.
  - reference: PMID:32335906
    reference_title: "Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group)."
    explanation: In-frame exon 15-16 deletions in three HCM families extend the allele spectrum to copy-number variants affecting the same region.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most pathogenic FHOD3 variants associated with HCM so far seem to be restricted to non-truncating variants (missense, splice-site, and in-frame deletions/insertions variants) and cluster to two DID regions, to exon 12 and to the coiled-coil domain encoded by exons 15 and 16"
    explanation: Summarises the non-truncating, clustered allele spectrum across prior FHOD3 HCM studies.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Over 50 variants (missense, nonsense, splice variants and in frame del/dup variants) have been reported in >100 probands in at least 6 publications."
    explanation: >-
      ClinGen's synthesis of the reported FHOD3 HCM allele spectrum. Note that
      it lists nonsense variants among reported alleles, so the spectrum is
      predominantly but not exclusively non-truncating; this node's name
      describes the majority class, not every reported allele. Quoted
      from the medRxiv preprint of the expert-panel reappraisal because the
      peer-reviewed version (PMID:39971408) is cached as abstract only.
  downstream:
  - target: Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
    causal_link_type: UNKNOWN
    description: >-
      Assumed, not demonstrated. The step from a patient allele to altered
      FHOD3 actin-assembly activity has not been measured; the edge is drawn
      because the variants fall in regulatory and sarcomere-targeting regions
      of a protein whose actin-assembly activity is required for sarcomere
      integrity.
    evidence:
    - reference: PMID:35205353
      reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: "Along with the predominance of missense variants in previous FHOD3 studies, this allows us to speculate that the mechanism of FHOD3 malfunctioning is dominant-negative rather than haploinsufficiency, although there are still not enough data to make that assertion with confidence."
      explanation: >-
        The only explicit statement of how patient alleles might alter FHOD3,
        based on in silico prediction that all known splice alleles skip
        in-frame cardiac exons; the authors themselves flag it as speculation.
- name: Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
  description: >-
    The heart-enriched long isoform FHOD3L nucleates actin and elongates
    filaments, and its elongation activity specifically is required for
    sarcomere formation and contraction. Its sarcomeric position depends on
    the cardiac-specific N-terminal region, which binds cardiac myosin-binding
    protein C and directs FHOD3 to the C-zone of the A-band; myofibril
    targeting is also regulated by CK2 phosphorylation of a muscle-specific
    exon. Disease alleles are predicted to disturb this localised actin
    assembly, either by reducing activity or by mislocalising it, but which of
    these happens for patient alleles is unknown. All evidence for this node
    is from cell-culture and animal systems.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: FHOD3
    term:
      id: hgnc:26178
      label: FHOD3
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: actin filament polymerization
    term:
      id: GO:0030041
      label: actin filament polymerization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: A band
    term:
      id: GO:0031672
      label: A band
  - preferred_term: actin filament
    term:
      id: GO:0005884
      label: actin filament
  evidence:
  - reference: PMID:40663059
    reference_title: "Human formin FHOD3-mediated actin elongation is required for sarcomere integrity in cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that FHOD3L's elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes."
    explanation: Function-separating mutants identify actin elongation as the FHOD3L activity the sarcomere depends on.
  - reference: PMID:29686099
    reference_title: "Interaction between cardiac myosin-binding protein C and formin Fhod3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone."
    explanation: Shows in mouse that sarcomeric positioning of FHOD3 depends on its cardiac-specific cMyBP-C-binding region. That this region is encoded by exon 12 comes from the background statement below, not from this sentence.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Cardiac-specific exon 12 of the FHOD3 encodes a region that is required for the localisation of the long FHOD3 isoform to sarcomeric C-zone, a process mediated through interaction between FHOD3 and cardiac myosin-binding protein C."
    explanation: Introduction statement (summarising prior experimental work) that ties exon 12, one of the human variant clusters, to C-zone targeting via cMyBP-C. Whether exon-12 patient variants actually mislocalise FHOD3 has not been tested.
  - reference: PMID:21149568
    reference_title: "Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The specific targeting of muscle FHOD3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of CK2."
    explanation: A second, independent regulatory input that controls where FHOD3 acts in the cardiomyocyte.
  downstream:
  - target: Sarcomere Disorganization and Impaired Myofibril Maintenance
    causal_link_type: DIRECT
    description: >-
      Loss of FHOD3 actin-assembly activity disorganises the sarcomere, and the
      defect is rescued by wild-type FHOD3 but not by actin-assembly-dead
      mutants, which ties the structural defect to the actin-assembly activity
      itself.
    evidence:
    - reference: PMID:19706596
      reference_title: "Mammalian formin fhod3 regulates actin assembly and sarcomere organization in striated muscles."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These defects are rescued by expression of wild-type Fhod3 but not by that of mutant proteins carrying amino acid substitution for conserved residues for actin assembly."
      explanation: The rescue design establishes that the sarcomeric defect follows from loss of FHOD3 actin assembly specifically.
    - reference: PMID:23213483
      reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "As shown in the present study, overexpression of a mutant Fhod3 protein with the I1127A substitution, defective in an in vivo actin-assembling activity (Taniguchi et al., 2009), can induce cardiomyopathic changes with immature myofibrils even in the presence of a wild-type allele."
      explanation: >-
        An actin-assembly-defective FHOD3 disturbs myofibrils in vivo despite a
        wild-type allele, the closest model evidence for an interfering mutant
        protein. It is an overexpressed engineered mutant, not a patient allele.
- name: Sarcomere Disorganization and Impaired Myofibril Maintenance
  description: >-
    Without adequate FHOD3 activity, thin filaments are lost and the sarcomere
    is disorganised and degraded; in human stem-cell-derived cardiomyocytes
    this is accompanied by impaired calcium handling and mitochondrial
    function. This is the primary cardiomyocyte insult from which the
    hypertrophic and contractile consequences follow. The evidence is from
    knockdown and knockout systems, which remove FHOD3 rather than express a
    patient allele.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: DECREASED
  - preferred_term: cardiac myofibril assembly
    term:
      id: GO:0055003
      label: cardiac myofibril assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: sarcomere
    term:
      id: GO:0030017
      label: sarcomere
  evidence:
  - reference: PMID:19706596
    reference_title: "Mammalian formin fhod3 regulates actin assembly and sarcomere organization in striated muscles."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA interference-mediated depletion of Fhod3 results in a marked reduction in filamentous actin and disruption of the sarcomeric structure."
    explanation: FHOD3 depletion in cardiomyocytes reduces filamentous actin and disrupts sarcomeres.
  - reference: PMID:21149568
    reference_title: "Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, we show that muscle FHOD3 efficiently promotes the polymerization of actin filaments in cardiomyocytes and that the down-regulation of its expression severely affects myofibril integrity."
    explanation: Independent group showing that reduced FHOD3 compromises myofibril integrity.
  - reference: PMID:29158260
    reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development."
    explanation: In vivo cardiac deletion produces severely impaired myofibrils in enlarged hearts.
  - reference: PMID:41540467
    reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
    explanation: Reproduces the sarcomere defect in human cardiomyocytes, alongside calcium-handling and mitochondrial defects.
  downstream:
  - target: Reduced Cardiomyocyte Contractility
    causal_link_type: DIRECT
    description: Disorganised sarcomeres generate less force.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
      explanation: The authors place reduced contractility as the consequence of the sarcomeric, calcium and mitochondrial defects in FHOD3-null human cardiomyocytes.
  - target: CaMKII Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      FHOD3 loss is followed by CaMKII autophosphorylation; the intermediate
      steps (for example, the calcium-handling defect) are not resolved.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
      explanation: Links FHOD3 deficiency to CaMKII activation in human cardiomyocytes.
- name: Reduced Cardiomyocyte Contractility
  description: >-
    Reduced force generation by FHOD3-deficient cardiomyocytes. Shown in human
    stem-cell-derived cardiomyocytes, rat ventricular myocytes, adult
    conditional-knockout mice (mild) and the fly heart; in patients the
    corresponding finding is the minority with reduced ejection fraction. How
    contractility of FHOD3 variant hearts compares with the hypercontractile
    state typical of sarcomeric HCM has not been measured.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:23255317
    reference_title: "Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction."
    explanation: Invertebrate evidence that the FHOD3 orthologue is needed for normal systolic contraction.
  - reference: PMID:29158260
    reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
    explanation: Adult-onset deletion in mouse heart produces a mild, sustained functional impairment.
  downstream:
  - target: Reduced left ventricular ejection fraction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: reduced cardiomyocyte force is the plausible cellular basis of
      the reduced ejection fraction seen in 14% of carriers, but this has not
      been shown in patient myocardium.
  - target: Left ventricular thrombus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: thrombus formed in a poorly contracting, noncompacted left
      ventricle in the one reported family; stasis is the presumed but
      unmeasured intermediate.
    evidence:
    - reference: PMID:35205353
      reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
      explanation: Thrombotic complications in an FHOD3 family with systolic dysfunction; the link to reduced contractility is inferred.
- name: CaMKII Activation
  description: >-
    Autophosphorylation of CaMKII at Thr286 in FHOD3-null human
    cardiomyocytes. CaMKII is an established driver of cardiac hypertrophic
    and maladaptive remodelling, so this is a candidate link from the
    sarcomeric lesion to the hypertrophic response; it is shown in one
    knockout cell model and is not yet demonstrated in patient tissue or with
    patient alleles.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  molecular_functions:
  - preferred_term: calcium/calmodulin-dependent protein kinase activity
    term:
      id: GO:0004683
      label: calcium/calmodulin-dependent protein kinase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:41540467
    reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
    explanation: Reports CaMKII activation in FHOD3-knockout human cardiomyocytes.
  downstream:
  - target: Maladaptive Hypertrophic Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the authors of the knockout study on the basis of CaMKII's
      known role; not tested by CaMKII inhibition in an FHOD3 model.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
      explanation: The link to remodelling rests on CaMKII's general role, which the sentence invokes, rather than on an FHOD3-specific intervention.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The knockout study attributes its heart-failure-like phenotype in part to CaMKII activation.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "This model allows for extensive investigation into the phenotypes caused by FHOD3 deficiency and identifies CaMKII activation as a crucial factor contributing to the HF phenotype."
      explanation: An in vitro heart-failure-like phenotype is extrapolated to clinical heart failure, hence INDIRECT.
- name: Maladaptive Hypertrophic Remodeling
  description: >-
    The ventricular myocardium responds with cardiomyocyte hypertrophy and a
    fetal gene programme, producing the asymmetric, septum-predominant wall
    thickening that defines the clinical disease. In adult Fhod3-deleted mice
    the hypertrophic gene response to a pressor stimulus is exaggerated,
    suggesting FHOD3 restrains hypertrophic remodelling; whether patient
    alleles act the same way is inferred. Fibrosis and, in a minority,
    systolic dysfunction follow.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy in response to stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:29158260
    reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart."
    explanation: Loss of FHOD3 in the adult mouse heart exaggerates the hypertrophic gene response to stress.
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
    explanation: The human tissue-level outcome of the remodelling node in 70 carriers of (likely) pathogenic variants.
  downstream:
  - target: Arrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Arrhythmia arises in the remodelled myocardium of FHOD3 carriers; the
      electrophysiological intermediates have not been studied.
    evidence:
    - reference: PMID:35205353
      reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
      explanation: Arrhythmia co-occurs with fibrosis and remodelling in an FHOD3 family; the causal route is inferred.
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: The remodelled, thickened ventricle is the clinical hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:30442288
      reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males."
      explanation: Establishes clinical HCM as the outcome in FHOD3 carriers; that remodelling is the route to it is inferred, not shown by this sentence.
  - target: Asymmetric septal hypertrophy
    causal_link_type: DIRECT
    description: Cardiomyocyte hypertrophy summed across the septum is the clinical septal hypertrophy.
    evidence:
    - reference: PMID:30442288
      reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
      explanation: Asymmetric septal hypertrophy is the dominant expression of remodelling in FHOD3 carriers.
  - target: Myocardial fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fibroblast activation and matrix deposition within the remodelling
      ventricle; documented in the FHOD3 noncompaction family, with no
      FHOD3-specific fibrosis mechanism study.
    evidence:
    - reference: PMID:35205353
      reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We described the presence of intramyocardial fibrosis cosegregating with the reported variant, thus expanding the spectrum of known genotype–phenotype correlations for the FHOD3 gene."
      explanation: Documents fibrosis cosegregating with an FHOD3 allele; the remodelling step that produces it is inferred.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progression to heart failure occurs in a minority; reported mainly from
      the noncompaction family.
    evidence:
    - reference: PMID:35205353
      reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we observed a remarkable phenotype of noncompaction progressing to heart failure, moderate dilatation and fibrosis in siblings with burdened family history harboring the FHOD3 splicing variant."
      explanation: Clinical progression to heart failure in FHOD3 carriers; the mechanistic route is not resolved.
- name: Impaired Ventricular Trabecular Compaction
  description: >-
    A minority of carriers have left ventricular hypertrabeculation, and one
    family presented with predominant noncompaction. Fhod3-null mouse embryos
    fail to form trabeculae, so a developmental myocardial-architecture
    defect is a candidate explanation. This node is HYPOTHETICAL: it rests on
    a complete embryonic knockout, whereas patients are heterozygous and
    hypertrabeculation may be under-ascertained without cardiac MRI.
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: cardiac muscle tissue development
    term:
      id: GO:0048738
      label: cardiac muscle tissue development
    modifier: ABNORMAL
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:23213483
    reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
    explanation: Complete loss of FHOD3 in mouse embryos aborts trabecular myocardial development.
  downstream:
  - target: Left ventricular noncompaction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred link from an embryonic trabeculation defect in null mice to
      adult hypertrabeculation in heterozygous patients; not demonstrated.
    evidence:
    - reference: PMID:30442288
      reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
      explanation: Supplies the human hypertrabeculation finding at the end of the edge; the causal connection to the mouse defect is inference.
mechanistic_hypotheses:
- hypothesis_group_id: fhod3_allele_mechanism
  hypothesis_label: Non-truncating FHOD3 alleles act through an altered (interfering) protein rather than haploinsufficiency
  status: EMERGING
  description: >-
    Three observations point away from simple haploinsufficiency: the disease
    alleles are overwhelmingly non-truncating and clustered in regulatory and
    sarcomere-targeting regions; all known splice alleles are predicted to
    skip in-frame cardiac exons; and Fhod3 heterozygous mice are normal. An
    overexpressed actin-assembly-dead FHOD3 causes cardiomyopathic changes in
    mice despite a wild-type allele, which shows that a defective FHOD3 can
    interfere in vivo. None of this tests a patient allele, so the hypothesis
    remains open; it is not encoded as DOMINANT_NEGATIVE on the pathway.
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Along with the predominance of missense variants in previous FHOD3 studies, this allows us to speculate that the mechanism of FHOD3 malfunctioning is dominant-negative rather than haploinsufficiency, although there are still not enough data to make that assertion with confidence."
    explanation: The explicit, self-qualified statement of the hypothesis.
  - reference: PMID:23213483
    reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
    explanation: Halving Fhod3 dosage in mice produces no overt phenotype, which argues against haploinsufficiency as the disease mechanism (with the caveat of species difference).
phenotypes:
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  description: >-
    The defining diagnosis. Typically diagnosed in adulthood (mean 46 years in
    the founding cohort), with clinical events rare before age 30.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males."
    explanation: Defines the clinical HCM phenotype and adult age at diagnosis in FHOD3 carriers.
  - reference: PMID:33586461
    reference_title: "Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the basis of familial segregation, we identified one truncating variant (c.1286+2delT) as a causal variant in 4 patients."
    explanation: Replication of FHOD3 HCM in a Chinese cohort with a segregating splice allele.
  - reference: PMID:31742804
    reference_title: "Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A non-frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member."
    explanation: Family segregation of an exon-12 in-frame deletion with HCM, including an unaffected young carrier consistent with age-dependent penetrance.
- category: Cardiovascular
  name: Asymmetric septal hypertrophy
  description: >-
    The predominant morphology, present in 82% of carriers of (likely)
    pathogenic variants, with mean maximal septal thickness of 18.8 mm.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
    explanation: 82% frequency maps to VERY_FREQUENT.
- category: Cardiovascular
  name: Left ventricular noncompaction
  description: >-
    Left ventricular hypertrabeculation in 16% of carriers in the founding
    cohort. One Russian family carrying a canonical splice-donor variant
    after exon 12 (c.1646+1G>A) met noncompaction criteria, initially
    diagnosed as HCM until cardiac MRI; the authors suggest noncompaction may
    be under-ascertained in FHOD3 carriers.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
    explanation: Hypertrabeculation in 16% maps to OCCASIONAL.
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
    explanation: A family in which noncompaction was the principal phenotype, cosegregating with an FHOD3 splice variant.
- category: Cardiovascular
  name: Reduced left ventricular ejection fraction
  description: >-
    Left ventricular ejection fraction below 50% in 14% of carriers;
    severe systolic dysfunction was documented in
    the proband of the noncompaction family.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%."
    explanation: 14% with LVEF below 50% maps to OCCASIONAL.
- category: Cardiovascular
  name: Myocardial fibrosis
  description: >-
    Intramyocardial fibrosis on cardiac MRI cosegregated with the FHOD3 splice
    variant in the noncompaction family. Cohort-level fibrosis frequency has
    not been reported.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
    explanation: Reports myocardial fibrosis in FHOD3 carriers (single family).
- category: Cardiovascular
  name: Arrhythmia
  description: >-
    Arrhythmic complications are documented in the noncompaction family,
    including atrial fibrillation and nonsustained ventricular tachycardia on
    Holter monitoring. In the Balkan founder cohort, nonsustained ventricular
    tachycardia was present in 3 of 13 carriers (Table 1) and atrial
    fibrillation was not observed. No frequency from a larger cohort is
    available, so no frequency band is assigned.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HM-ECG showed atrial fibrillation and nonsustained ventricular tachycardia."
    explanation: Documents atrial and ventricular arrhythmia in the proband of an FHOD3 family.
- category: Cardiovascular
  name: Dyspnea
  description: >-
    Exertional dyspnoea was among the presenting symptoms in the Balkan founder cohort; half of carriers were asymptomatic at diagnosis. No frequency is given in the text.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
    explanation: Reports dyspnea among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
- category: Cardiovascular
  name: Palpitations
  description: >-
    Reported among presenting symptoms in the Balkan founder cohort. No frequency is given in the text.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
    explanation: Reports palpitations among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
- category: Cardiovascular
  name: Syncope
  description: >-
    Reported among presenting symptoms in the Balkan founder cohort. No frequency is given in the text.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
    explanation: Reports syncope among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
- category: Cardiovascular
  name: Chest pain
  description: >-
    Reported among presenting symptoms in the Balkan founder cohort. No frequency is given in the text.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the individuals were asymptomatic at diagnosis, while others reported chest pain, dyspnoea on exertion, fatigue, palpitations and syncope."
    explanation: Reports chest pain among presenting symptoms in Balkan founder-allele carriers, half of whom were asymptomatic at diagnosis.
- category: Cardiovascular
  name: Left ventricular thrombus
  description: >-
    Recurrent left ventricular apical thrombus in the proband of the
    noncompaction family, in the setting of severe systolic dysfunction.
  phenotype_term:
    preferred_term: Left ventricular thrombus
    term:
      id: HP:0040412
      label: Left ventricular thrombus
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene."
    explanation: Thrombotic complications in an FHOD3 family; the full text specifies left ventricular apical thrombosis.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Progression to heart failure occurs in a minority and is best documented
    in the noncompaction family, whose proband died of the disease.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we observed a remarkable phenotype of noncompaction progressing to heart failure, moderate dilatation and fibrosis in siblings with burdened family history harboring the FHOD3 splicing variant."
    explanation: Heart failure in two affected FHOD3 carriers.
genetic:
- name: FHOD3
  gene_term:
    preferred_term: FHOD3
    term:
      id: hgnc:26178
      label: FHOD3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    FHOD3 (18q12.2) encodes a diaphanous-related formin with GBD, DID,
    coiled-coil, FH1, FH2 and DAD domains; the heart-enriched long isoform
    includes exon 12, which encodes the cMyBP-C-binding region. Pathogenic HCM
    alleles are mostly non-truncating and cluster in the coiled-coil segment
    (aa 622-655, exons 15-16), the DID and exon 12. Recurrent or founder
    alleles include the Balkan splice-donor c.1646+2T>C (estimated to have
    arisen about 58 generations ago), exon-12 p.Ser527del and p.Tyr528Cys,
    the Chinese splice allele c.1286+2delT, and in-frame exon 15-16 deletions
    that are only detected if CNV analysis is performed.
  notes: >-
    gene_disease_validity is deliberately left empty. ClinGen's Hereditary
    Cardiovascular Disease GCEP classifies FHOD3 as Definitive (AD), but that
    assertion is filed against generic hypertrophic cardiomyopathy
    (MONDO:0005045), not against MONDO:0030317, so under the repository rule it
    is a different disease pair (other_disease); it is cited as ordinary
    evidence below. CAUSATIVE is consistent with that Definitive tier. ClinGen
    also notes that experimental studies show FHOD3's role in sarcomere
    development but that no model has yet shown a clear HCM phenotype.
    A Chinese whole-exome cohort found that carriers of FHOD3 candidate
    variants (a set that includes variants of uncertain significance) had a
    higher adjusted risk of cardiovascular and all-cause death; this conflicts
    with the founding cohort's conclusion that event rates resemble unselected
    HCM and with the absence of adverse events among Balkan founder carriers.
  case_fractions:
  - population: Unrelated hypertrophic cardiomyopathy probands, Spain and UK (founding cohort)
    case_fraction_low: 1.0
    case_fraction_high: 2.0
    cohort_size: 3189
    notes: >-
      Authors' summary estimate of the FHOD3-attributable share. Candidate
      protein-altering variants were present in 2.32% of probands versus 0.65%
      of disease controls, so the raw candidate-variant rate overstates the
      attributable share.
    evidence:
    - reference: PMID:30442288
      reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases."
      explanation: The FHOD3 share of HCM cases in the founding cohort.
  - population: Chinese hypertrophic cardiomyopathy patients (whole-exome cohort)
    case_fraction_percent: 3.3
    cohort_size: 1000
    notes: >-
      Candidate variants, not curated pathogenic variants; 1.6% of controls
      also carried candidates, so this is an upper bound on the attributable
      share.
    evidence:
    - reference: PMID:33586461
      reference_title: "Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In detail, there were 27 candidate variants detected in 33 (3.3%) patients with HCM, which was significantly higher than in the 12 controls (3.3% versus 1.6%; odds ratio, 2.13; P<0.05)."
      explanation: Candidate-variant frequency in Chinese HCM patients versus controls.
  - population: Genetically solved hypertrophic cardiomyopathy probands, Balkans (Slovenia and neighbouring populations)
    case_fraction_percent: 16
    notes: >-
      A single founder allele (c.1646+2T>C) in 8 of 134 exome-sequenced
      probands; the 16% denominator is probands with a known genetic cause,
      not all HCM probands.
    evidence:
    - reference: PMID:38051749
      reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5-2% for causal FHOD3 variants."
      explanation: Founder-population case fraction, contrasted by the authors with the 0.5-2% estimate elsewhere.
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001)."
    explanation: Case-control burden evidence for FHOD3 in HCM.
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
    explanation: Segregation evidence for causation.
  - reference: CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z
    reference_title: "FHOD3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FHOD3 | HGNC:26178 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: ClinGen Definitive classification for FHOD3 in (generic) autosomal dominant HCM.
  - 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: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive)."
    explanation: The peer-reviewed ClinGen reappraisal reporting FHOD3 as Definitive.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, it should be noted that while experimental studies have shown an important role for FHOD3 in heart and sarcomeric development, no studies have demonstrated a clear HCM phenotype."
    explanation: ClinGen's own caveat that the experimental support is developmental and sarcomeric rather than a modelled HCM phenotype (quoted from the preprint version).
  - reference: PMID:34526680
    reference_title: "Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    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 FHOD3 among the minor, non-sarcomeric HCM genes.
  - reference: PMID:33586461
    reference_title: "Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, the FHOD3 candidate variant experienced significantly more risk of cardiovascular death and all-cause death (adjusted hazard ratio [HR], 3.71; 95%, 1.32-8.59; P=0.016; and adjusted HR, 3.02; 95% CI, 1.09-6.85; P=0.035, respectively)."
    explanation: Prognostic association in a Chinese cohort; the variant set includes variants of uncertain significance.
- name: FHOD3 p.Arg637Gln
  gene_term:
    preferred_term: FHOD3
    term:
      id: hgnc:26178
      label: FHOD3
  association: Intermediate-effect risk allele
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    A recurrent coiled-coil missense allele, enriched about five-fold in an
    Iberian HCM cohort but with an estimated heterozygous penetrance of only
    about 1%, so on its own it is a predisposing intermediate-effect variant
    rather than a Mendelian cause. Six of seven homozygotes had early, severe
    HCM, which is a dosage effect of this allele and is not recorded as
    autosomal recessive inheritance. In a larger multi-gene analysis,
    intermediate-effect variants (p.Arg637Gln accounting for about half of
    carriers) worsened outcomes when combined with a monogenic variant.
  case_fractions:
  - population: Unrelated hypertrophic cardiomyopathy probands, Spain (single-centre NGS series)
    case_fraction_percent: 2.94
    cohort_size: 9668
    notes: Heterozygous p.Arg637Gln carriers; 0.58% of gnomAD controls carried the allele.
    evidence:
    - reference: PMID:38160043
      reference_title: "Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07)."
      explanation: Carrier frequency and enrichment of the allele among HCM probands.
  evidence:
  - reference: PMID:38160043
    reference_title: "Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%."
    explanation: Establishes low heterozygous penetrance and the risk-factor character of the allele.
  - reference: PMID:38160043
    reference_title: "Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype."
    explanation: Homozygosity produces a more severe, earlier phenotype.
  - reference: PMID:40879562
    reference_title: "Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "IEVs also modified disease expression in individuals with monogenic variants, causing a more aggressive phenotype than in individuals from the monogenic-only group with HCM onset at younger age and a higher left ventricular maximum wall thickness (all P<0.0001), with major adverse cardiac event-free survival being significantly lower (93.3% versus 69.3% at 70 years of age; P<0.0001)."
    explanation: Pooled across genes (FHOD3 is one of five non-sarcomeric genes analysed), intermediate-effect variants act as modifiers of monogenic disease; the sentence does not name FHOD3, hence INDIRECT.
  - reference: PMID:40879562
    reference_title: "Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because the FHOD3:p.Arg637Gln variant was identified in 50% of probands carrying IEVs, we compared its effects with the other IEVs."
    explanation: p.Arg637Gln accounts for half of intermediate-effect-variant carriers in this cohort, which is what links the pooled finding above to this allele.
- name: FHOD3 rs516514 / p.Val1151Ile common variants
  gene_term:
    preferred_term: FHOD3
    term:
      id: hgnc:26178
      label: FHOD3
  association: Common-variant association
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Common FHOD3 variants associated with HCM in a genome-wide association
    study. They are susceptibility alleles for HCM in general, not causes of
    CMH28, and homozygous p.1151Ile carriers did not differ phenotypically.
  evidence:
  - reference: PMID:23255317
    reference_title: "Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified an intronic FHOD3 variant (rs516514) associated with HCM (odds ratio, 2.45; 95% confidence interval, 1.76-3.41; P=1.25×10(-7)) and validated this finding in an independent cohort."
    explanation: Genome-wide association of a common FHOD3 variant with HCM.
diagnosis:
- name: Echocardiography
  description: >-
    Imaging for unexplained left ventricular wall thickening, most often
    asymmetric septal hypertrophy, and for systolic function.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:42291545
    reference_title: "A novel FHOD3 splice-site variant in a Chinese family with hypertrophic cardiomyopathy: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a young male patient with asymmetric myocardial hypertrophy assessed by echocardiography, who was asymptomatic."
    explanation: Echocardiography detected asymmetric hypertrophy in an asymptomatic FHOD3 carrier.
- name: Cardiac Magnetic Resonance Imaging
  description: >-
    Cardiac MRI characterises hypertrabeculation or noncompaction and
    myocardial fibrosis. In the reported noncompaction family, both affected
    siblings were first diagnosed with HCM and reclassified only after MRI.
  diagnosis_term:
    preferred_term: cardiac MRI
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It should be noted that, in the present case, the proband and his sister were initially diagnosed with HCM, and the diagnosis of LVNC was clarified after the cMRI analysis was performed."
    explanation: MRI changed the diagnosis from HCM to noncompaction in FHOD3 carriers.
- name: Molecular Genetic Testing Including FHOD3 and CNV Analysis
  description: >-
    Multigene HCM panel or exome sequencing that includes FHOD3, with
    copy-number analysis so that in-frame exon 15-16 deletions are not
    missed. Interpretation should distinguish Mendelian alleles from the
    intermediate-effect p.Arg637Gln allele.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels."
    explanation: Recommendation to include FHOD3 in HCM gene panels.
  - reference: PMID:32335906
    reference_title: "Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease."
    explanation: Supports routine CNV analysis to detect FHOD3 exon deletions.
progression:
- phase: Genotype-positive relative before age 30
  notes: >-
    Clinical events are rare before age 30 and mean age at diagnosis is in the
    mid-forties, but onset as early as 4 years is reported for the Balkan
    founder allele, so carriers need longitudinal surveillance from childhood.
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up."
    explanation: Low event rate before 30 defines the early pre-event phase.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with this variant had a wide range of ages at onset of the disease (4-63 years)."
    explanation: Onset can occur in childhood.
- phase: Established hypertrophic cardiomyopathy
  notes: >-
    Course and event rate resemble unselected HCM in the founding cohort, with
    annual cardiovascular death about 1%. Outcome data conflict: Balkan founder
    carriers had no adverse cardiac events, while a Chinese cohort associated
    candidate variants with higher mortality. A minority progress to systolic
    dysfunction and heart failure.
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts."
    explanation: Overall prognosis is that of unselected HCM.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No adverse cardiac events were observed."
    explanation: Benign course among founder-allele carriers, one side of the conflicting outcome data.
treatments:
- name: Cascade Screening and Cardiac Surveillance of At-Risk Relatives
  description: >-
    Predictive testing of first-degree relatives for the familial FHOD3
    variant, followed by serial cardiac evaluation of carriers. Strong
    cosegregation makes a relative's genotype informative; incomplete
    penetrance and adult onset mean an unaffected young carrier is not
    discharged. The intermediate-effect p.Arg637Gln allele is a special case:
    with about 1% heterozygous penetrance, a positive cascade result conveys
    only modest risk.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cascade genetic and cardiac screening of at-risk relatives
    term:
      id: NCIT:C168126
      label: Cardiac Disease Screening
  evidence:
  - reference: PMID:30442288
    reference_title: "Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation."
    explanation: Cosegregation is what makes cascade genotyping of relatives informative.
  - reference: PMID:31742804
    reference_title: "Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies."
    explanation: Identifying the familial allele enables family-based counselling and testing.
- name: Genetic Counseling
  description: >-
    Counselling should convey autosomal dominant transmission, incomplete penetrance with onset from childhood to late adulthood,
    and the distinct low-penetrance, dosage-sensitive behaviour of
    p.Arg637Gln, whose homozygotes are at risk of early severe disease.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38160043
    reference_title: "Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers."
    explanation: Supplies the allele-specific penetrance and dosage information counselling must convey.
- name: Pharmacotherapy for Symptomatic Hypertrophic Cardiomyopathy
  description: >-
    Standard HCM pharmacotherapy (beta-blockers, non-dihydropyridine calcium
    channel blockers, disopyramide) for symptoms and outflow obstruction.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
    - preferred_term: verapamil
      term:
        id: CHEBI:9948
        label: verapamil
    - preferred_term: disopyramide
      term:
        id: CHEBI:4657
        label: disopyramide
  notes: >-
    Deliberately carries no evidence item. No FHOD3-specific treatment study
    exists; management follows general HCM guidelines (2024 AHA/ACC,
    PMID:38718139), whose cached abstract contains no quotable recommendation
    text, so no snippet is claimed.
- name: Cardiac Myosin Inhibitor Therapy
  description: >-
    Mavacamten improves exercise capacity and outflow obstruction in
    symptomatic obstructive HCM. The pivotal trial was not genotype
    stratified, no FHOD3 carriers are reported separately, and FHOD3
    knockout cardiomyocytes are hypocontractile, so whether myosin inhibition
    suits FHOD3 disease is untested; it is listed as general obstructive-HCM
    therapy, not as an FHOD3-directed one. Outflow obstruction, the indication,
    was not observed among the Balkan founder carriers, so it may be
    relevant to a minority of FHOD3 patients only.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."
    explanation: Efficacy in obstructive HCM generally; applying it to FHOD3 carriers is an inference.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left outflow obstruction, severely impaired left ventricular filling pattern, apical aneurysm, reduced left ventricular ejection fraction, and atrial fibrillation were not observed."
    explanation: Outflow obstruction, the indication for myosin inhibition, was absent in the Balkan founder carriers.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Primary or secondary prevention of sudden death on standard HCM risk
    criteria. Annual cardiovascular mortality of about 1% in the founding
    cohort, and nonsustained ventricular tachycardia in the noncompaction
    family, keep arrhythmic risk stratification in scope.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  notes: >-
    Deliberately carries no evidence item. No FHOD3-specific ICD outcome data
    or risk model exist and the CMH28 literature does not evaluate device
    therapy; indications are guideline-generic.
- name: Guideline-Directed Heart Failure Therapy
  description: >-
    Standard medical therapy for systolic dysfunction and heart failure, with
    anticoagulation for ventricular thrombus; in the noncompaction family this
    stabilised the proband for a time.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:35205353
    reference_title: "A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient refused immunosuppressive therapy for myocarditis; he received the standard therapy for heart failure, due to which his condition stabilized."
    explanation: Single-patient report of stabilisation on standard heart-failure therapy.
- name: Omecamtiv Mecarbil (Preclinical)
  description: >-
    The cardiac myosin activator omecamtiv mecarbil partially restored
    contractility in FHOD3-knockout human stem-cell-derived cardiomyocytes
    without correcting calcium handling. This is a single in vitro result in
    a loss-of-function model, not in patients or with patient alleles, and is
    recorded as a hypothesis-generating preclinical finding only.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: omecamtiv mecarbil
      term:
        id: CHEBI:188664
        label: omecamtiv mecarbil
  target_mechanisms:
  - target: Reduced Cardiomyocyte Contractility
    treatment_effect: INHIBITS
    description: Myosin activation counteracts the contractile deficit downstream of sarcomere loss, without addressing the sarcomeric lesion itself.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy."
      explanation: Partial rescue of contractility in FHOD3-knockout human cardiomyocytes.
  evidence:
  - reference: PMID:41540467
    reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy."
    explanation: In vitro only; no clinical use in CMH28 is reported.
animal_models:
- name: Fhod3 constitutive knockout mouse
  species: Mouse
  genotype: Fhod3-/- (germline null); Fhod3+/- heterozygotes
  publication: PMID:23213483
  description: >-
    Germline Fhod3 nulls die by E11.5 because premyofibrils fail to mature and
    chamber formation and trabeculation abort. Heterozygotes, the genotype
    closest to the human dosage, are phenotypically normal. Transgenic cardiac
    re-expression of wild-type Fhod3 rescues the embryos.
  evidence:
  - reference: PMID:23213483
    reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, these premyofibrils fail to mature and myocardial development does not continue, leading to embryonic lethality by E11.5."
    explanation: Establishes the embryonic lethal null phenotype.
  modeled_mechanisms:
  - target: Impaired Ventricular Trabecular Compaction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Trabecular myocardial development aborts in null embryos.
    limitations: >-
      A complete embryonic-lethal null; patients are heterozygous for mostly
      non-truncating alleles and present with adult hypertrabeculation, and
      heterozygous mice are normal.
    readouts:
    - name: Embryonic trabecular development
      target: Impaired Ventricular Trabecular Compaction
      direction: DECREASED
      interpretation: Trabeculation fails in the absence of FHOD3.
      evidence:
      - reference: PMID:23213483
        reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
        explanation: Reports the trabeculation measurement.
    evidence:
    - reference: PMID:23213483
      reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although the developing heart tube of Fhod3−/− embryos initiates rightward looping, subsequent chamber formation and myocardial development with trabeculation are aborted."
      explanation: Supports the model as informative for the trabeculation node.
  - target: Heterozygous FHOD3 Non-Truncating Variant
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: Halving Fhod3 dosage produces no overt phenotype.
    limitations: >-
      A null allele, not a patient non-truncating allele, and mouse lifespan
      and haemodynamics differ; it rules out haploinsufficiency only for the
      mouse.
    evidence:
    - reference: PMID:23213483
      reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
      explanation: The heterozygous null does not model the dominant human disease.
- name: Cardiac Fhod3 I1127A transgenic mouse
  species: Mouse
  genotype: alpha-MHC-driven Fhod3 I1127A (actin-assembly-defective) transgene on a wild-type background
  publication: PMID:23213483
  description: >-
    Overexpression of an actin-assembly-defective FHOD3 in the heart causes
    cardiomyopathic changes with immature myofibrils despite wild-type Fhod3.
  modeled_mechanisms:
  - target: Sarcomere Disorganization and Impaired Myofibril Maintenance
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: A defective FHOD3 disturbs myofibrils in the presence of the wild-type protein.
    limitations: >-
      Engineered point mutant in the FH2 domain, expressed from a transgene at
      non-physiological levels; it is not a patient allele or a hotspot
      region.
    evidence:
    - reference: PMID:23213483
      reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, cardiomyopathic changes with immature myofibrils are caused in mice overexpressing a mutant Fhod3, defective in binding to actin."
      explanation: Reports the myofibrillar and cardiomyopathic phenotype of the mutant transgene.
- name: Cardiac Fhod3 conditional knockout mouse (perinatal and adult inducible)
  species: Mouse
  genotype: floxed Fhod3 with cardiac Cre (perinatal) or tamoxifen-inducible cardiac Cre (adult)
  publication: PMID:29158260
  description: >-
    Perinatal cardiac deletion causes juvenile death with enlarged hearts and
    severely impaired myofibrils; adult deletion causes slight cardiomegaly,
    mild dysfunction and an exaggerated fetal-gene response to phenylephrine,
    without sarcomere disruption.
  modeled_mechanisms:
  - target: Maladaptive Hypertrophic Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Adult deletion yields slight cardiomegaly and an exaggerated hypertrophic gene response to stress.
    limitations: >-
      Complete cardiac deletion rather than a heterozygous patient allele; the
      adult hearts show slight cardiomegaly, not asymmetric septal
      hypertrophy, and ClinGen notes that no model has shown a clear HCM
      phenotype.
    readouts:
    - name: Fetal cardiac gene expression after phenylephrine
      target: Maladaptive Hypertrophic Remodeling
      direction: INCREASED
      interpretation: The hypertrophic gene programme is exaggerated without FHOD3.
      evidence:
      - reference: PMID:29158260
        reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart."
        explanation: Reports the fetal-gene readout.
    evidence:
    - reference: PMID:29158260
      reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
      explanation: Adult deletion produces a mild cardiomyopathy, partially modelling remodelling.
  - target: Reduced Cardiomyocyte Contractility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Mild, sustained impairment of cardiac function after adult deletion.
    limitations: Whole-heart function after complete deletion; magnitude is mild and the allele is not a patient allele.
    evidence:
    - reference: PMID:29158260
      reference_title: "The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging."
      explanation: Reports reduced cardiac function in the adult deletion model.
- name: Drosophila fhos heart model
  species: Fruit fly
  genotype: reduced fhos (FHOD3 orthologue) in the heart
  publication: PMID:23255317
  modeled_mechanisms:
  - target: Reduced Cardiomyocyte Contractility
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: The fly orthologue is needed for normal adult systolic contraction.
    limitations: Invertebrate tubular heart without a ventricular septum; models contractile requirement, not hypertrophy.
    evidence:
    - reference: PMID:23255317
      reference_title: "Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction."
      explanation: Reports the systolic contraction defect in the fly model.
experimental_models:
- name: FHOD3-knockout hESC-derived cardiomyocytes
  description: >-
    CRISPR/Cas9 FHOD3-null human embryonic stem cell line differentiated to
    cardiomyocytes. Models complete loss of FHOD3 in human cells, not a
    heterozygous patient allele, and the cells are developmentally immature.
  experimental_model_type: OTHER
  publication: PMID:41540467
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Sarcomere Disorganization and Impaired Myofibril Maintenance
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Marked sarcomere disorganisation and degradation in human cardiomyocytes.
    limitations: Homozygous null in immature stem-cell-derived cardiomyocytes; patients are heterozygous for mostly non-truncating alleles.
    readouts:
    - name: Sarcomere organisation
      target: Sarcomere Disorganization and Impaired Myofibril Maintenance
      direction: DECREASED
      interpretation: Sarcomeres disorganise and degrade without FHOD3.
      evidence:
      - reference: PMID:41540467
        reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
        explanation: Reports the sarcomere readout.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Transcriptomic analysis revealed significant downregulation of sarcomere-related genes and calcium-handling genes, with enrichment in pathways associated with cardiomyopathy and calcium signaling."
      explanation: Transcriptomic support that the model engages sarcomeric and cardiomyopathy pathways.
  - target: CaMKII Activation
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: CaMKII Thr286 phosphorylation rises in FHOD3-null cardiomyocytes.
    limitations: Only system in which this has been shown; not tested in patient tissue or with patient alleles.
    readouts:
    - name: CaMKII Thr286 phosphorylation
      target: CaMKII Activation
      direction: INCREASED
      interpretation: CaMKII is activated by FHOD3 loss.
      evidence:
      - reference: PMID:41540467
        reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
        explanation: Reports the phosphorylation readout.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure."
      explanation: Supports the model as the source of the CaMKII node.
  - target: Reduced Cardiomyocyte Contractility
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced contractility, partially rescued by omecamtiv mecarbil.
    limitations: Immature cardiomyocytes and a null genotype.
    evidence:
    - reference: PMID:41540467
      reference_title: "FHOD3 deficiency disrupts sarcomere organization and activates caMKII signaling in human stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility."
      explanation: Reports reduced contractility.
- name: Neonatal rat ventricular myocytes with function-separating FHOD3L mutants
  description: >-
    Knockdown-and-replacement of FHOD3L in neonatal rat ventricular myocytes
    with mutants that separate nucleation, elongation, capping and bundling,
    used to identify which biochemical activity the sarcomere requires.
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:40663059
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Selectively removes FHOD3L elongation activity and reads out sarcomere formation and contraction.
    limitations: Engineered mutants, not patient alleles; neonatal rat cells.
    evidence:
    - reference: PMID:40663059
      reference_title: "Human formin FHOD3-mediated actin elongation is required for sarcomere integrity in cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that FHOD3L's elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes."
      explanation: Identifies elongation as the required FHOD3L activity.
discussions:
- discussion_id: fhod3_patient_allele_mechanism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    What do heterozygous non-truncating FHOD3 patient alleles actually do to
    FHOD3 activity and localisation in adult cardiomyocytes?
  attaches_to:
  - pathophysiology#Heterozygous FHOD3 Non-Truncating Variant
  - pathophysiology#Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
  - animal_models#Fhod3 constitutive knockout mouse
  rationale: >-
    Every functional system used so far removes FHOD3 (knockdown, knockout,
    conditional deletion) or overexpresses an engineered mutant, whereas
    patients are heterozygous for mostly non-truncating alleles clustered in
    the coiled-coil/DID region and exon 12. Null mice die as embryos and
    heterozygous nulls are normal, so neither reproduces adult-onset HCM, and
    ClinGen explicitly notes that no study has demonstrated a clear HCM
    phenotype in a model. The mechanism chain in this entry is therefore
    built from loss-of-function systems, and the allele-to-protein step is
    UNKNOWN. A patient-allele knock-in (for example a coiled-coil missense,
    p.Arg637Gln, or the exon 15-16 deletion) in mice or isogenic iPSC-derived
    cardiomyocytes would test whether these alleles reduce actin assembly,
    mislocalise FHOD3 away from the C-zone, or interfere with the wild-type
    protein.
  evidence:
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, it should be noted that while experimental studies have shown an important role for FHOD3 in heart and sarcomeric development, no studies have demonstrated a clear HCM phenotype."
    explanation: Expert-panel statement of the model gap.
  - reference: PMID:23213483
    reference_title: "Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult heterozygous Fhod3+/− mice appeared phenotypically normal and fertile."
    explanation: The dosage-matched null mouse has no phenotype.
- discussion_id: fhod3_expression_direction_in_cardiomyopathy
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is FHOD3 expression increased or decreased in diseased human myocardium,
    and does mislocalised FHOD3 contribute to hypertrophy?
  attaches_to:
  - pathophysiology#Perturbed FHOD3-Directed Actin Assembly in the Cardiac Sarcomere
  rationale: >-
    One group found FHOD3 expression increased in HCM myectomy tissue; another
    found reduced FHOD3 with an isoform switch in murine and human
    cardiomyopathy. In cMyBP-C-null mice, where FHOD3 is mislocalised,
    overexpressing FHOD3 worsened and reducing it partially relieved the
    cardiomyopathy, which suggests mislocalised FHOD3 can be harmful rather
    than merely insufficient. These observations come from different disease
    contexts (not FHOD3-variant hearts) and are not reconciled, which is why
    the pathway does not commit to a single direction of FHOD3 dysfunction.
  evidence:
  - reference: PMID:23255317
    reference_title: "Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHOD3 expression is increased in the setting of HCM, and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue."
    explanation: Increased FHOD3 expression in human HCM tissue.
  - reference: PMID:21149568
    reference_title: "Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In murine and human cardiomyopathy, we observe reduced FHOD3 expression with a concomitant isoform switch and change of subcellular targeting."
    explanation: Reduced FHOD3 expression in cardiomyopathic myocardium, the opposite direction. The sentence pools mouse and human tissue; HUMAN_CLINICAL is kept because the human samples are the part relevant here, but the observation is not human-only.
  - reference: PMID:29686099
    reference_title: "Interaction between cardiac myosin-binding protein C and formin Fhod3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized."
    explanation: Mislocalised FHOD3 is deleterious in a mouse HCM model, supporting a toxic-mislocalisation branch.
- discussion_id: fhod3_dcm_association
  kind: OPEN_QUESTION
  status: OPEN
  prompt: Do FHOD3 variants also cause dilated cardiomyopathy?
  attaches_to:
  - genetic#FHOD3
  rationale: >-
    A single FHOD3 missense variant (p.Tyr1249Asn) was reported in a Japanese
    adult-onset DCM case with in vitro functional impairment, and the
    noncompaction family showed moderate dilatation late in its course, but
    the DCM association is regarded as unproven. DCM is therefore not
    curated as a CMH28 phenotype.
  evidence:
  - reference: PMID:24088304
    reference_title: "Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3."
    explanation: The single-case functional evidence for a DCM association.
  - reference: PMID:38051749
    reference_title: "A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "while the role of rare FHOD3 variants in dilated cardiomyopathy remains as yet unproven"
    explanation: States that the DCM association is unproven.
notes: >-
  GeneReviews: no FHOD3- or CMH28-specific chapter exists. The Nonsyndromic
  Hypertrophic Cardiomyopathy Overview chapter (PMID:20301725) covers HCM
  generally; its cached abstract only states the chapter's purpose and has no
  quotable findings, so it is tagged in references but carries no evidence
  items. ClinGen
  gene-disease validity is not recorded in gene_disease_validity because the
  Definitive FHOD3 assertion is for generic hypertrophic cardiomyopathy
  (MONDO:0005045), not MONDO:0030317; it is cited as evidence instead.
  Symptom and arrhythmia data come from small series only: the Balkan founder
  cohort reports that half of carriers were asymptomatic at diagnosis, with
  chest pain, exertional dyspnoea, fatigue, palpitations and syncope in the
  others, nonsustained VT in 3 of 13 and no atrial fibrillation; the
  noncompaction family adds atrial fibrillation and nonsustained VT. No
  frequency bands are assigned because none come from a large cohort. Sudden cardiac death is not
  curated as a phenotype: the founding cohort reports annual cardiovascular
  death (about 1%) without separating sudden death. No CMH28-specific
  treatment trial exists; management is general HCM care. Septal reduction
  therapy and aficamten are deliberately not listed: outflow obstruction, their
  indication, was not observed in the Balkan founder cohort, and no
  FHOD3-specific data exist for either.
📚

References & Deep Research

References

5
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:30442288
Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.
No top-level findings curated for this source.
PMID:39971408
Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.
No top-level findings curated for this source.
PMID:38160043
Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers.
No top-level findings curated for this source.
PMID:38051749
A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Hypertrophic_Cardiomyopathy_28 · 2026-10-08T19:07:27Z · View source

Created the CMH28 (FHOD3, MONDO:0030317) entry from the validated claude_code deep-research report (falcon fallback; preflight PASS, 23/23 references resolved). Key sources: Ochoa 2018 founding cohort PMID:30442288 (3,189 probands, LOD 7.92, coiled-coil hotspot, 82% ASH, 14% LVEF<50%, 16% hypertrabeculation), Ochoa 2020 exon 15-16 CNVs PMID:32335906, Balkan founder c.1646+2T>C PMID:38051749, Chinese cohort PMID:33586461, p.S527del family PMID:31742804, LVNC family PMID:35205353, p.Arg637Gln intermediate-effect allele PMID:38160043 and PMID:40879562, ClinGen Definitive (CGGV assertion for MONDO:0005045; PMID:39971408, preprint PMID:39132495), mechanism/model papers PMID:19706596, 21149568, 23213483, 29158260, 29686099, 40663059, 41540467, 23255317. Pathophysiology chain: heterozygous non-truncating FHOD3 variant (functional impact UNKNOWN) -> perturbed FHOD3L actin assembly -> sarcomere disorganization (conforms to cardiomyopathy_maladaptive_remodeling Primary Cardiomyocyte Insult) -> reduced contractility and CaMKII activation -> maladaptive hypertrophic remodeling (conforms to Ventricular Remodeling) -> ASH/HCM/fibrosis/heart failure; separate hypothetical trabecular-compaction node -> LV noncompaction. ClinGen tier not recorded in gene_disease_validity because the assertion is for MONDO:0005045, not MONDO:0030317. GeneReviews check --online: NO_CHAPTER. Stub deleted. Validation: just validate pass, count-verified-snippets 100% verified, entity-refs, causal-targets, enum-values, duplicate-keys, snippet-length/grading/title, coarse-phenotypes and model-scale-audit OK; validate-disorders run as final gate. Review round 1 fixes: added FHOD3 gene and GO:0051015 actin filament binding (modifier ABNORMAL) on the actin-assembly node so the gene-activity grounding gate passes for all three genetic rows; added INDIRECT plus the FHOD3:p.Arg637Gln 50%-of-IEV-carriers sentence (PMID:40879562); added Balkan cohort symptom phenotypes (dyspnea, palpitations, syncope, chest pain) and corrected the arrhythmia description and notes (NSVT 3/13, no AF, PMID:38051749); added the exon-12/C-zone background quote and narrowed the cMyBP-C explanation; noted nonsense alleles in the ClinGen spectrum explanation; added remodeling->arrhythmia and contractility->LV thrombus edges (INDIRECT); added no-outflow-obstruction evidence to mavacamten; marked the remodeling->HCM edge INDIRECT. Kept COMPUTATIONAL on the PMID:35205353 dominant-negative speculation (based on in-silico splice prediction) and did not conform the contractility node to Progressive Contractile Dysfunction (that module node is a downstream pump-failure effector of remodeling, not a cellular upstream defect). validate-disorders: 109 snippets, 0 issues.

Claude Code ▸
Hypertrophic Cardiomyopathy 28 (CMH28; FHOD3-related HCM): research report
claude-haiku-5-5, claude-opus-5-5 6 citations 2026-10-08T14:35:31.645118

I'm searching PubMed for the main FHOD3 papers so I can pull exact abstract quotes.

I'm caching the key FHOD3 papers with the repo's fetcher so I can quote their abstracts word for word.

I'm reading the cached abstracts for the mechanism and model papers now. Next I'll check the ontology terms, then write the report.

Hypertrophic Cardiomyopathy 28 (CMH28; FHOD3-related HCM): research report

Target: cardiomyopathy, familial hypertrophic, 28, MONDO:0030317 Prepared: 2026-10-08 for the kb/disorders/Hypertrophic_Cardiomyopathy_28.yaml entry

How the evidence was gathered. I fetched 17 PubMed records into references_cache/ with just fetch-reference. Every quotation below was copied from those cache files or from an existing structured record. A few points come only from web search and are marked [unverified lead]; check them before citing.

Housekeeping: this run added 17 new references_cache/PMID_*.md files. They are untracked in the worktree. One of them, PMID_30442289.md (the Pinto & Reckman JACC editorial), came back with no quotable text. Remove it unless a retry with --force returns an abstract.

1. Disease information

Overview. CMH28 is autosomal dominant hypertrophic cardiomyopathy caused by heterozygous variants in FHOD3. FHOD3 is a formin, a protein that assembles actin filaments, and it organises the sarcomere in heart muscle. FHOD3 is not itself a sarcomere protein; it is one of the main "non-sarcomeric" HCM genes. The disease typically appears in adulthood, penetrance is incomplete, and expression is variable. Most patients have asymmetric septal hypertrophy, and some also have left ventricular hypertrabeculation or noncompaction.

The gene was established by Ochoa et al. 2018, which studied 3,189 HCM probands:

"FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases." (PMID:30442288)

Identifiers

System ID Status
MONDO MONDO:0030317 "cardiomyopathy, familial hypertrophic, 28" In the repo cache
OMIM 619402 (CMH28); FHOD3 gene *609691 619402 confirmed by web search. 609691 [unverified lead]
HGNC hgnc:26178 FHOD3 In the repo cache
MedGen 1779612 [unverified lead] (DrugMap record)
ICD-10 I42.1 / I42.2 Generic HCM codes, not specific to this subtype
Orphanet No FHOD3-specific disorder. It falls under familial isolated HCM Code not verified
Parent MONDO MONDO:0005045 hypertrophic cardiomyopathy —

Synonyms: CMH28; FHOD3-related hypertrophic cardiomyopathy; familial hypertrophic cardiomyopathy 28.

Data provenance. The knowledge comes from aggregated disease-level resources (OMIM, ClinGen) and from cohort and family studies. No EHR data were used.

2. Etiology

Primary cause. The cause is a heterozygous germline FHOD3 variant. The variants are mostly non-truncating: missense, in-frame indels, splice-site changes and exon deletions.

ClinGen. FHOD3 is classified Definitive for HCM: - Expert panel paper: "Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive)." (PMID:39971408) - ClinGen record row: FHOD3 | HGNC:26178 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive (CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z)

Curation caveat: that ClinGen assertion is filed against MONDO:0005045 (HCM in general), not MONDO:0030317. Under the repo's gene-validity rules it is an other_disease case. Record it in gene_disease_validity only if the entry carries a MONDO:0005045 exactMatch mapping, which would be wrong for a numbered subtype. Otherwise cite it as ordinary evidence, or explain in notes.

Review context (PMID:34526680):

"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."

Genetic risk and modifier factors

  • Intermediate-effect allele p.Arg637Gln (PMID:38160043). This variant was enriched in HCM: "284 of 9668 probands; 2.94%" against "0.58%" in gnomAD controls, an OR of about 5.2. In heterozygotes it "can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%." Homozygotes are more severe (see Section 9). This makes p.Arg637Gln a RISK_FACTOR or SUSCEPTIBILITY allele, not a simple Mendelian one.
  • Intermediate-effect variants in general (PMID:40879562). FHOD3 is among the five non-sarcomeric genes included. Across genes, "IEVs are present in 6.1% of HCM cases and account for 4.8% of HCM genetic burden. IEVs also influence disease severity and outcomes, particularly when combined with monogenic disease-causing variants."
  • Common variants (PMID:23255317). A GWAS found "an intronic FHOD3 variant (rs516514) associated with HCM (odds ratio, 2.45…)". It also found that the missense variant FHOD3-V1151I (rs2303510) gave "an even stronger association with HCM (P=1.76×10(-9))". These are susceptibility or modifier variants, not CMH28-causing alleles.
  • Possible cosegregating modifiers in one family (PMID:31742804). "RNF207 (p.Q268P), CCM2 (p. E233K) and SGCZ (p.Q134X) may be related to the clinical heterogeneity of the family." This is weak evidence from a single family.

Environmental, protective and gene-environment factors. None is documented specifically for CMH28. A large HCM GWAS (PMID:33495597, not fetched) links diastolic blood pressure mainly to sarcomere-negative HCM. That makes hypertension a plausible but unestablished modifier for FHOD3 carriers. No protective factors are reported.

3. Phenotypes

The main quantitative source is the Ochoa 2018 cohort of 70 carriers of (likely) pathogenic variants (PMID:30442288):

"Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up."

Phenotype Suggested HPO term (in repo cache) Frequency / notes Evidence
Hypertrophic cardiomyopathy HP:0001639 Hypertrophic cardiomyopathy Defining feature, adult onset PMID:30442288
Asymmetric septal hypertrophy HP:0001670 Asymmetric septal hypertrophy 82%; mean thickness 18.8 mm PMID:30442288
Left ventricular hypertrophy HP:0001712 Left ventricular hypertrophy Near-universal among affected carriers —
Hypertrabeculation / LV noncompaction HP:0030682 Left ventricular noncompaction 16% hypertrabeculation PMID:30442288
Noncompaction as the main phenotype HP:0012817 Noncompaction cardiomyopathy One family with a splice variant, with "arrhythmic and thrombotic complications, myocardial fibrosis and heart failure" PMID:35205353
Reduced LVEF / systolic dysfunction HP:0012664 Reduced left ventricular ejection fraction 14% have LVEF <50% PMID:30442288
Myocardial fibrosis HP:0001685 Myocardial fibrosis Case-level evidence PMID:35205353
Thromboembolism HP:0001907 Thromboembolism Case-level evidence (LVNC family) PMID:35205353
Heart failure HP:0001635 Congestive heart failure Variable PMID:35205353; PMID:41540467 (in vitro)
Cardiovascular / sudden death HP:0001645 Sudden cardiac death About 1%/yr CV death in one cohort. Higher risk for candidate-variant carriers in a Chinese cohort PMID:30442288; PMID:33586461
Atrial fibrillation HP:0005110 Atrial fibrillation From the OMIM summary [unverified lead] — no quotable PMID found
Nonsustained VT HP:0004756 Ventricular tachycardia From the OMIM summary [unverified lead]
Dyspnea HP:0002094 Dyspnea OMIM says it is the most common symptom and that more than half of patients are asymptomatic [unverified lead]
Mode of inheritance HP:0000006 Autosomal dominant inheritance; HP:0003828 Variable expressivity; HP:0003581 Adult onset — —

Mortality in the Chinese cohort (PMID:33586461):

"the FHOD3 candidate variant experienced significantly more risk of cardiovascular death and all-cause death (adjusted hazard ratio [HR], 3.71 …"

Severity and progression: variable, ranging from asymptomatic to heart failure. The Ochoa cohort's event rates are "similar to those reported in unselected cohorts" (PMID:30442288).

Quality of life: no CMH28-specific data (EQ-5D, SF-36 or similar) were found.

4. Genetic and molecular information

Gene: FHOD3 (formin homology 2 domain containing 3), chromosome 18q12.2 (gene table), hgnc:26178.

Structure and isoforms. The domains are GBD, DID, coiled-coil, FH1, FH2 and DAD. The heart-enriched long isoform (FHOD3L) includes exon 12. That exon encodes the region that binds cMyBP-C (cardiac myosin-binding protein C) and targets FHOD3 to the sarcomere C-zone (PMID:29686099; PMID:38051749 introduction).

Variant spectrum and clustering (PMID:30442288):

"One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects"

Variant Class Population / evidence Reference
Coiled-coil cluster (aa 622–655), e.g. p.Arg637Gln Missense Hotspot. p.Arg637Gln is an intermediate-effect, low-penetrance allele PMID:30442288; PMID:38160043
Deletion of exons 15–16 CNV (in-frame) Found in 3 HCM families and 0 controls. "These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM." PMID:32335906
c.1646+2T>C (NM_001281740.3) Splice donor Balkan founder variant, "arisen 58 generations ago". Present in "16% of probands with a known genetic cause of HCM" in a Slovenian cohort. Onset 4–63 years PMID:38051749
c.1286+2delT Splice Causal by segregation in 4 Chinese patients PMID:33586461
p.S527del In-frame deletion One Chinese family PMID:31742804
Splice-altering variant Splice LVNC family PMID:35205353

Burden test (PMID:30442288). Candidate variants were found in 2.32% of HCM probands, against 0.65% of disease controls and 0.76% in gnomAD. Cosegregation in 17 families gave a combined LOD score of 7.92.

Somatic or germline: germline.

Functional consequence. The functional consequence is unresolved, and this is the key open question for curation: - Pathogenic HCM variants "seem to be restricted to non-truncating variants (missense, splice-site, and in-frame deletions/insertions variants)" and cluster in the DID domain, exon 12 and the coiled-coil (PMID:38051749 introduction, a background statement). - This pattern argues against simple haploinsufficiency. It is consistent with dominant-negative or altered-regulation (DID/DAD autoinhibition) mechanisms, but that is an inference. - Recommendation: leave functional_impact_category unset, or explain in notes why it is not set, rather than asserting GAIN_OF_FUNCTION or LOSS_OF_FUNCTION.

Other phenotypes reported with FHOD3. LVNC (PMID:35205353). FHOD3 variants have also been reported in dilated cardiomyopathy (PMID:24088304, Arimura 2013; not fetched), but the DCM association "remains as yet unproven" (PMID:38051749 introduction).

Epigenetics and chromosomal abnormalities: nothing reported. RBM20 and PTBP1 regulate alternative splicing of FHOD3 (PMID:30468920, not fetched). This is relevant to isoform balance but has not been linked to CMH28.

5. Environmental information

There are no known environmental, lifestyle or infectious causes. General HCM lifestyle advice applies (Section 13). Leave environmental: empty, or add a "Left deliberately uncited." waiver only if an exposure is listed.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Heterozygous germline FHOD3 variant, most often non-truncating and clustered in the DID or coiled-coil region (aa 622–655, exons 15–16), leads to an altered FHOD3 protein. Demonstrated genetically: PMID:30442288, PMID:32335906. Inferred: how a coiled-coil or DID change alters protein function has not been shown biochemically for patient alleles.
  2. Normal role of FHOD3L: it nucleates and, critically, elongates actin filaments, and it is recruited to the sarcomere C-zone by cMyBP-C. Its elongation activity is needed for sarcomere formation and contraction. Demonstrated in vitro: PMID:40663059 ("FHOD3L's elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes"); PMID:19706596; PMID:29686099.
  3. A disturbed FHOD3 function results in defective thin-filament (actin) organisation and impaired sarcomere and myofibril maintenance in cardiomyocytes. Demonstrated for loss of FHOD3 (knockdown or knockout), not for patient alleles: "RNA interference-mediated depletion of Fhod3 results in a marked reduction in filamentous actin and disruption of the sarcomeric structure" (PMID:19706596). In FHOD3-/- human embryonic stem cell–derived cardiomyocytes, "marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility" (PMID:41540467).
  4. Branch A (mislocalisation, dominant effect): wrongly placed FHOD3 is harmful. In cMyBP-C-null mice, "Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized" (PMID:29686099). This is a mouse model and inferred to apply to CMH28.
  5. Branch B (deficiency): loss of FHOD3 activates CaMKII. "FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling" (PMID:41540467). This is a knockout model; patient variants are mostly non-truncating.
  6. Sarcomere dysfunction and stress signalling lead to a maladaptive hypertrophic response of cardiomyocytes, with fetal gene reactivation. Model evidence: in adult Fhod3-deleted mice, phenylephrine "induced expression of fetal cardiac genes that was more pronounced … suggesting that Fhod3 modulates hypertrophic changes in the adult heart" (PMID:29158260). The step from this to human septal hypertrophy is inferred.
  7. Cardiomyocyte hypertrophy results in left ventricular and asymmetric septal hypertrophy (82%). Disturbed myocardial development or maintenance may account for hypertrabeculation or LVNC (16%). Clinical: PMID:30442288. Link to trabeculation: Fhod3-/- embryos show aborted "chamber formation and myocardial development with trabeculation" (PMID:23213483). This is a developmental knockout; the link to adult hypertrabeculation is inferred.
  8. Downstream, myocardial fibrosis, systolic dysfunction (14% LVEF <50%), arrhythmia and thromboembolism lead to heart failure and cardiovascular or sudden death (about 1%/yr). Sources: PMID:30442288; PMID:35205353; PMID:33586461.

Suggested ontology terms

All of these are in the repo caches.

  • GO biological process: GO:0045214 sarcomere organization; GO:0055003 cardiac myofibril assembly; GO:0030239 myofibril assembly; GO:0030041 actin filament polymerization; GO:0045010 actin nucleation; GO:0003300 cardiac muscle hypertrophy; GO:0014898 cardiac muscle hypertrophy in response to stress; GO:0060048 cardiac muscle contraction; GO:0055117 regulation of cardiac muscle contraction; GO:0048738 cardiac muscle tissue development.
  • GO cellular component: GO:0030017 sarcomere; GO:0031672 A band (the C-zone sits within it); GO:0005884 actin filament; GO:0030016 myofibril.
  • Cell types: CL:0000746 cardiac muscle cell; CL:0002131 regular ventricular cardiac myocyte; CL:0002548 fibroblast of cardiac tissue (for the fibrosis node).

Scale tags: steps 1–2 are MOLECULAR, 3 is CELLULAR, 4–5 are TISSUE, and 6 is ORGANISM.

Molecular profiling. The only omics data are bulk transcriptomics of FHOD3-KO human cardiomyocytes, which showed "significant downregulation of sarcomere-related genes and calcium-handling genes" (PMID:41540467). FHOD3 expression "is increased in the setting of HCM" in myectomy tissue (PMID:23255317). No single-cell, spatial, proteomic or metabolomic data specific to CMH28 were found.

Reproducibility caveat. PMID_23213483.md caches the full-text body without a separate abstract block. Quotes from its "Here we show…" introduction paragraph are the authors' own results, so record quote_role: PRIMARY_RESULT.

7. Anatomical structures affected

  • Organ: heart (UBERON:0000948). Cardiovascular system only; there are no reported extracardiac features.
  • Sites: interventricular septum (UBERON:0002094; asymmetric septal hypertrophy), heart left ventricle (UBERON:0002084), myocardium (UBERON:0002349), cardiac muscle tissue (UBERON:0001133).
  • Cells: ventricular cardiomyocytes. FHOD3L is "predominantly expressed in striated muscle" (PMID:40663059).
  • Subcellular: sarcomere C-zone in the A band, and actin thin filaments. Fhod3 also localises near the M-line (PMID:22509354).
  • Lateralisation: asymmetric, septum-predominant hypertrophy.

8. Temporal development

  • Onset: mainly adult. Carriers "were diagnosed after age 30 years (mean 46.1 ± 18.7 years)" (PMID:30442288). The Balkan founder variant shows "a wide range of ages at onset of the disease (4-63 years)" (PMID:38051749). Homozygous p.Arg637Gln gives "an early presentation" (PMID:38160043).
  • Course: chronic and lifelong, insidious, and slowly progressive. "Events were rare before age 30 years" (PMID:30442288).
  • Stages: the generic HCM progression applies (preclinical carrier → hypertrophy → possible systolic dysfunction or heart failure). No CMH28-specific staging exists.
  • Remission: none.
  • Window for intervention: before age 30, when cascade screening of relatives can identify carriers before events.

9. Inheritance and population

  • Inheritance: autosomal dominant (ClinGen AD Definitive). Incomplete penetrance is noted repeatedly (PMID:38051749). Expressivity is variable.
  • Biallelic dosage effect: homozygous p.Arg637Gln causes more severe disease. "Seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype." (PMID:38160043) This suggests semidominant behaviour for that allele. Do not encode it as recessive inheritance.
  • Frequency within HCM: about 1–2% of HCM cases (PMID:30442288). Background HCM prevalence is "∼1 in 500" (PMID:39971408). That implies a CMH28 prevalence of roughly 1–4 per 100,000. This is derived, not measured; do not record it as a sourced rate_per_100000.
  • Founder effects: Balkan c.1646+2T>C (PMID:38051749). The Iberian cohorts carry p.Arg637Gln at 2.94% of probands (PMID:38160043).
  • Sex ratio: "two-thirds (66%) were males" (PMID:30442288).
  • Ancestry: cohorts from Spain/UK, China (3.3% of HCM vs 1.6% of controls; PMID:33586461), the Balkans and Russia.
  • Not reported: consanguinity, anticipation and germline mosaicism.

10. Diagnostics

  • Imaging: echocardiography and cardiac MRI showing LV wall thickness ≥15 mm, which is the standard HCM criterion (PMID:38051749 introduction). CMR also assesses hypertrabeculation or LVNC and fibrosis (late gadolinium enhancement).
  • ECG and Holter: for AF, NSVT and T-wave abnormalities (NCIT:C38053 Electrocardiography).
  • Genetic testing: a multigene HCM panel that includes FHOD3. "The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels." (PMID:30442288)
  • CNV analysis is required: "This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM" (PMID:32335906).
  • Exome or genome sequencing is useful for panel-negative cases (PMID:31742804; PMID:33586461).
  • Variant interpretation: pay attention to intermediate-effect alleles such as p.Arg637Gln. "Evaluation of IEVs should be considered when HCM genetic testing is performed." (PMID:40879562)
  • Not applicable: karyotype, FISH, mtDNA testing and repeat-expansion testing.
  • Biomarkers: none specific to CMH28. Generic HCM markers are NT-proBNP and high-sensitivity troponin. A troponin I GWAS hit near FHOD3 (PMID:33961016) is not established as diagnostic.
  • Differential diagnosis:
  • sarcomeric HCM (MYH7, MYBPC3 and others)
  • other non-sarcomeric HCM (ALPK3, FLNC, TRIM63, CSRP3)
  • phenocopies: Fabry disease, PRKAG2, Danon disease, transthyretin amyloidosis, RASopathies
  • isolated LVNC
  • hypertensive heart disease
  • athlete's heart
  • Screening: cascade genetic and clinical screening of first-degree relatives. No newborn screening exists.

11. Outcome and prognosis

  • Mortality: annual cardiovascular death incidence of 1% (PMID:30442288). In a Chinese cohort, FHOD3 candidate variants were "an independent risk for cardiovascular death and all-cause death in HCM" (PMID:33586461). In contrast, the Balkan founder carriers had "No adverse cardiac events" (PMID:38051749). The literature conflicts here, so record both.
  • Prognostic modifiers: an intermediate-effect variant added to a monogenic variant gives a more aggressive course. Major adverse cardiac event–free survival at 70 years was 93.3% vs 69.3% (PMID:40879562; this is a pooled finding across genes). Homozygosity for p.Arg637Gln also worsens prognosis (PMID:38160043).
  • Complications: heart failure, systolic dysfunction, arrhythmia, thromboembolism (LVNC) and sudden death.
  • Not found: CMH28-specific survival curves and quality-of-life data.

12. Treatment

No FHOD3-specific therapy exists, so management follows HCM guidelines. Suggested bindings, all in the repo caches:

Treatment treatment_term therapeutic_agent Modality
Beta-blockers (e.g. metoprolol) NCIT:C15986 Pharmacotherapy CHEBI:35530 beta-adrenergic antagonist; CHEBI:6904 metoprolol SMALL_MOLECULE
Verapamil NCIT:C15986 CHEBI:9948 verapamil SMALL_MOLECULE
Disopyramide (obstructive HCM) NCIT:C15986 CHEBI:4657 disopyramide SMALL_MOLECULE
Cardiac myosin inhibitors NCIT:C15986 CHEBI:756998 mavacamten; CHEBI:747213 aficamten SMALL_MOLECULE
Antiarrhythmic (AF) NCIT:C15986 CHEBI:2663 amiodarone SMALL_MOLECULE
ICD for sudden-death prevention NCIT:C80435 Implantable Cardioverter-Defibrillator Placement — DEVICE
Septal myectomy / alcohol septal ablation No NCIT term verified; bind NCIT:C15329 Surgical Procedure only after a lookup — SURGERY
Heart transplantation (end-stage) NCIT:C15246 Heart Transplantation — SURGERY
Genetic counselling NCIT:C15240 Genetic Counseling — OTHER

Caveat on myosin inhibitors. Their trials enrolled obstructive HCM regardless of genotype. There are no FHOD3-stratified efficacy data.

Experimental. The only FHOD3-specific therapeutic signal is in vitro. In FHOD3-KO human cardiomyocytes, "Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling" (PMID:41540467). This is IN_VITRO evidence, based on a loss-of-function model and not on patient alleles. It is a hypothesis, not a treatment. I found no CMH28 trials, gene therapy or RNA-based programmes.

Pharmacogenomics: mavacamten dosing depends on CYP2C19 genotype (generic, not FHOD3-specific) [unverified lead; source it before use].

13. Prevention

  • Primary: none is possible. Genetic counselling covers the 50% transmission risk, and preimplantation or prenatal testing is possible when a pathogenic variant is known. Incomplete penetrance complicates counselling.
  • Secondary: cascade genotyping of relatives followed by serial echocardiography and ECG of carriers.
  • Tertiary: sudden-death risk stratification and ICD; anticoagulation for AF or LVNC thrombus; managing hypertension as a possible modifier (inferred).
  • Not applicable: immunisation and public-health or environmental measures.

14. Other species and natural disease

  • Naturally occurring FHOD3 cardiomyopathy: none found in OMIA during this search. Feline and canine HCM are mainly MYBPC3-associated.
  • Orthologues: mouse Fhod3, rat Fhod3, and Drosophila fhos. "its fly homolog fhos is required for normal adult heart systolic contraction" (PMID:23255317).
  • Zebrafish: fhod3 paralogues are involved in skeletal myofibril stability (PMID:41416849, not fetched).
  • Not verified: NCBI Gene IDs for the orthologues.

15. Model organisms and systems

Model Type Recapitulation Key quote Ref
Fhod3-/- mouse Germline knockout Embryonic lethal. Fails to recapitulate adult HCM "knock out of the Fhod3 gene in mice confers lethality by embryonic day (E) 11.5"; trabeculation and chamber formation "aborted" PMID:23213483
Perinatal cardiac Fhod3 cKO mouse Conditional knockout Juvenile cardiomegaly "juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils" PMID:29158260
Adult inducible cardiac Fhod3 cKO mouse Tamoxifen-induced cKO Partial: "slight cardiomegaly and mild impairment of cardiac function"; exaggerated fetal gene response to phenylephrine — PMID:29158260
α-MHC Fhod3 transgenic, I1127A mutant Transgenic overexpression Mutant that cannot assemble actin; the paper reports cardiomyopathic changes — PMID:23213483
cMyBP-C-null × Fhod3 dosage mouse Compound genetic Fhod3 overexpression exacerbates HCM; reducing it partially ameliorates — PMID:29686099
FHOD3-/- human ESC-derived cardiomyocytes iPSC/ESC, CRISPR Sarcomere disorganisation, Ca²⁺ handling defect, CaMKII activation — PMID:41540467
Neonatal rat ventricular myocytes with function-separating FHOD3L mutants In vitro Shows that elongation activity is the required function — PMID:40663059
Drosophila fhos Invertebrate Systolic dysfunction — PMID:23255317

Limitations. Every in vivo model is a knockout or overexpression model. No knock-in of a patient allele exists, for example a coiled-coil missense variant, p.Arg637Gln, or the exon 15–16 deletion. A complete knockout is embryonic lethal, while the human disease is heterozygous, non-truncating and adult-onset.

This is a good candidate for a HUMAN_MODEL_MISMATCH discussion: the models remove or overexpress FHOD3, whereas patients carry heterozygous non-truncating alleles. The proposed experiment is a patient-allele knock-in in mice or iPSC-derived cardiomyocytes.

Model divergence typing for modeled_mechanisms: - BOUNDARY_OMISSION — no patient allele is modelled. - PROXY_QUANTITY — knockout loss stands in for altered function of a variant protein. - SPECIES_MISMATCH — mouse and rat models.

Curation notes for the entry

  1. Fill in the stub fields. The existing draft has a one-line description and a single phenotype. The evidence above supports roughly 6–7 pathophysiology nodes, about 10 phenotypes with frequencies, 3–5 genetic rows and the treatments in Section 12.
  2. Do not write functional_impact_category for the causal alleles, because the mechanism is unresolved. Record that reasoning in notes.
  3. Model p.Arg637Gln as a separate genetic row with relationship_type: RISK_FACTOR, plus a homozygous-severity note.
  4. ClinGen: the Definitive tier is against MONDO:0005045, so use it as evidence rather than as a gene_disease_validity assertion for this entry (see Section 2).
  5. Unverified leads: the AF, NSVT and dyspnoea frequencies come only from the OMIM/MalaCards text. They need an exact quotable source before they go into the entry. A GeneReviews chapter specific to FHOD3 is unlikely; run just check-genereviews to confirm.

Sources (all PMIDs cached in references_cache/ unless marked)

  • PMID:30442288 Ochoa 2018 JACC
  • PMID:39971408 Hespe 2025 JACC (ClinGen)
  • CGGV:assertion_c31027fe-… (ClinGen FHOD3/HCM Definitive)
  • PMID:34526680 Walsh 2022 Nat Rev Cardiol
  • PMID:38160043 Piqueras-Flores 2024 J Med Genet
  • PMID:40879562 García Hernández 2025 Circulation
  • PMID:32335906 Ochoa 2020 Clin Genet
  • PMID:38051749 Vodnjov 2023 PLoS One
  • PMID:33586461 Wu 2021 JAHA
  • PMID:31742804 Huang 2020 J Gene Med
  • PMID:35205353 Myasnikov 2022 Genes
  • PMID:23255317 Wooten 2013 Circ Cardiovasc Genet
  • PMID:19706596 Taniguchi 2009 JBC
  • PMID:23213483 Kan-o 2012 Biol Open
  • PMID:22509354 Kan-o 2012 PLoS One
  • PMID:29158260 Ushijima 2018 JBC
  • PMID:29686099 Matsuyama 2018 PNAS
  • PMID:40663059 Valencia 2025 eLife
  • PMID:41540467 Wei 2026 Stem Cell Res Ther
  • Not fetched: PMID:24088304, PMID:30468920, PMID:33495597, PMID:33961016, PMID:41416849
  • Web: PubMed 30442288, MalaCards CMH28, DrugMap DISIHJ7B, Gene Table ref 30442288, Mayo Clinic Wooten 2013, UCL Discovery

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 23
Resolved 23
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 25
Quoted claims found in source 24
Quoted claims not found in source 1
References weighed for topical relevance 23
On topic 22
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:29158260: "induced expression of fetal cardiac genes that was more pronounced … suggesting that Fhod3 modulates hypertrophic changes in the adult heart"
  • closest text in source: "In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 54
Resolved 53
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 3
Terms named correctly 0
Terms named as a different term 2
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0005045 (5 mentions) - the report calls it "HCM in general"; MONDO calls it hypertrophic cardiomyopathy
  • NCIT:C15986 (5 mentions) - the report calls it "Verapamil", "Disopyramide (obstructive HCM)", "Cardiac myosin inhibitors", "Antiarrhythmic (AF)"; NCIT calls it Pharmacotherapy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0000948 (1 mention) - the report calls it "Organ: heart"; UBERON calls it heart**, and lists "branchial heart" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • NCIT:C15986 - called "Verapamil", "Disopyramide (obstructive HCM)", "Cardiac myosin inhibitors", "Antiarrhythmic (AF)"