Hypertrophic Cardiomyopathy 17

Mendelian MONDO:0013474 Pathograph 7 Show in embeddings browser Hypertrophic Cardiomyopathy Cardiomyopathy Genetic Disease

Hypertrophic cardiomyopathy 17 (CMH17) is the JPH2-attributed member of the numbered familial hypertrophic cardiomyopathy series. JPH2 encodes junctophilin-2, which is not a sarcomeric protein: it is the structural bridge that holds the T-tubule membrane against the junctional sarcoplasmic reticulum, keeping the L-type calcium channel and the ryanodine receptor close enough for calcium-induced calcium release to work. The proposed mechanism is therefore failure of dyad architecture and of excitation-contraction coupling, rather than the altered actin-myosin cross-bridge kinetics of classic sarcomeric HCM. Evidence for the gene-disease relationship is real but not definitive, and the entry states this rather than implying otherwise. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies JPH2 for autosomal dominant hypertrophic cardiomyopathy as **Moderate** - above the Limited tier that most non-sarcomeric HCM candidates occupy, below the Definitive tier of the eight core sarcomeric genes. The supporting evidence is three unrelated probands from a 388-patient screen with functional characterisation, a separate Japanese association, and a Finnish founder variant with documented segregation across nine families. JPH2 also carries a separate and differently graded relationship with dilated cardiomyopathy - Strong for autosomal recessive inheritance, Limited for autosomal dominant - so the gene is not simply an HCM gene, and genotype interpretation depends on the allele and the inheritance pattern.

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1
Inheritance
4
Pathophys.
5
Phenotypes
1
Hypotheses
7
Pathograph
1
Genes
2
Medical Actions
1
Subtypes
1
Models
2
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Reported HCM-associated JPH2 variants are heterozygous and segregate as an autosomal dominant trait. Penetrance is age-dependent and incomplete: in the Finnish p.(Thr161Lys) founder families it was 71% by age 60 and 100% by age 80, so an unaffected middle-aged carrier does not exclude the variant.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
Quantifies age-dependent penetrance in heterozygotes, establishing the dominant but incompletely penetrant inheritance pattern.
◆

Subtypes

1
Finnish p.(Thr161Lys) founder variant
A Finnish founder allele (c.482C>A) identified in nine index families and described by its authors as causing atypical HCM: alongside left ventricular hypertrophy it carries prominent conduction disease and progression to systolic heart failure with non-dilated chamber geometry. Penetrance is age-dependent, reaching 100% only by age 80.
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM"
The authors' own designation of this allele as a distinct, atypical founder form.
◈

Mechanistic Hypotheses

1
CMH17 arises from dyad architectural failure rather than altered sarcomeric cross-bridge kinetics
dyad_architecture_not_sarcomere CANONICAL
Evidence balance 2 support
The eight definitive HCM genes encode sarcomeric proteins, and the dominant model of HCM is altered actin-myosin cross-bridge kinetics with increased myofilament calcium sensitivity. JPH2 encodes no part of the sarcomere. The proposed mechanism for CMH17 is instead that loss of the junctophilin-2 bridge widens or disorganizes the dyad, uncouples the L-type channel from the ryanodine receptor, and drives hypertrophy through disordered calcium signalling. The chain is supported by a knockout model, by siRNA silencing sufficient to produce hypertrophy in isolation, and by functional characterisation of the three original human variants. What it does not yet have is direct demonstration of dyad ultrastructural disruption in myocardium from a genotyped human CMH17 patient, so the human step of the argument rests on reduced JPH2 protein in HCM tissue rather than on imaging the junction itself.
Show evidence (2 references)
PMID:17509612 SUPPORT In Vitro
"The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM"
The authors' own statement of the mechanism as distinct from established sarcomeric HCM pathogenesis.
PMID:34526680 SUPPORT Human Clinical
"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"
Places JPH2 explicitly among the non-sarcomeric HCM genes, which is the premise of this hypothesis.
⚙

Pathophysiology

4
Junctophilin-2 Structural Deficit
Junctophilin-2 spans the narrow gap of the cardiac dyad, anchoring in the sarcoplasmic reticulum membrane and binding the plasma membrane, so that the junctional membrane complex is physically held together. Both routes documented in human disease reduce the amount of functional protein at that junction: missense variants at key functional domains reorganize the protein, and JPH2 expression is itself reduced in myocardium from patients with hypertrophic cardiomyopathy. The lesion is architectural rather than contractile - nothing about the sarcomere's force-generating machinery is directly altered.
Junctional sarcoplasmic reticulum membrane GO:0014701 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Junctional sarcoplasmic reticulum membrane (GO:0014701). GO:0014701 is a cellular component from the Gene Ontology.
Downstream
Dyad Disruption and Uncoupling of the L-Type Channel from the Ryanodine Receptor Losing the physical bridge separates the two channels that must be apposed for calcium-induced calcium release.
Show evidence (2 references)
PMID:17509612 SUPPORT In Vitro
"each human mutation caused (i) protein reorganization of junctophilin-2"
Functional characterisation showing each HCM-associated variant reorganizes the protein itself, which is the structural deficit this node describes.
PMID:21216834 SUPPORT Human Clinical
"JPH2 expression was reduced in flash-frozen human cardiac tissue procured from patients with HCM compared with ostensibly healthy traumatic death victims."
Shows reduced junctophilin-2 in human HCM myocardium, an expression-level route to the same structural deficit as the coding variants.
Dyad Disruption and Uncoupling of the L-Type Channel from the Ryanodine Receptor
The cardiac dyad exists so that calcium entering through the L-type channel reaches the ryanodine receptor at a high enough local concentration to trigger sarcoplasmic reticulum calcium release. Widening or disorganizing that junction breaks the trigger. In JPH2-silenced myocytes the calcium transient loses its dependence on L-type channel activation, which is the signature of a broken structural coupling rather than of a channel that has itself stopped working.
Cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Release of sequestered calcium into cytosol by sarcoplasmic reticulum GO:0014808 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Release of sequestered calcium into cytosol by sarcoplasmic reticulum, annotated with release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808). GO:0014808 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disordered Intracellular Calcium Handling An untriggered or weakly triggered release produces an abnormal calcium transient.
Show evidence (1 reference)
PMID:17476457 SUPPORT Model Organism
"the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels"
The Jph2 knockout mouse establishes the uncoupling mechanism directly, naming both channel partners.
Disordered Intracellular Calcium Handling
Calcium transients are reduced in amplitude and sarcoplasmic reticulum stores are depleted. Because intracellular calcium is simultaneously the contractile trigger and the input to hypertrophic signalling, this node is modelled as the shared origin of both clinical arms - the hypertrophic remodelling and the arrhythmic vulnerability. That shared origin is the canonical reading, not a settled one. Beavers et al argue the opposite for E169K specifically: they attribute its arrhythmogenicity to reduced JPH2-RyR2 binding while stating that HCM development in JPH2 disease likely involves other cellular mechanisms still to be explored. Their E169K mice were AF-susceptible with no structural cardiomyopathy at two months, which is the observation that separates the arms.
Intracellular calcium ion homeostasis GO:0006874 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology. ↓ DECREASED Regulation of cardiac muscle contraction by calcium ion signaling GO:0010882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882). GO:0010882 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
JPH2 p.(Thr161Lys) patient-derived iPSC cardiomyocytes IPSC DERIVED MODEL The mutant cardiomyocytes show prolonged action potential duration and increased arrhythmogenicity, attributed to slower inactivation of calcium channels - a calcium-handling abnormality in a human cell carrying the disease allele.
Downstream
Prohypertrophic Cardiomyocyte Remodeling Altered calcium handling engages the hypertrophic signalling programme in the cardiomyocyte.
Arrhythmia Disordered calcium release is the substrate for the arrhythmic vulnerability and conduction disease seen in carriers, and the steps between the two are identified rather than assumed. Spontaneous sarcoplasmic reticulum calcium release appears as cell-wide calcium waves; these activate the sodium-calcium exchanger, which generates delayed afterdepolarizations, and the resulting triggered activity is the arrhythmia. This was worked out for the E169K allele, found in hypertrophic cardiomyopathy patients with juvenile-onset paroxysmal atrial fibrillation and modelled in pseudoknock-in mice.
Show evidence (2 references)
PMID:17509612 SUPPORT In Vitro
"each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia"
All three human HCM variants produced calcium-signalling perturbation on functional characterisation.
PMID:23973696 REFUTE Model Organism
"it is likely that the proarrhythmogenic effects of the E169K mutation are due to the reduced binding of E169K-JPH2 to RyR2, whereas HCM development likely involves other cellular mechanisms that remain to be explored in future studies"
Contradicts modelling one calcium disturbance as the shared origin of both arms - for E169K these authors separate the arrhythmic mechanism from the hypertrophic one and place the latter outside this node.
Prohypertrophic Cardiomyocyte Remodeling
Cardiomyocytes enlarge and induce the canonical hypertrophic gene programme, producing the left ventricular hypertrophy that defines the clinical phenotype. In a subset of patients the disease progresses beyond hypertrophy to systolic failure with normal or only mildly enlarged diastolic dimensions - an end-stage picture that is not typical burnt-out HCM and was one reason the Finnish cohort was described as atypical.
Cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac muscle hypertrophy in response to stress GO:0014898 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. ↑ INCREASED
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.
Experimental models
JPH2 p.(Thr161Lys) patient-derived iPSC cardiomyocytes IPSC DERIVED MODEL The mutant cardiomyocytes reproduce the cellular hallmarks of hypertrophic cardiomyopathy - cellular hypertrophy, multi-nucleation and sarcomeric disarray.
Downstream
Left ventricular hypertrophy Cardiomyocyte hypertrophy summed across the ventricular wall is the macroscopic hypertrophy.
Show evidence (1 reference)
PMID:21216834 SUPPORT In Vitro
"resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy"
Documents the cellular hypertrophy and hypertrophic marker induction that constitute this node.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 17 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Left ventricular hypertrophy Cardiovascular HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
Left ventricular hypertrophy is the leading feature across nine families carrying the founder variant.
Hypertrophic cardiomyopathy Cardiovascular 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 (1 reference)
PMID:17509612 SUPPORT Human Clinical
"were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles"
Establishes the association with clinically diagnosed HCM, with an allele-frequency control.
Arrhythmia Cardiovascular 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:30235249 SUPPORT Human Clinical
"Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
Reports arrhythmia vulnerability among the main clinical features of the cohort.
Atrioventricular block Cardiovascular HP:0001678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular block (HP:0001678). HP:0001678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"conduction abnormalities including third degree AV-block"
Documents high-grade conduction block in JPH2 variant carriers.
Congestive heart failure Cardiovascular 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:30235249 SUPPORT Human Clinical
"In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected."
Describes the end-stage systolic failure seen in a subset, and its distinguishing chamber geometry.
🧬

Genetic Associations

1
JPH2 (Causal)
Gene: JPH2 hgnc:14202 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JPH2 (hgnc:14202). hgnc:14202 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (9 references)
PMID:23973696 SUPPORT Human Clinical
"Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF)."
The human cohort finding that establishes E169K as an HCM allele and ties it to juvenile-onset atrial fibrillation.
PMID:23973696 SUPPORT Human Clinical
"The patient with the other HCM-associated JPH2 mutation, A405S, did not exhibit atrial arrhythmias, similar to all other previously reported HCM patients with JPH2 mutations"
The allele-specific control - other JPH2 HCM alleles carried no atrial arrhythmia, so the arrhythmic phenotype should not be generalized across the gene.
CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z SUPPORT Other
"JPH2 | HGNC:14202 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Moderate | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2022-10-12T16:00:00.000Z"
The current ClinGen gene-disease validity classification for JPH2 in autosomal dominant hypertrophic cardiomyopathy.
+ 6 more references
💊

Medical Actions

2
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 once the familial JPH2 variant is known, followed by longitudinal cardiac surveillance of those who carry it. Cosegregation of the variant with the HCM phenotype across the Finnish founder families is what makes a relative's genotype actionable here. Because penetrance is age-dependent and incomplete, an unaffected middle-aged carrier is not evidence against the variant and cannot be discharged from surveillance. Diagnostic sequencing of the proband is a diagnostic procedure and is curated under `diagnosis`; this entry covers only the management of relatives.
Show evidence (2 references)
PMID:30235249 SUPPORT Human Clinical
"Co-segregation of the variant with HCM phenotype was observed in six families."
Cosegregation across the founder families is what makes a relative's JPH2 genotype informative for cascade screening.
PMID:30235249 SUPPORT Human Clinical
"We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
Age-dependent penetrance is why a genotype-positive relative stays under surveillance rather than being cleared by one normal evaluation.
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
Counseling should convey the autosomal dominant inheritance, the age-dependent and incomplete penetrance documented in the founder families, and the Moderate strength of the underlying gene-disease relationship.
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
Provides the age-dependent penetrance figures that counseling must convey.
🔬

Diagnosis

3
Echocardiography
Imaging for the defining feature, unexplained left ventricular hypertrophy. Conduction disease up to third-degree AV block accompanying the hypertrophy is a phenotype-first clue toward a non-sarcomeric, JPH2-type mechanism rather than classic sarcomeric HCM; the cited series assessed these patients by echocardiography together with resting 12-lead ECG.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30235249 SUPPORT Human Clinical
"Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
Establishes the combination of left ventricular hypertrophy with conduction disease that distinguishes the JPH2 presentation.
Electrocardiography and Ambulatory Rhythm Monitoring
Resting 12-lead ECG, extended with ambulatory rhythm monitoring where symptoms or ECG findings warrant it. This is the test that detects the feature distinguishing the JPH2 presentation from classic sarcomeric HCM: high-grade conduction disease up to third-degree AV block, alongside the atrial and ventricular arrhythmia burden documented in the Finnish founder families. Imaging alone does not capture it, so ECG belongs in the initial evaluation rather than being reserved for symptomatic patients.
electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30235249 SUPPORT Human Clinical
"resting 12-lead ECG, appropriate laboratory tests and transthoracic echocardiography (TTE)."
Records that resting 12-lead ECG was part of the standard clinical assessment of the JPH2 families alongside echocardiography.
PMID:30235249 SUPPORT Human Clinical
"conduction abnormalities including third degree AV-block"
Names the conduction finding that ECG detects and that distinguishes this presentation from classic sarcomeric HCM.
Molecular Genetic Testing (JPH2 Sequencing)
Confirms the molecular diagnosis, but a JPH2 result must be weighed against its Moderate ClinGen classification rather than treated as definitive - a lower interpretive tier than a variant in one of the eight core sarcomeric genes.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A qualifying JPH2 variant supports but does not by itself establish the molecular diagnosis, given the gene's Moderate evidence tier.
Show evidence (1 reference)
PMID:30681346 SUPPORT Other
"Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."
States why a JPH2 finding must be reported and weighted according to the gene's own validity tier rather than as a definitive cause.
📊

Prevalence

1
Unrelated hypertrophic cardiomyopathy probands
Unknown Unknown
Reported as a yield within an HCM cohort, not a population prevalence: three of 388 unrelated HCM patients carried an HCM-associated JPH2 variant in the original screen. JPH2 is a minor HCM gene; the eight core sarcomeric genes account for more than 90% of pathogenic variants in HCM.
Show evidence (1 reference)
PMID:17509612 SUPPORT Human Clinical
"were discovered in 3/388 unrelated patients with HCM"
The reported yield of JPH2 variants among unrelated HCM probands.
🧫

Experimental Models

1
JPH2 p.(Thr161Lys) patient-derived iPSC cardiomyocytes IPSC_DERIVED_MODEL
Skin fibroblasts from a Finnish patient carrying the p.(Thr161Lys) founder allele were reprogrammed to iPSCs and differentiated to cardiomyocytes, with an isogenic CRISPR-corrected counterpart as control. The isogenic design is what makes this informative: the comparison is against the same genetic background rather than an unrelated line, so the differences are attributable to the variant. It models the exact allele curated as a has_subtypes entry on this disease.
Cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses 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:37371654
Pathograph links
Prohypertrophic Cardiomyocyte Remodeling recapitulates fidelity: moderate observes: cellular The mutant cardiomyocytes reproduce the cellular hallmarks of hypertrophic cardiomyopathy - cellular hypertrophy, multi-nucleation and sarcomeric disarray.
Limitations: iPSC-derived cardiomyocytes are immature relative to adult myocardium, with fetal-like calcium handling and underdeveloped T-tubules. That last point matters more here than usual: the disease mechanism is dyad architecture, and the dyad is precisely the structure these cells have not fully formed.
Readouts
Cellular hypertrophy, multi-nucleation and sarcomeric disarray
Direction: INCREASED
Interpretation: The cellular correlates of the hypertrophic phenotype are present in the mutant line.
Show evidence (1 reference)
PMID:37371654 SUPPORT In Vitro
"JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray)."
Directly reports the hypertrophic cellular phenotype in the patient-derived line.
Show evidence (1 reference)
PMID:37371654 SUPPORT In Vitro
"JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray)."
Supports treating this line as informative for the hypertrophic remodeling node.
Disordered Intracellular Calcium Handling recapitulates fidelity: moderate observes: cellular The mutant cardiomyocytes show prolonged action potential duration and increased arrhythmogenicity, attributed to slower inactivation of calcium channels - a calcium-handling abnormality in a human cell carrying the disease allele.
Limitations: Immature calcium handling and incomplete T-tubule development mean the magnitude of the defect should not be read across to adult myocardium.
Readouts
Action potential duration and arrhythmogenicity
Direction: INCREASED
Interpretation: Prolonged action potential with increased arrhythmic events in the mutant line.
Show evidence (1 reference)
PMID:37371654 SUPPORT In Vitro
"JPH2-hiPSC-CMs exhibit a higher degree of arrhythmia and longer action potential duration associated with slower inactivation of calcium channels"
Reports the electrophysiological and calcium-handling abnormality measured in the patient-derived line.
Show evidence (1 reference)
PMID:37371654 SUPPORT In Vitro
"Functional evaluation supported clinical observations, with differences in beating characteristics when compared with isogenic-hiPSC-CMs."
The isogenic comparison supports attributing the functional differences to the variant.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 17
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
synonyms:
- CMH17
- cardiomyopathy, familial hypertrophic, 17
- hypertrophic cardiomyopathy type 17
- JPH2 hypertrophic cardiomyopathy
- hypertrophic cardiomyopathy caused by mutation in JPH2
description: >-
  Hypertrophic cardiomyopathy 17 (CMH17) is the JPH2-attributed member of the
  numbered familial hypertrophic cardiomyopathy series. JPH2 encodes
  junctophilin-2, which is not a sarcomeric protein: it is the structural
  bridge that holds the T-tubule membrane against the junctional sarcoplasmic
  reticulum, keeping the L-type calcium channel and the ryanodine receptor
  close enough for calcium-induced calcium release to work. The proposed
  mechanism is therefore failure of dyad architecture and of
  excitation-contraction coupling, rather than the altered actin-myosin
  cross-bridge kinetics of classic sarcomeric HCM.

  Evidence for the gene-disease relationship is real but not definitive, and
  the entry states this rather than implying otherwise. ClinGen's Hereditary
  Cardiovascular Disease Gene Curation Expert Panel classifies JPH2 for
  autosomal dominant hypertrophic cardiomyopathy as **Moderate** - above the
  Limited tier that most non-sarcomeric HCM candidates occupy, below the
  Definitive tier of the eight core sarcomeric genes. The supporting evidence
  is three unrelated probands from a 388-patient screen with functional
  characterisation, a separate Japanese association, and a Finnish founder
  variant with documented segregation across nine families.

  JPH2 also carries a separate and differently graded relationship with dilated
  cardiomyopathy - Strong for autosomal recessive inheritance, Limited for
  autosomal dominant - so the gene is not simply an HCM gene, and genotype
  interpretation depends on the allele and the inheritance pattern.
disease_term:
  preferred_term: hypertrophic cardiomyopathy 17
  term:
    id: MONDO:0013474
    label: hypertrophic cardiomyopathy 17
parents:
- Hypertrophic Cardiomyopathy
- Cardiomyopathy
- Genetic Disease
references:
- reference: PMID:17509612
  title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Reported HCM-associated JPH2 variants are heterozygous and segregate as an
    autosomal dominant trait. Penetrance is age-dependent and incomplete: in
    the Finnish p.(Thr161Lys) founder families it was 71% by age 60 and 100% by
    age 80, so an unaffected middle-aged carrier does not exclude the variant.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
    explanation: Quantifies age-dependent penetrance in heterozygotes, establishing the dominant but incompletely penetrant inheritance pattern.
pathophysiology:
- name: Junctophilin-2 Structural Deficit
  description: >-
    Junctophilin-2 spans the narrow gap of the cardiac dyad, anchoring in the
    sarcoplasmic reticulum membrane and binding the plasma membrane, so that
    the junctional membrane complex is physically held together. Both routes
    documented in human disease reduce the amount of functional protein at that
    junction: missense variants at key functional domains reorganize the
    protein, and JPH2 expression is itself reduced in myocardium from patients
    with hypertrophic cardiomyopathy. The lesion is architectural rather than
    contractile - nothing about the sarcomere's force-generating machinery is
    directly altered.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Junctional sarcoplasmic reticulum membrane
    term:
      id: GO:0014701
      label: junctional sarcoplasmic reticulum membrane
  downstream:
  - target: Dyad Disruption and Uncoupling of the L-Type Channel from the Ryanodine Receptor
    causal_link_type: DIRECT
    description: >-
      Losing the physical bridge separates the two channels that must be
      apposed for calcium-induced calcium release.
    evidence:
    - reference: PMID:25659516
      reference_title: "Ca²⁺ microdomains organized by junctophilins."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In muscle cells, junctophilin deficiency prevents JMC formation and functional crosstalk between cell-surface Ca(2+) channels and ER/SR Ca(2+) release channels."
      explanation: States the direct structural-to-functional consequence - without junctophilin the junctional complex does not form and the two channel classes stop communicating.
  evidence:
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "each human mutation caused (i) protein reorganization of junctophilin-2"
    explanation: Functional characterisation showing each HCM-associated variant reorganizes the protein itself, which is the structural deficit this node describes.
  - reference: PMID:21216834
    reference_title: "Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium handling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JPH2 expression was reduced in flash-frozen human cardiac tissue procured from patients with HCM compared with ostensibly healthy traumatic death victims."
    explanation: Shows reduced junctophilin-2 in human HCM myocardium, an expression-level route to the same structural deficit as the coding variants.
- name: Dyad Disruption and Uncoupling of the L-Type Channel from the Ryanodine Receptor
  description: >-
    The cardiac dyad exists so that calcium entering through the L-type channel
    reaches the ryanodine receptor at a high enough local concentration to
    trigger sarcoplasmic reticulum calcium release. Widening or disorganizing
    that junction breaks the trigger. In JPH2-silenced myocytes the calcium
    transient loses its dependence on L-type channel activation, which is the
    signature of a broken structural coupling rather than of a channel that has
    itself stopped working.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Release of sequestered calcium into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DECREASED
  downstream:
  - target: Disordered Intracellular Calcium Handling
    causal_link_type: DIRECT
    description: >-
      An untriggered or weakly triggered release produces an abnormal calcium
      transient.
    evidence:
    - reference: PMID:21216834
      reference_title: "Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "shJPH2 cells demonstrated depressed maximal Ca(2+) transient amplitudes that were insensitive to L-type Ca(2+) channel activation with JPH2 knockdown"
      explanation: The loss of L-type sensitivity is the specific signature of structural uncoupling, and it is the measured consequence of reducing junctophilin-2.
  evidence:
  - reference: PMID:17476457
    reference_title: "Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels"
    explanation: The Jph2 knockout mouse establishes the uncoupling mechanism directly, naming both channel partners.
- name: Disordered Intracellular Calcium Handling
  description: >-
    Calcium transients are reduced in amplitude and sarcoplasmic reticulum
    stores are depleted. Because intracellular calcium is simultaneously the
    contractile trigger and the input to hypertrophic signalling, this node is
    modelled as the shared origin of both clinical arms - the hypertrophic
    remodelling and the arrhythmic vulnerability.

    That shared origin is the canonical reading, not a settled one. Beavers et
    al argue the opposite for E169K specifically: they attribute its
    arrhythmogenicity to reduced JPH2-RyR2 binding while stating that HCM
    development in JPH2 disease likely involves other cellular mechanisms
    still to be explored. Their E169K mice were AF-susceptible with no
    structural cardiomyopathy at two months, which is the observation that
    separates the arms.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DECREASED
  - preferred_term: Regulation of cardiac muscle contraction by calcium ion signaling
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: DECREASED
  downstream:
  - target: Prohypertrophic Cardiomyocyte Remodeling
    causal_link_type: DIRECT
    description: >-
      Altered calcium handling engages the hypertrophic signalling programme in
      the cardiomyocyte.
    evidence:
    - reference: PMID:21216834
      reference_title: "Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Partial silencing of JPH2 expression in HL-1 cells by a small interfering RNA probe targeted to murine JPH2 mRNA (shJPH2) resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy."
      explanation: Reducing junctophilin-2 alone is sufficient to produce myocyte hypertrophy with induction of hypertrophic markers.
  - target: Arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disordered calcium release is the substrate for the arrhythmic
      vulnerability and conduction disease seen in carriers, and the steps
      between the two are identified rather than assumed. Spontaneous
      sarcoplasmic reticulum calcium release appears as cell-wide calcium
      waves; these activate the sodium-calcium exchanger, which generates
      delayed afterdepolarizations, and the resulting triggered activity is
      the arrhythmia. This was worked out for the E169K allele, found in
      hypertrophic cardiomyopathy patients with juvenile-onset paroxysmal
      atrial fibrillation and modelled in pseudoknock-in mice.
    evidence:
    - reference: PMID:23973696
      reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These cell-wide spontaneous Ca2+ waves can directly activate NCX, trigger delayed afterdepolarizations (DADs) and cause triggered activity associated with AF"
      explanation: Names the intermediates that lie between disordered calcium release and the arrhythmia itself - calcium waves, sodium-calcium exchanger activation, delayed afterdepolarizations, triggered activity.
    - reference: PMID:23973696
      reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These changes were attributed to reduced binding of E169K-JPH2 to RyR2."
      explanation: Upstream allele context - loss of JPH2-RyR2 binding is what makes the calcium release abnormal in the first place, so it is the reason this edge is engaged rather than a step within it.
    - reference: PMID:23973696
      reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca(2+) release events."
      explanation: Demonstrates the abnormal calcium release that constitutes the arrhythmic substrate, with an allele-specific control.
    - reference: PMID:17476457
      reference_title: "Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels"
      explanation: Independent knockout-model support for arrhythmic calcium signalling arising from the same uncoupling.
  evidence:
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia"
    explanation: All three human HCM variants produced calcium-signalling perturbation on functional characterisation.
  - reference: PMID:23973696
    reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "it is likely that the proarrhythmogenic effects of the E169K mutation are due to the reduced binding of E169K-JPH2 to RyR2, whereas HCM development likely involves other cellular mechanisms that remain to be explored in future studies"
    explanation: Contradicts modelling one calcium disturbance as the shared origin of both arms - for E169K these authors separate the arrhythmic mechanism from the hypertrophic one and place the latter outside this node.
- name: Prohypertrophic Cardiomyocyte Remodeling
  description: >-
    Cardiomyocytes enlarge and induce the canonical hypertrophic gene
    programme, producing the left ventricular hypertrophy that defines the
    clinical phenotype. In a subset of patients the disease progresses beyond
    hypertrophy to systolic failure with normal or only mildly enlarged
    diastolic dimensions - an end-stage picture that is not typical
    burnt-out HCM and was one reason the Finnish cohort was described as
    atypical.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Left ventricular hypertrophy
    causal_link_type: DIRECT
    description: >-
      Cardiomyocyte hypertrophy summed across the ventricular wall is the
      macroscopic hypertrophy.
    evidence:
    - reference: PMID:30235249
      reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
      explanation: Reports left ventricular hypertrophy as the leading clinical feature in the largest JPH2 HCM cohort.
  evidence:
  - reference: PMID:21216834
    reference_title: "Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy"
    explanation: Documents the cellular hypertrophy and hypertrophic marker induction that constitute this node.
mechanistic_hypotheses:
- hypothesis_group_id: dyad_architecture_not_sarcomere
  hypothesis_label: CMH17 arises from dyad architectural failure rather than altered sarcomeric cross-bridge kinetics
  status: CANONICAL
  description: >-
    The eight definitive HCM genes encode sarcomeric proteins, and the dominant
    model of HCM is altered actin-myosin cross-bridge kinetics with increased
    myofilament calcium sensitivity. JPH2 encodes no part of the sarcomere. The
    proposed mechanism for CMH17 is instead that loss of the junctophilin-2
    bridge widens or disorganizes the dyad, uncouples the L-type channel from
    the ryanodine receptor, and drives hypertrophy through disordered calcium
    signalling. The chain is supported by a knockout model, by siRNA silencing
    sufficient to produce hypertrophy in isolation, and by functional
    characterisation of the three original human variants. What it does not yet
    have is direct demonstration of dyad ultrastructural disruption in
    myocardium from a genotyped human CMH17 patient, so the human step of the
    argument rests on reduced JPH2 protein in HCM tissue rather than on imaging
    the junction itself.
  evidence:
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM"
    explanation: The authors' own statement of the mechanism as distinct from established sarcomeric HCM pathogenesis.
  - reference: PMID:34526680
    reference_title: "Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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 JPH2 explicitly among the non-sarcomeric HCM genes, which is the premise of this hypothesis.
phenotypes:
- category: Cardiovascular
  name: Left ventricular hypertrophy
  description: >-
    Unexplained left ventricular hypertrophy is the defining and most
    consistently reported feature in JPH2 variant carriers.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
    explanation: Left ventricular hypertrophy is the leading feature across nine families carrying the founder variant.
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  description: >-
    The clinical diagnosis under which affected individuals present, ascertained
    in unrelated HCM cohorts screened for JPH2 variants.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles"
    explanation: Establishes the association with clinically diagnosed HCM, with an allele-frequency control.
- category: Cardiovascular
  name: Arrhythmia
  description: >-
    Arrhythmia vulnerability is a prominent feature and is mechanistically
    expected from disordered calcium release rather than being merely secondary
    to the hypertrophy.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
    explanation: Reports arrhythmia vulnerability among the main clinical features of the cohort.
- category: Cardiovascular
  name: Atrioventricular block
  description: >-
    Conduction disease up to third-degree AV block was reported in the Finnish
    founder families, and is part of why that cohort was described as atypical
    HCM.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conduction abnormalities including third degree AV-block"
    explanation: Documents high-grade conduction block in JPH2 variant carriers.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    A subset progress to end-stage systolic heart failure with normal or only
    mildly enlarged diastolic dimensions - a picture distinct from the
    ventricular dilatation of dilated cardiomyopathy.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected."
    explanation: Describes the end-stage systolic failure seen in a subset, and its distinguishing chamber geometry.
genetic:
- name: JPH2
  association: Causal
  gene_term:
    preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  notes: >-
    Heterozygous JPH2 missense variants are reported in HCM: S101R, Y141H and
    S165F in three of 388 unrelated probands (Landstrom et al), G505S with a
    statistically significant case-control excess in a Japanese cohort
    (Matsushita et al), and the Finnish founder allele c.482C>A p.(Thr161Lys)
    segregating across nine families (Vanninen et al). ClinGen's Hereditary
    Cardiovascular Disease Gene Curation Expert Panel grades JPH2 for autosomal
    dominant HCM as Moderate. Separately, JPH2 is graded Strong for autosomal
    recessive dilated cardiomyopathy and Limited for autosomal dominant DCM by
    the Dilated Cardiomyopathy GCEP, so allele and inheritance pattern both
    matter to interpretation. The 2024 HCM reappraisal left JPH2 at Moderate
    rather than downgrading it, so that grade is current.

    Allele matters to phenotype as well as to validity. E169K was found in 2
    of 203 unrelated HCM probands screened by Beavers et al, both with
    juvenile-onset paroxysmal atrial fibrillation - an index case whose
    fibrillation began at 22, before significant atrial remodeling, and his
    father, who had supraventricular tachycardia. A405S, identified in the
    same cohort, was not associated with atrial arrhythmia, and neither were
    the previously reported HCM alleles. The arrhythmic phenotype of this
    entry is therefore an E169K observation rather than a general property of
    JPH2-associated HCM.
  evidence:
  - reference: PMID:23973696
    reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF)."
    explanation: The human cohort finding that establishes E169K as an HCM allele and ties it to juvenile-onset atrial fibrillation.
  - reference: PMID:23973696
    reference_title: "Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient with the other HCM-associated JPH2 mutation, A405S, did not exhibit atrial arrhythmias, similar to all other previously reported HCM patients with JPH2 mutations"
    explanation: The allele-specific control - other JPH2 HCM alleles carried no atrial arrhythmia, so the arrhythmic phenotype should not be generalized across the gene.
  - reference: CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z
    reference_title: "JPH2 / hypertrophic cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JPH2 | HGNC:14202 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Moderate | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2022-10-12T16:00:00.000Z"
    explanation: The current ClinGen gene-disease validity classification for JPH2 in autosomal dominant hypertrophic cardiomyopathy.
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%)"
    explanation: Places JPH2 in the moderate-evidence tier against the definitive sarcomeric genes, giving the comparative context for this entry's confidence.
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel HCM-susceptibility mutations: S101R, Y141H and S165F, which localize to key functional domains, were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles."
    explanation: The original variant discovery with an allele-frequency control, which is the foundation of the gene-disease claim.
  - reference: PMID:17476457
    reference_title: "Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only the G505S mutation showed statistical significance (4/296 HCM patients and 0/472 control individuals, P=0.022)"
    explanation: An independent case-control association for a distinct JPH2 allele, surviving correction for multiple comparisons.
  - 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
    snippet: "1 no evidence ( TNNC2), 6 limited ( KLF10, NEXN, OBSCN, PDLIM3, RYR2, TTN ), 1 moderate (JPH2), and 3 definitive evidence (CACNA1C, FLNC, PRKAG2)"
    explanation: The 2024 reappraisal left JPH2 at Moderate rather than downgrading it, so the classification cited here is the current one and not a stale grade.
  - reference: CGGV:assertion_7aa138ae-114c-46b0-84e4-5bfc5a7db51b-2025-01-24T170000.000Z
    reference_title: "JPH2 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel | 2025-01-24T17:00:00.000Z"
    explanation: Source for the autosomal recessive dilated cardiomyopathy grading asserted in these notes.
  - reference: CGGV:assertion_8d310e47-1f84-4c61-b06a-b273a4b1b601-2025-01-24T170000.000Z
    reference_title: "JPH2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited | SOP11 | Dilated Cardiomyopathy Gene Curation Expert Panel | 2025-01-24T17:00:00.000Z"
    explanation: Source for the autosomal dominant dilated cardiomyopathy grading, and the contrast with the recessive grade that makes inheritance pattern matter to interpretation.
has_subtypes:
- name: Thr161Lys
  display_name: Finnish p.(Thr161Lys) founder variant
  description: >-
    A Finnish founder allele (c.482C>A) identified in nine index families and
    described by its authors as causing atypical HCM: alongside left
    ventricular hypertrophy it carries prominent conduction disease and
    progression to systolic heart failure with non-dilated chamber geometry.
    Penetrance is age-dependent, reaching 100% only by age 80.
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM"
    explanation: The authors' own designation of this allele as a distinct, atypical founder form.
experimental_models:
- name: JPH2 p.(Thr161Lys) patient-derived iPSC cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:37371654
  description: >-
    Skin fibroblasts from a Finnish patient carrying the p.(Thr161Lys) founder
    allele were reprogrammed to iPSCs and differentiated to cardiomyocytes,
    with an isogenic CRISPR-corrected counterpart as control. The isogenic
    design is what makes this informative: the comparison is against the same
    genetic background rather than an unrelated line, so the differences are
    attributable to the variant. It models the exact allele curated as a
    has_subtypes entry on this disease.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Prohypertrophic Cardiomyocyte Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The mutant cardiomyocytes reproduce the cellular hallmarks of
      hypertrophic cardiomyopathy - cellular hypertrophy, multi-nucleation and
      sarcomeric disarray.
    limitations: >-
      iPSC-derived cardiomyocytes are immature relative to adult myocardium,
      with fetal-like calcium handling and underdeveloped T-tubules. That last
      point matters more here than usual: the disease mechanism is dyad
      architecture, and the dyad is precisely the structure these cells have
      not fully formed.
    readouts:
    - name: Cellular hypertrophy, multi-nucleation and sarcomeric disarray
      target: Prohypertrophic Cardiomyocyte Remodeling
      direction: INCREASED
      interpretation: The cellular correlates of the hypertrophic phenotype are present in the mutant line.
      evidence:
      - reference: PMID:37371654
        reference_title: "The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray)."
        explanation: Directly reports the hypertrophic cellular phenotype in the patient-derived line.
    evidence:
    - reference: PMID:37371654
      reference_title: "The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray)."
      explanation: Supports treating this line as informative for the hypertrophic remodeling node.
  - target: Disordered Intracellular Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The mutant cardiomyocytes show prolonged action potential duration and
      increased arrhythmogenicity, attributed to slower inactivation of calcium
      channels - a calcium-handling abnormality in a human cell carrying the
      disease allele.
    limitations: >-
      Immature calcium handling and incomplete T-tubule development mean the
      magnitude of the defect should not be read across to adult myocardium.
    readouts:
    - name: Action potential duration and arrhythmogenicity
      target: Disordered Intracellular Calcium Handling
      direction: INCREASED
      interpretation: Prolonged action potential with increased arrhythmic events in the mutant line.
      evidence:
      - reference: PMID:37371654
        reference_title: "The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "JPH2-hiPSC-CMs exhibit a higher degree of arrhythmia and longer action potential duration associated with slower inactivation of calcium channels"
        explanation: Reports the electrophysiological and calcium-handling abnormality measured in the patient-derived line.
    evidence:
    - reference: PMID:37371654
      reference_title: "The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional evaluation supported clinical observations, with differences in beating characteristics when compared with isogenic-hiPSC-CMs."
      explanation: The isogenic comparison supports attributing the functional differences to the variant.
prevalence:
- population: Unrelated hypertrophic cardiomyopathy probands
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Reported as a yield within an HCM cohort, not a population prevalence:
    three of 388 unrelated HCM patients carried an HCM-associated JPH2 variant
    in the original screen. JPH2 is a minor HCM gene; the eight core sarcomeric
    genes account for more than 90% of pathogenic variants in HCM.
  evidence:
  - reference: PMID:17509612
    reference_title: "Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were discovered in 3/388 unrelated patients with HCM"
    explanation: The reported yield of JPH2 variants among unrelated HCM probands.
diagnosis:
- name: Echocardiography
  description: >-
    Imaging for the defining feature, unexplained left ventricular hypertrophy.
    Conduction disease up to third-degree AV block accompanying the hypertrophy
    is a phenotype-first clue toward a non-sarcomeric, JPH2-type mechanism
    rather than classic sarcomeric HCM; the cited series assessed these
    patients by echocardiography together with resting 12-lead ECG.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block."
    explanation: Establishes the combination of left ventricular hypertrophy with conduction disease that distinguishes the JPH2 presentation.
- name: Electrocardiography and Ambulatory Rhythm Monitoring
  description: >-
    Resting 12-lead ECG, extended with ambulatory rhythm monitoring where
    symptoms or ECG findings warrant it. This is the test that detects the
    feature distinguishing the JPH2 presentation from classic sarcomeric HCM:
    high-grade conduction disease up to third-degree AV block, alongside the
    atrial and ventricular arrhythmia burden documented in the Finnish founder
    families. Imaging alone does not capture it, so ECG belongs in the initial
    evaluation rather than being reserved for symptomatic patients.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resting 12-lead ECG, appropriate laboratory tests and transthoracic echocardiography (TTE)."
    explanation: Records that resting 12-lead ECG was part of the standard clinical assessment of the JPH2 families alongside echocardiography.
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conduction abnormalities including third degree AV-block"
    explanation: Names the conduction finding that ECG detects and that distinguishes this presentation from classic sarcomeric HCM.
- name: Molecular Genetic Testing (JPH2 Sequencing)
  description: >-
    Confirms the molecular diagnosis, but a JPH2 result must be weighed
    against its Moderate ClinGen classification rather than treated as
    definitive - a lower interpretive tier than a variant in one of the eight
    core sarcomeric genes.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A qualifying JPH2 variant supports but does not by itself establish the
    molecular diagnosis, given the gene's Moderate evidence tier.
  evidence:
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."
    explanation: States why a JPH2 finding must be reported and weighted according to the gene's own validity tier rather than as a definitive cause.
treatments:
- name: Cascade Screening and Cardiac Surveillance of At-Risk Relatives
  description: >-
    Predictive testing of first-degree relatives once the familial JPH2 variant
    is known, followed by longitudinal cardiac surveillance of those who carry
    it. Cosegregation of the variant with the HCM phenotype across the Finnish
    founder families is what makes a relative's genotype actionable here.
    Because penetrance is age-dependent and incomplete, an unaffected
    middle-aged carrier is not evidence against the variant and cannot be
    discharged from surveillance. Diagnostic sequencing of the proband is a
    diagnostic procedure and is curated under `diagnosis`; this entry covers
    only the management of relatives.
  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:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Co-segregation of the variant with HCM phenotype was observed in six families."
    explanation: Cosegregation across the founder families is what makes a relative's JPH2 genotype informative for cascade screening.
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
    explanation: Age-dependent penetrance is why a genotype-positive relative stays under surveillance rather than being cleared by one normal evaluation.
- name: Genetic Counseling
  description: >-
    Counseling should convey the autosomal dominant inheritance, the
    age-dependent and incomplete penetrance documented in the founder families,
    and the Moderate strength of the underlying gene-disease relationship.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30235249
    reference_title: "Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80."
    explanation: Provides the age-dependent penetrance figures that counseling must convey.
notes: >-
  Management of established hypertrophic cardiomyopathy in JPH2 variant
  carriers follows general HCM care and is not curated here as
  JPH2-specific; no gene-directed therapy exists. The conduction disease
  reported in the Finnish founder families may warrant device consideration on
  standard indications, but no JPH2-specific device evidence was found and none
  is asserted.
📚

References & Deep Research

References

2
PMID:17509612
Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
No top-level findings curated for this source.
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
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 17 (JPH2) · 2026-09-04T01:45:28Z · View source

New Disease entry for MONDO:0013474 (hypertrophic cardiomyopathy 17), the JPH2-attributed member of the numbered familial HCM series. Follows Hypertrophic_Cardiomyopathy_20.yaml (NEXN) as the precedent for a standalone numbered-HCM entry whose gene-disease relationship is not Definitive. Gene-disease validity, which claim issue #10799 specifically asked to check rather than assume: ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel grades JPH2 for autosomal dominant HCM as Moderate (SOP9, 2022-10-12). Cited directly from the structured ClinGen source as CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z, quoting the validity row, and corroborated with the ClinGen HCM gene-validity paper (PMID:30681346), which places JPH2 in the moderate tier alongside CSRP3 and TNNC1 against eight definitive sarcomeric genes. This is a stronger relationship than NEXN's Limited, and the entry says Moderate rather than implying either Definitive or disputed. Also recorded: the ClinGen cache carries two further JPH2 assertions for dilated cardiomyopathy - Strong for autosomal recessive, Limited for autosomal dominant. Noted in genetic notes and the description because it means allele and inheritance pattern both matter to interpretation; JPH2 is not simply an HCM gene. Deep research: 'just research-disorder claude_code Hypertrophic_Cardiomyopathy_17' (report and citations sidecar committed). The run emitted no reference_validation or term_validation frontmatter, so both were retro-fitted with 'just validate-research-reference' and 'just validate-research-terms' per the skill. Results: 9/9 references resolved, no confabulation; 23/24 terms resolved, one mislabelled (HP:0004758, reported as 'Paroxysmal atrial fibrillation', actually 'Effort-induced polymorphic ventricular tachycardia') - not bound in this entry. Note the report also lacks a template_sha, so which prompt version produced it is inferred rather than stamped. Mechanism is curated as a chain and deliberately framed as non-sarcomeric: Junctophilin-2 Structural Deficit -> Dyad Disruption and Uncoupling of the L-Type Channel from the Ryanodine Receptor -> Disordered Intracellular Calcium Handling -> Prohypertrophic Cardiomyocyte Remodeling -> Left ventricular hypertrophy, with a second branch to Arrhythmia typed INDIRECT_UNKNOWN_INTERMEDIATES because the arrhythmia link rests on knockout-mouse calcium data and the human intervening steps are not established. The mechanistic hypothesis (dyad_architecture_not_sarcomere, CANONICAL) states explicitly what the chain still lacks: no direct demonstration of dyad ultrastructural disruption in myocardium from a genotyped human CMH17 patient. The human step currently rests on reduced JPH2 protein in HCM tissue (PMID:21216834) rather than on imaging the junction. Added a has_subtypes entry for the Finnish p.(Thr161Lys) founder allele, which its authors describe as causing atypical HCM - prominent conduction disease including third-degree AV block, and progression to systolic failure with non-dilated geometry. Penetrance 71% by age 60 and 100% by age 80, recorded in inheritance and used in the genetic-counseling treatment. Prevalence is recorded as measure_type UNKNOWN with an explicit note that 3/388 is a yield within an HCM cohort, not a population prevalence. A top-level note records that general HCM management is not curated here as JPH2-specific, and that no JPH2-specific device evidence was found despite the reported conduction disease, so none is asserted. Validation: 'just validate' passed with 26/26 snippets verified (including the ClinGen row); 'just validate-terms' passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and check-enum-values all clean. Five references fetched and committed; PMID:30681346, PMID:34526680 and the CGGV assertion were already cached on main and are cited unmodified. Incidental references fetched by the validator but not cited were removed from the diff. Two drafting errors were caught and fixed: an unquoted colon inside an explanation broke YAML parsing, and 'anatomical_entities' is not a Pathophysiology slot (the slot is 'locations').

Claude Code ▸
Hypertrophic Cardiomyopathy 17 (CMH17 / JPH2-Related Hypertrophic Cardiomyopathy) — Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-09-04T01:43:47.006307

Hypertrophic Cardiomyopathy 17 (CMH17 / JPH2-Related Hypertrophic Cardiomyopathy) — Research Report

1. Disease Information

Overview. Hypertrophic Cardiomyopathy 17 (CMH17) is a rare, autosomal dominant form of familial hypertrophic cardiomyopathy (HCM) caused by heterozygous missense mutations in JPH2 (junctophilin-2, chromosome 20q13.12), a non-sarcomeric structural protein essential for cardiac excitation–contraction coupling. It represents one of the "minor" genetic subtypes of HCM — distinct from the major sarcomeric-protein loci (MYH7/CMH1, MYBPC3/CMH4, etc.) — and was the first human disease linked to genetic defects in a junctional membrane complex (JMC) protein rather than a sarcomere or Z-disc component (Landstrom et al., 2007, PMID:17509612).

Key identifiers: - OMIM phenotype: #613873 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 17; CMH17 (OMIM entry 613873) - OMIM gene: 605267 — JUNCTOPHILIN 2; JPH2 (chr 20q13.12) - HGNC: JPH2, hgnc:19420 - MONDO: The general "familial hypertrophic cardiomyopathy" umbrella term is MONDO:0005045 (also cross-referenced as MONDO:0024573 for the broader "familial hypertrophic cardiomyopathy" concept); no CMH17-specific MONDO subtype term was found in the searches performed — CMH17 currently maps as a JPH2-caused subtype under the general HCM MONDO node, consistent with ClinGen's own use of MONDO:0005045 for the JPH2–HCM gene-disease validity curation. - ClinGen Gene-Disease Validity: JPH2–HCM classified Moderate (autosomal dominant), re-affirmed on 2022 re-curation (ClinGen CGGV assertion) - Inheritance: Autosomal dominant (for the HCM phenotype; biallelic JPH2 loss-of-function variants instead cause a distinct, more severe dilated cardiomyopathy/early heart-failure phenotype — see §9) - Synonyms:* CMH17; Junctophilin-2-related hypertrophic cardiomyopathy; JPH2 cardiomyopathy

Provenance of information: Data are aggregated disease-level findings from case series/cohort studies (Landstrom 2007; Matsushita 2007, PMID for Japanese G505S/R436C cohort; Vanninen et al. Finnish T161K family study, PMC6147424) rather than a single large EHR-derived cohort — reflecting the rarity of this HCM subtype (only ~16 probands/6 unique variants reported across 5 publications as of the 2022 ClinGen curation).

Sources: OMIM #613873, OMIM *605267, ClinGen JPH2-HCM, PubMed 17509612

2. Etiology

Disease causal factor: Purely genetic/monogenic — heterozygous missense variants in JPH2 disrupting the junctophilin-2 protein's calcium-handling scaffolding function at the cardiomyocyte junctional membrane complex.

Genetic risk factors: - Causal heterozygous JPH2 missense variants: S101R, Y141H, S165F (Landstrom 2007, PMID:17509612); G505S, R436C (Matsushita 2007, Japanese cohort, Journal of Human Genetics); T161K/p.(Thr161Lys) (Vanninen et al., Finnish founder variant, PMC6147424); E169K (Beavers/Landstrom et al. 2013, JACC, PMID:23973696 — associated with juvenile-onset paroxysmal atrial fibrillation in the context of HCM screening). - The ClinGen panel notes "considerable background noise" in the JPH2 variant literature — i.e., population-level rare-variant burden complicates unambiguous pathogenicity assignment for novel missense changes, which is part of why the gene-disease validity is capped at Moderate rather than Definitive/Strong. - No modifier genes for CMH17 specifically were identified in the literature reviewed; general HCM modifier-gene concepts (e.g., ACE, hypertension-associated loci influencing hypertrophy severity) apply nonspecifically across HCM genotypes but were not documented for JPH2 carriers specifically.

Environmental/lifestyle risk factors: None specific to CMH17 were identified; as with sarcomeric HCM, intense athletic conditioning and systemic hypertension can influence phenotypic expression/exacerbation of LVH in genotype-positive individuals generically, but no JPH2-specific environmental interaction data were found.

Protective factors: None reported specifically for JPH2; variant absence from gnomAD/ExAC/1000 Genomes population databases is used as supporting evidence against the variant being common/benign, not as a described protective factor per se.

Gene-environment interaction: Not specifically studied for JPH2-HCM in the literature surveyed.

Sources: PMID:17509612, Matsushita et al., J Hum Genet (nature.com/articles/jhg200774), PMC6147424, PMID:23973696

3. Phenotypes

Because CMH17 is a form of HCM, its core phenotype overlaps substantially with sarcomeric HCM but with a documented additional burden of conduction disease and arrhythmia, reflecting JPH2's specific role in calcium-channel/ryanodine-receptor coupling (rather than pure sarcomeric hypercontractility).

Phenotype Frequency/detail (from JPH2 cohorts) Suggested HP term
Left ventricular hypertrophy Defining feature; mean max wall thickness 20.4±5.2 mm in the Finnish T161K cohort (n=20 heterozygotes) HP:0001639 (Hypertrophic cardiomyopathy) / HP:0001712 (Left ventricular hypertrophy)
Atrial/ventricular arrhythmia 13/20 (65%) of T161K heterozygotes HP:0011675 (Arrhythmia)
Conduction defects (3rd-degree AV block, bundle branch block) ~45% of T161K-affected individuals HP:0011711 (Third degree atrioventricular block) / HP:0005110 (Atrioventricular block)
Systolic dysfunction / heart failure (some end-stage) ~45% of T161K cohort HP:0001635 (Congestive heart failure)
Paroxysmal atrial fibrillation (juvenile onset) Reported in E169K carriers (2/203 screened HCM probands) HP:0004758 (Paroxysmal atrial fibrillation)
Age-dependent penetrance 71% penetrant by age 60, 100% by age 80 (T161K) n/a (penetrance descriptor)
Age of onset Mean 26.9±20.6 years at diagnosis (T161K cohort) — wide variance reflecting age-dependent penetrance —

Progression: Age-dependent, progressive — increasing penetrance with age and progression to systolic heart failure documented in a subset of carriers, distinguishing it somewhat from the more classically "stable" hypertrophic phenotype of some sarcomeric HCM forms. The authors of the Finnish study characterize T161K-associated disease as "atypical HCM" given the prominent conduction-system and heart-failure component.

Quality of life: Not separately quantified in JPH2-specific literature; general HCM QoL burden (exertional dyspnea, arrhythmia-related limitation) applies.

Sources: PMC6147424 (Vanninen et al.), PMID:23973696

4. Genetic/Molecular Information

Causal gene: JPH2 (HGNC:19420; OMIM *605267), chromosome 20q13.12. Encodes junctophilin-2, a cardiac-specific member of the junctophilin family that spans the sarcoplasmic reticulum (SR) membrane via a C-terminal transmembrane domain while its N-terminal MORN (Membrane Occupation and Recognition Nexus) repeat domain tethers to the plasma membrane/T-tubule, physically bridging the L-type calcium channel (CaV1.2) at the T-tubule with the ryanodine receptor (RyR2) on the SR — the structural basis of cardiac calcium-induced calcium release (CICR).

Reported pathogenic/likely pathogenic missense variants (heterozygous, HCM-associated):

Variant (protein) Cohort/publication Notes
p.Ser101Arg (S101R) Landstrom 2007, PMID:17509612 1 of 388 unrelated white HCM probands negative for 8 myofilament + 5 Z-disc genes
p.Tyr141His (Y141H) Landstrom 2007 Same cohort
p.Ser165Phe (S165F) Landstrom 2007; mechanistic follow-up in Communications Biology 2025 (PMID:41291214) Absent in 1000 ethnic-matched control alleles; shown to cause JPH2 autoinhibition disrupting CaV1.2 binding
p.Gly505Ser (G505S) Matsushita et al. 2007, Japanese cohort Identified in 4 unrelated Japanese probands; statistically significant vs. controls; not found in DCM or RCM patients
p.Arg436Cys (R436C) Matsushita et al. 2007 Found but did not reach statistical significance vs controls
p.Thr161Lys / T161K Vanninen et al., PLOS ONE 2018, PMC6147424; functional iPSC-CM study PMID:37371654 Finnish founder variant; 20 affected individuals across 9 families; co-segregation in 6/9 families
p.Glu169Lys / E169K Beavers/Landstrom et al. 2013, JACC, PMID:23973696 Found in 2/203 unrelated HCM probands screened for juvenile-onset paroxysmal AF; impairs JPH2–RyR2 binding, causing SR Ca²⁺ leak

Variant classification (ACMG/ClinVar): Most JPH2 variants are submitted to ClinVar but "are often classified as variants of uncertain significance (VUS) due to a lack of family member surveillance and segregation studies," though several (e.g., T161K, S165F) have been upgraded from VUS to likely pathogenic/pathogenic with additional segregation and functional evidence. Population database absence (gnomAD, ExAC, 1000 Genomes) is consistently cited as supporting evidence across these variants.

Functional consequences: All studied HCM-associated JPH2 missense variants converge on a mechanism of disrupted intracellular calcium handling and junctional membrane complex disorganization, rather than the sarcomeric hypercontractility mechanism of MYH7/MYBPC3 HCM: - Landstrom (2007): "Each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia [hypertrophy]" in cellular overexpression models. - S165F (Nature Communications Biology 2025, PMID:41291214): induces an aberrant intramolecular ("autoinhibitory") interaction within JPH2 that folds back onto its own N-terminal MORN-repeat inner groove — the normal CaV1.2 cytoplasmic-tail binding site — thereby disrupting the JPH2–CaV1.2 interaction, compromising ER/SR–plasma-membrane junctions, and producing hypertrophy in COS7 and H9c2 cell models. - T161K (Biomedicines 2023, PMID:37371654): iPSC-cardiomyocytes show prolonged action potential duration (APD50, APD90), slowed L-type calcium current (ICa) inactivation kinetics, and phase-3 early afterdepolarizations (EADs) correlating with slower ICa inactivation — providing a direct cellular arrhythmogenic mechanism. - E169K (JACC 2013, PMID:23973696): impairs JPH2 binding to RyR2, reducing RyR2 stabilization and promoting SR Ca²⁺ leak → triggered activity → atrial arrhythmia, replicated in a JPH2-E169K mouse model.

Modifier genes: None specifically documented for CMH17.

Epigenetic information: No JPH2/CMH17-specific epigenetic (DNA methylation/histone) data identified.

Chromosomal abnormalities: None — CMH17 is caused by point (missense) mutations, not structural chromosomal rearrangements.

Genetic heterogeneity note: Biallelic (homozygous/compound heterozygous), typically loss-of-function, JPH2 variants cause a distinct, more severe recessive phenotype — early-onset dilated cardiomyopathy (DCM) and heart failure — as opposed to the dominant missense-driven HCM phenotype of CMH17 (see §9 and the systematic review below).

Sources: PMID:17509612, Matsushita 2007 (J Hum Genet), PMID:41291214 / Commun Biol 2025, PMID:37371654 / Biomedicines 2023, PMID:23973696 / JACC 2013, OMIM *605267

5. Environmental Information

No JPH2/CMH17-specific environmental, toxin, occupational, or infectious-agent contributors were identified in the literature surveyed. As a monogenic structural-protein cardiomyopathy, environmental contribution is presumed secondary/modifying rather than causal (as with general HCM, systemic hypertension and intense endurance exercise are nonspecific modifiers of hypertrophy severity, but this was not documented specifically for JPH2 carriers).

6. Mechanism / Pathophysiology

Causal chain (ordered)

  1. A heterozygous missense mutation in JPH2 (e.g., S165F, T161K, E169K, G505S) alters the structure of junctophilin-2's N-terminal MORN-repeat domain or its RyR2/CaV1.2-binding surfaces, demonstrated directly for S165F, which is shown by AlphaFold-guided structural and biochemical analysis to fold back and autoinhibit its own CaV1.2-binding groove (PMID:41291214).
  2. This structural perturbation impairs JPH2's tethering function at the junctional membrane complex (JMC) — the specialized ER/SR–T-tubule junction where JPH2 normally holds the plasma-membrane L-type Ca²⁺ channel (CaV1.2) in close apposition (~12–15 nm) to the SR ryanodine receptor (RyR2), leading to (i) impaired CaV1.2 tethering (S165F) and/or (ii) impaired RyR2 stabilization (E169K).
  3. Loss of JMC integrity and impaired JPH2–RyR2/CaV1.2 coupling disrupts calcium-induced calcium release (CICR): SR Ca²⁺ leak (E169K mechanism, via reduced RyR2 stabilization) or altered ICa inactivation kinetics (T161K mechanism, via prolonged L-type current) — both documented directly in patient-derived/mutant cellular models.
  4. Disrupted calcium signaling drives two parallel downstream consequences, branching by which aspect of Ca²⁺ handling is most affected:
  5. Branch A (hypertrophic remodeling): Chronic altered intracellular Ca²⁺ handling and JMC disorganization triggers compensatory/maladaptive cardiomyocyte hypertrophic signaling, producing cardiomyocyte enlargement in cellular overexpression models (S101R/Y141H/S165F; Landstrom 2007) and, in vivo, hypertrophic interventricular septum, increased LV mass, and asymmetric LV hypertrophy in a JPH2 mouse model, with histology confirming cardiomyocyte hypertrophy and disarray "consistent with HCM" (per ClinGen curation).
  6. Branch B (arrhythmogenesis): SR Ca²⁺ leak / prolonged Ca²⁺ current inactivation causes triggered activity — early afterdepolarizations documented directly in T161K iPSC-cardiomyocytes ("The occurrence of phase 3 EADs during the spontaneous beating was only observed in T161K hiPSC-CMs") and atrial arrhythmia in E169K carriers and mice via impaired RyR2 stabilization → SR Ca²⁺ leak → triggered activity.
  7. Clinically, Branch A manifests as left ventricular hypertrophy, diastolic dysfunction, and (in a subset) progression to systolic heart failure; Branch B manifests as atrial/ventricular arrhythmia, atrioventricular conduction block, and increased sudden cardiac death risk — the two branches co-occurring within the same patients/families (e.g., 65% arrhythmia prevalence and 45% conduction-defect prevalence alongside LVH in the T161K Finnish cohort), which is the basis for characterizing JPH2-HCM as clinically "atypical" relative to purely sarcomeric HCM.
  8. This dual hypertrophic + arrhythmogenic mechanism is inferred to be distinct from sarcomeric HCM's primary mechanism (myofilament hypercontractility/inefficient ATP utilization from MYH7/MYBPC3/TNNT2 variants), and is instead grounded in a calcium-handling/JMC-structural pathway — making CMH17 mechanistically closer to certain arrhythmia syndromes (e.g., catecholaminergic polymorphic ventricular tachycardia, which also involves RyR2 dysregulation) than to classical sarcomeric HCM, though the downstream hypertrophic phenotype converges with sarcomeric HCM.

Category detail

  • Molecular pathways: Calcium-induced calcium release (CICR) at the cardiac junctional membrane complex; L-type calcium channel (CaV1.2)–ryanodine receptor 2 (RyR2) coupling.
  • Cellular processes: Impaired excitation–contraction coupling; cardiomyocyte hypertrophic remodeling; SR Ca²⁺ leak; triggered arrhythmic activity (early afterdepolarizations).
  • Protein dysfunction: Loss of normal JPH2 tertiary structure/binding-groove accessibility (autoinhibition in S165F); impaired protein–protein interaction with CaV1.2 and RyR2; reported "protein reorganization" of junctophilin-2 in cellular models.
  • Biochemical/ion-channel abnormalities: Slowed L-type Ca²⁺ current (ICa) inactivation kinetics (T161K); reduced RyR2 stabilization / increased SR Ca²⁺ leak (E169K).
  • Tissue damage mechanisms: Cardiomyocyte hypertrophy and myocyte disarray (general HCM hallmark, documented in the JPH2 mouse model).
  • Single-cell/advanced technology findings: Perforated patch-clamp electrophysiology and digital-image-correlation contractility analysis in CRISPR-corrected isogenic iPSC-cardiomyocyte pairs (T161K study) represent the most granular functional dataset available for a JPH2 HCM variant.

Suggested GO terms: GO:0086013 (membrane repolarization in ventricular cardiac muscle cell), GO:0086036 (regulation of cardiac muscle cell membrane potential), GO:0014809 (regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion — analogous cardiac process is GO:0010881, regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion), GO:0007512 (adult heart development, for hypertrophic remodeling context). Suggested CL term: CL:0002129 (cardiac muscle myoblast) / CL:0000746 (cardiac muscle cell).

Sources: PMID:17509612, PMID:41291214, PMID:37371654, PMID:23973696, ClinGen JPH2-HCM curation

7. Anatomical Structures Affected

  • Organ level: Heart (primary); cardiovascular system. Secondary complications from arrhythmia/heart failure can involve pulmonary congestion, cerebral embolism (from AF-related thrombus, general HCM risk), etc.
  • Anatomical site (UBERON): Left ventricle (specifically the interventricular septum, per the JPH2 mouse model showing "hypertrophic interventricular septum"), UBERON:0002082 (cardiac ventricle) / UBERON:0006566 (interventricular septum).
  • Tissue/cell level: Cardiac muscle tissue; cardiomyocytes (CL:0000746) specifically at the T-tubule/sarcoplasmic-reticulum junction.
  • Subcellular level (GO Cellular Component): Junctional sarcoplasmic reticulum membrane / T-tubule (GO:0014701, junctional sarcoplasmic reticulum membrane), plasma membrane, L-type calcium channel complex, ryanodine receptor complex.
  • Laterality: Not applicable (LVH is typically asymmetric-septal in HCM generally, as noted in the mouse model — "asymmetric LV hypertrophy").

8. Temporal Development

  • Onset: Variable, age-dependent; mean age at diagnosis 26.9±20.6 years in the largest documented JPH2-HCM cohort (T161K, Finnish), reflecting a wide range from young adulthood into later life.
  • Progression: Age-dependent penetrance — 71% penetrant by age 60, 100% by age 80 (T161K cohort) — with disease course progressing from isolated LVH to, in a substantial subset (~45%), systolic dysfunction/heart failure, including some cases of "end-stage severe left ventricular failure."
  • Pattern: Progressive overall, but arrhythmic events (atrial/ventricular arrhythmia in 65% of T161K carriers) can be episodic/paroxysmal within an overall progressive structural disease course.
  • Critical periods: Not specifically defined for JPH2-HCM; general HCM natural-history literature emphasizes adolescence/young adulthood as when LVH typically becomes echocardiographically apparent, consistent with the mean age-of-diagnosis data above.

9. Inheritance and Population

  • Epidemiology: CMH17 has no disease-specific prevalence estimate (extremely rare; only ~16 probands / 6 unique variants across 5 publications reported through 2022 per ClinGen). General HCM prevalence (all genetic causes combined) is estimated at 1:500 by echocardiographic LVH criteria, with some estimates as high as 1:200–1:250 when genetic testing and family cascade screening are incorporated.
  • Inheritance pattern: Autosomal dominant for the HCM phenotype (heterozygous missense variants). Notably, JPH2 displays two distinct modes of inheritance mapping to different phenotypes: a systematic review ("One gene, two modes of inheritance, four diseases," Trends in Cardiovascular Medicine, 2021, ScienceDirect) of 61 variant-positive individuals found that:
  • Autosomal dominant, heterozygous missense variants → HCM (76% of AD cases) and arrhythmia/SCD (24% of AD cases).
  • Autosomal recessive, homozygous/compound-heterozygous, typically loss-of-function variants → early-onset dilated cardiomyopathy (DCM) with severe early heart failure (distinct from CMH17 proper).
  • Overall breakdown across the reviewed cohort: ~80% had cardiac disease, comprising 47% HCM, 18% DCM, and 14% arrhythmia/SCD.
  • Penetrance: Age-dependent and incomplete at younger ages — 71% by age 60, 100% by age 80 in the best-documented (T161K) family series — consistent with typical incomplete/age-dependent penetrance seen across HCM genotypes generally.
  • Expressivity: Variable — carriers of the same variant (T161K) range from isolated LVH to arrhythmia/conduction block to end-stage heart failure.
  • Founder effects: T161K is described as a Finnish founder variant, identified across nine unrelated Finnish families.
  • Consanguinity: Relevant primarily to the distinct recessive/biallelic JPH2-DCM phenotype (not CMH17 itself), where homozygous loss-of-function variants have been reported, e.g., in a Greater Middle Eastern cohort with a novel homozygous variant causing neonatal DCM (PMC6588559).
  • Sex ratio / geographic distribution: No JPH2-specific sex-ratio data were identified; variants have been reported in white/Caucasian (Landstrom 2007), Japanese (Matsushita 2007), and Finnish (Vanninen 2018) cohorts, indicating the gene is not population-restricted, though individual variants (T161K) show founder-population clustering.

Sources: PMC6147424, ScienceDirect systematic review, PMC6588559, ClinGen curation

10. Diagnostics

  • Clinical tests: Echocardiography (2D/Doppler) to document LV wall thickness ≥15 mm (or ≥13 mm with family history) in the absence of another cause; cardiac MRI for detailed wall-thickness/fibrosis (late gadolinium enhancement) assessment (general HCM standard, not JPH2-specific in the sources reviewed).
  • Electrophysiology: 12-lead ECG and ambulatory Holter monitoring are of particular relevance for CMH17 given the documented high burden of arrhythmia (65%) and conduction defects including third-degree AV block (LOINC/clinical neurophysiology standard tests); electrophysiologic study may be warranted given the AV-block burden.
  • Genetic testing: JPH2 is included as a "minor"/secondary gene on comprehensive HCM multi-gene panels (alongside the core sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, and other minor genes such as PRKAG2, CSRP3, TNNC1, PLN, JPH2 itself). Given the Moderate (not Definitive) ClinGen gene-disease validity classification, JPH2 variant results should be interpreted with caution and ideally supported by segregation data.
  • Functional/research-grade diagnostics: Patient-specific iPSC-cardiomyocyte modeling with isogenic CRISPR-corrected controls has been used as a research-grade functional validation tool for a specific JPH2 variant (T161K) to establish pathogenicity via electrophysiological phenotyping.
  • Differential diagnosis: Other genetic HCM causes (sarcomeric-gene HCM, RASopathy-associated HCM, glycogen-storage/PRKAG2 cardiomyopathy, Fabry disease, Danon disease, amyloidosis/transthyretin or AL) — general HCM differential, not JPH2-specific literature found.
  • Screening: Cascade family genetic screening is implied as standard given the autosomal dominant inheritance and documented within-family segregation (6/9 Finnish families) with age-dependent penetrance, supporting periodic re-screening of genotype-positive/phenotype-negative relatives as they age (given 100% penetrance is not reached until age 80).

Sources: PMC6147424, PMID:37371654

11. Outcome/Prognosis

  • Mortality/SCD risk: No JPH2-specific SCD incidence rate was identified; general HCM literature reports an overall SCD incidence of ~1%/year in adults, and HCM is the most common identifiable cause of sudden cardiac death in individuals under 35 in the U.S., including athletes. Given CMH17's documented arrhythmia burden (65% arrhythmia, 45% conduction block, and specific EAD-driven arrhythmogenic mechanism for T161K), individualized SCD risk stratification is particularly relevant, though no JPH2-specific SCD risk model exists.
  • Heart failure progression: Systolic dysfunction develops in ~45% of the T161K cohort, with a subset progressing to end-stage LV failure — indicating a comparatively higher heart-failure burden than typically reported for classic sarcomeric HCM cohorts (where heart failure with reduced ejection fraction, or "burnt-out" HCM, occurs in a minority, generally cited around 5–10% over long-term follow-up in sarcomeric HCM literature, though this comparison figure was not independently re-verified for this report).
  • Complications: Third-degree AV block requiring consideration of pacemaker implantation; atrial fibrillation/flutter with thromboembolic risk; ventricular arrhythmia.
  • Prognostic factors: Age (penetrance and disease burden both increase with age); specific variant (T161K carries a well-documented conduction-disease/heart-failure phenotype; E169K is specifically linked to arrhythmia rather than isolated LVH).

Sources: PMC6147424, StatPearls HCM overview

12. Treatment

No JPH2/CMH17-specific treatment trial data were identified; management follows general HCM treatment algorithms, informed by CMH17's particular arrhythmia/conduction-disease burden.

  • Pharmacotherapy (general HCM, applicable to CMH17):
  • Beta-blockers and non-dihydropyridine calcium channel antagonists (e.g., verapamil) — first-line for symptomatic obstructive/non-obstructive HCM (NCIT:C15986, Pharmacotherapy; therapeutic_agent classes: beta-adrenergic antagonists, calcium channel blockers).
  • Cardiac myosin inhibitors (novel disease-modifying drug class for obstructive HCM):
    • Mavacamten — first-in-class allosteric cardiac myosin ATPase inhibitor, FDA-approved 2022 for NYHA class II–III symptomatic obstructive HCM, reduces hypercontractility. Available only through a REMS program.
    • Aficamten — next-generation cardiac myosin inhibitor, FDA-approved December 2024/2025 based on the SEQUOIA-HCM phase 3 trial, which showed ~60% of aficamten-treated patients had improved physical-activity-limitation scores versus 24% placebo. Also REMS-restricted.
    • These agents target the hypercontractile sarcomeric mechanism and are approved for obstructive HCM broadly; no data specifically address efficacy in JPH2-driven (non-sarcomeric) HCM, where the primary mechanism is calcium-handling/JMC dysfunction rather than sarcomeric hypercontractility — a potentially important mechanistic mismatch for future study.
  • Antiarrhythmic therapy (e.g., amiodarone, disopyramide for obstructive symptoms) and anticoagulation for atrial fibrillation, given CMH17's documented AF burden.
  • Device/interventional therapy:
  • Permanent pacemaker implantation — particularly relevant given the ~45% third-degree AV block/conduction-defect burden documented in CMH17 (T161K cohort), an unusually high rate compared to classic sarcomeric HCM.
  • Implantable cardioverter-defibrillator (ICD) for primary/secondary SCD prevention per standard HCM risk stratification (NCIT device-category concept; clinical action term NCIT:C15329, Surgical Procedure, for implantation).
  • Septal reduction therapy (surgical myectomy or alcohol septal ablation) for drug-refractory obstructive physiology (NCIT:C15329, Surgical Procedure / NCIT:C16186, Orthopedic Surgical Procedure is not applicable — better mapped to general cardiac surgical procedure terms).
  • Supportive care: Standard heart-failure management (diuretics, guideline-directed medical therapy) for the subset progressing to systolic dysfunction.
  • Genetic counseling: Recommended given autosomal dominant inheritance with age-dependent penetrance (NCIT:C15240, Genetic Counseling).
  • Experimental/research-stage: JPH2 gene-therapy approaches (AAV-mediated JPH2 overexpression) have shown efficacy in rescuing heart-failure phenotypes in preclinical (non-HCM-specific, general heart-failure) models per search results (International Journal of Cardiology), representing a potential future targeted approach for JPH2-related cardiomyopathy specifically, though not yet in human trials for CMH17.

Sources: FDA aficamten approval / Healio, Mavacamten StatPearls, Eur Heart J mavacamten review

13. Prevention

No JPH2/CMH17-specific primary-prevention data exist (monogenic disease; primary prevention is not applicable in the traditional sense). Standard applicable measures:

  • Secondary prevention: Cascade genetic screening of at-risk relatives given autosomal dominant inheritance and documented within-family segregation; periodic re-screening given age-dependent penetrance (up to age 80).
  • Tertiary prevention: ICD implantation for SCD prevention in high-risk carriers; pacemaker for progressive conduction disease; anticoagulation for AF-related stroke prevention.
  • Genetic counseling: Reproductive counseling for carriers, standard for autosomal dominant cardiomyopathy.
  • Prenatal/preimplantation genetic testing: Not specifically documented for JPH2 in the sources reviewed, but methodologically available as for other monogenic AD cardiomyopathies via standard PGT-M workflows.

14. Other Species / Natural Disease

No naturally occurring JPH2-associated cardiomyopathy in companion animals or wildlife was identified in the literature surveyed (no OMIA hits found in this research pass). JPH2 orthologs are broadly conserved across vertebrates (mouse Jph2, NCBI Gene; part of the junctophilin gene family with evolutionary conservation documented in "Molecular evolution of the junctophilin gene family," PMC2685503), but disease association has only been established via engineered/induced models, not spontaneous natural disease.

15. Model Organisms

  • Genetically engineered mouse models:
  • Global JPH2 knockout mice: Embryonic lethal, with loss of junctional membrane complexes and poorly developed T-tubules, establishing JPH2's essential developmental role (fidelity: high for demonstrating protein necessity, but the phenotype—embryonic lethality—does not model postnatal HCM).
  • Cardiac-specific JPH2 knockdown/conditional knockout mice: Impaired cardiac contractility, heart failure, increased mortality — models the general consequence of JPH2 loss of function on cardiac performance, informative for the recessive/LOF-associated DCM phenotype rather than CMH17 specifically.
  • JPH2 E169K knock-in/expressing mice: Recapitulate triggered activity and supraventricular (atrial) arrhythmia matching the human E169K phenotype, directly linking impaired JPH2–RyR2 binding to arrhythmogenesis (PMID:23973696).
  • JPH2 mutant transgenic/knock-in mouse model (cited in ClinGen curation, likely G505S- or missense-variant based): Shows "hypertrophic interventricular septum, increased LV mass, asymmetric LV hypertrophy" with histology confirming "cardiomyocyte hypertrophy and disarray consistent with HCM" — the most direct in vivo recapitulation of the CMH17 hypertrophic phenotype.
  • Cellular/in vitro models:
  • Patient-derived iPSC-cardiomyocytes with CRISPR/Cas9-corrected isogenic controls (T161K) — the most granular functional model, recapitulating prolonged action potential duration, arrhythmogenic early afterdepolarizations, and slowed calcium-current inactivation kinetics characteristic of human CMH17 electrophysiology; explicitly validated by the authors as recapitulating "the cellular phenotype of HCM caused by a mutation in a non-sarcomeric gene."
  • COS7 and H9c2 cell overexpression models (S165F) — used to demonstrate autoinhibitory structural mechanism and resultant cellular hypertrophy.
  • Primary mouse skeletal myotube overexpression (S165F) — shows increased myotube diameter and resting cytosolic Ca²⁺, indicating the mechanism extends to skeletal muscle in overexpression systems (relevant to JPH2's dual cardiac/skeletal muscle isoform biology, though CMH17 itself is a cardiac-restricted phenotype).
  • Model limitations: No model captures the full clinical spectrum (LVH + conduction disease + heart failure) simultaneously in a single validated system; iPSC-CM models capture cellular electrophysiology but not tissue-level hypertrophic remodeling or conduction-system anatomy; mouse knock-in/knockout models capture structural hypertrophy or arrhythmia individually but published data reviewed here did not identify one model demonstrating the complete co-occurring phenotype triad seen in Finnish T161K patients.

Sources: PMID:23973696 (JACC 2013), PMID:37371654 (Biomedicines 2023), PMID:41291214 (Commun Biol 2025), ClinGen curation, Molecular evolution of junctophilin gene family, PMC2685503

Notes on Evidence Gaps and Curation Considerations

  1. Gene-disease validity is Moderate, not Definitive (ClinGen, re-affirmed 2022) — curation of CMH17 should reflect appropriate epistemic caution; the panel explicitly notes "the mechanism for disease remains unknown" (i.e., not conclusively established beyond the calcium-handling hypothesis) and that "more evidence is needed to establish this association definitively."
  2. MONDO mapping is ambiguous — no CMH17-specific MONDO term was confirmed in this research pass; verify against the live MONDO ontology/Monarch resolution before binding disease_term/mappings.mondo_mappings (likely skos:narrowMatch to MONDO:0005045 general familial HCM, pending confirmation).
  3. OMIM full-text access (omim.org direct fetch) was blocked by the environment's outbound proxy during this research session; all OMIM content above is derived from search-result excerpts rather than a direct page fetch, and should be re-verified against the live OMIM entry (#613873) before use as a primary citation source in curation, per this repository's evidence-fetching policy (just fetch-reference).
  4. JPH2 displays a genotype-phenotype spectrum broader than CMH17 alone (dominant missense → HCM/arrhythmia vs. recessive LOF → severe early DCM) — curators should ensure any dismech entry for CMH17 is scoped specifically to the dominant HCM phenotype and cross-references rather than conflates the distinct recessive JPH2-DCM entity, consistent with the "Digenic/Oligogenic" and general lump/split guidance in this repository's design decisions for genetically heterogeneous conditions.
  5. Several full-text sources (ScienceDirect systematic review, Nature Communications Biology S165F paper, direct OMIM pages) could not be directly fetched in this session due to proxy/access restrictions; findings from these sources here are based on search-engine-summarized excerpts and should be independently re-verified with exact-quote snippets against the primary source (or its cached/PMC mirror) before being used as curated evidence in the knowledge base, per the dismech-references skill's exact-quote requirement.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 24
Resolved 23
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 10
Terms named correctly 5
Terms named as a different term 1
Terms whose name is worth a second look 4

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:

  • HP:0004758 (1 mention) - the report calls it "Paroxysmal atrial fibrillation"; HP calls it Effort-induced polymorphic ventricular tachycardia

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:

  • GO:0086013 (1 mention) - the report calls it "membrane repolarization in ventricular cardiac muscle cell"; GO calls it membrane repolarization during cardiac muscle cell action potential
  • GO:0007512 (1 mention) - the report calls it "adult heart development, for hypertrophic remodeling context"; GO calls it adult heart development
  • CL:0002129 (1 mention) - the report calls it "cardiac muscle myoblast"; CL calls it regular atrial cardiac myocyte, and lists "atrial cardiac muscle cell" among its other names
  • UBERON:0006566 (1 mention) - the report calls it "interventricular septum"; UBERON calls it left ventricle myocardium, and lists "left ventricular myocardium" among its other names