Dilated Cardiomyopathy 2E

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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0030366 cardiomyopathy, dilated, 2E

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic JPH2 loss of function. The inheritance mode is the axis that separates this disease from the dominant JPH2 hypertrophic cardiomyopathy, and the separation is not merely nosological: the systematic review of JPH2 cardiac disease found that recessive loss-of-function alleles give severe early-onset dilated cardiomyopathy while dominant missense alleles give a wider range of disease including hypertrophic cardiomyopathy and arrhythmia.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and..."

The genotype-inheritance-phenotype split across all published JPH2 probands, and the sentence that justifies curating CMD2E separately from CMH17 rather than as one JPH2 entry.

PMID:31227780 SUPPORT Human Clinical

"This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation."

A segregation-confirmed recessive allele, which is the direct evidence for the inheritance mode in a specific kindred.

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Discussions and Knowledge Gaps

2

Does AAV9-mediated JPH2 delivery, which rescues a pressure-overload mouse, address the defect in a patient who has never had junctophilin-2?

HUMAN MODEL MISMATCH OPEN gap_cmd2e_gene_therapy_translation

Attached to

pathophysiology#Failure of Junctional Membrane Complex Assembly

The gene therapy result is real and striking: AAV9-JPH2 rescues contractility and preserves t-tubule structure in mice after transverse aortic constriction. But the model is not this disease. In transverse aortic constriction, junctophilin-2 falls secondarily as the heart fails, so the experiment restores a protein the animal once had, in a heart whose dyads were built normally. A CMD2E patient is a constitutive null whose dyads were never assembled, and whose myocardium has remodelled around their absence since before birth. Whether delivering junctophilin-2 to such a heart reassembles dyads, or arrives too late to reorganise a t-tubule system that never formed, is untested. The report treats this result as a strong preclinical rationale for CMD2E; that is a reasonable hope and it is not evidence, and the distinction matters because the patients are infants for whom transplantation is the alternative.

Proposed experiments

AAV9-JPH2 in a cardiac Jph2 conditional null rather than a pressure-overload model

exp_cmd2e_aav9_in_constitutive_null

Deliver AAV9-JPH2 to mice in which Jph2 has been deleted in cardiomyocytes from before dyad assembly, and measure junctional membrane complex number, plasmalemma-to-sarcoplasmic-reticulum distance and contractility against the pressure-overload rescue. A rescue in that model would support translation; a failure would locate the problem in dyad assembly rather than in protein supply.

Is the JPH2 dilated cardiomyopathy relationship recessive or semidominant, and do heterozygous loss-of-function carriers have cardiac disease?

KNOWLEDGE GAP OPEN gap_cmd2e_semidominant_boundary

Attached to

genetic#JPH2 inheritance#Autosomal recessive inheritance

This entry is titled and curated as autosomal recessive, and the segregation evidence in the Iranian kindred supports that. But ClinGen's curated position at the time of the systematic review was "semidominant" for the JPH2-dilated cardiomyopathy relationship, which is a different claim: it implies heterozygous carriers are not simply unaffected. Loss-of-function JPH2 variants are carried by 0.21% of Greater Middle Eastern individuals, so the carrier population is large enough to answer this, and none of the published work reports systematic cardiac phenotyping of heterozygous relatives. The stake is cascade screening: if carriers are at risk, the families already identified contain many people who should be under surveillance and are not.

Proposed experiments

Echocardiographic phenotyping of obligate heterozygous JPH2 LOF carriers

exp_cmd2e_heterozygote_phenotyping

Systematically image the obligate carrier parents and heterozygous relatives in the published consanguineous kindreds, and compare ventricular dimensions and systolic function against matched controls, to test whether one functional JPH2 allele is sufficient.

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Pathophysiology

4

JPH2 Loss of Function

Biallelic loss-of-function JPH2 alleles remove junctophilin-2. The reported recessive alleles are truncating: a homozygous single-nucleotide insertion producing p.E641* in consanguineous Iranian families, and a nonsense allele in a Finnish childhood cardiomyopathy kindred. This is the axis that separates CMD2E from the dominant JPH2 disease, which runs on missense alleles that alter the protein's regulation of the ryanodine receptor rather than removing it.

JPH2 hgnc:14202

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Failure of Junctional Membrane Complex Assembly Junctophilin-2 is the structural protein of the complex, so removing it prevents the complex from forming. Demonstrated in the germline null mouse, whose cardiomyocytes show deficient junctional membrane complexes.

Show evidence (1 reference)

PMID:31227780 SUPPORT Human Clinical

"Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*)."

The recessive allele and its consequence, named precisely. The same paper notes that loss-of-function JPH2 variants had not previously been described in disease, only missense ones.

Failure of Junctional Membrane Complex Assembly

Without junctophilin-2 the t-tubule sarcolemma and the junctional sarcoplasmic reticulum are not held together, so the dyad does not assemble and the distance between the two membranes becomes variable. The lesion is geometric: nothing about either channel is altered, they are simply no longer reliably apposed.

cardiac muscle cell CL:0000746

T-tubule GO:0030315 sarcoplasmic reticulum GO:0016529

Downstream

Failure of Calcium-Induced Calcium Release

Show evidence (2 references)

PMID:21339484 SUPPORT Model Organism

"JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance."

The geometric lesion measured directly: fewer complexes and a more variable membrane separation, with the functional consequence named in the same sentence.

PMID:27760414 SUPPORT BACKGROUND Model Organism

"Junctophilin-2 (JPH2) is the primary structural protein for the coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes (JMCs) in cardiomyocytes."

States the protein's structural role and what it couples. It is the introduction to a gene-therapy study rather than that study's finding, which is why it is marked as background.

Failure of Calcium-Induced Calcium Release

With the dyad disassembled, calcium entering through the L-type channel no longer reliably reaches a ryanodine receptor, so the amplification step of excitation-contraction coupling fails. The measurable consequences are abnormal and asynchronous calcium transients and a loss of excitation-contraction coupling gain.

release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 ↓ DECREASED

Downstream

Impaired Cardiac Contractility

Show evidence (2 references)

PMID:21339484 SUPPORT BACKGROUND Model Organism

"Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes."

The requirement this node's failure violates. It is the paper's background statement of the physiology rather than its result.

PMID:10949023 SUPPORT Model Organism

"Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal Ca2+ transients."

The calcium handling defect measured in null cardiomyocytes, alongside the structural defect that causes it.

Impaired Cardiac Contractility

Systolic dysfunction with ventricular dilation and progression to heart failure. In the acute knockdown mouse this is a direct and rapid consequence of losing junctophilin-2 in the adult heart, which matters for interpreting the human disease: it shows the protein is required continuously for contractile function, not only for building the dyad during development.

cardiac muscle contraction GO:0060048 ↓ DECREASED

heart UBERON:0000948

Downstream

Dilated cardiomyopathy

Congestive heart failure

Show evidence (1 reference)

PMID:21339484 SUPPORT Model Organism

"Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality."

Contractile failure and its outcome from an adult-onset, cardiac-restricted loss of the protein, which is the closest experimental analogue of the human recessive disease.

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Pathograph

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Phenotypes

2

Dilated cardiomyopathy OBLIGATE Cardiovascular HP:0001644

Show evidence (2 references)

PMID:31227780 SUPPORT Human Clinical

"Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*)."

The phenotype in the index patient, tied to the homozygous allele.

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and..."

Dilated cardiomyopathy as the phenotype of the recessive loss-of-function group specifically, which is what makes OBLIGATE defensible here: the genotype is defined by the phenotype it produces in this review's analysis.

Congestive heart failure VERY_FREQUENT Cardiovascular HP:0001635

Show evidence (1 reference)

PMID:31227780 SUPPORT Human Clinical

"A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure."

Cardiac failure as the cause of death in two affected children of a second family carrying the same allele.

🧬

Genetic Associations

1

JPH2

Gene: JPH2 hgnc:14202 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:31227780 SUPPORT Human Clinical

"Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described."

States what was known before this report and what it added, which is the distinction between this entry and the dominant JPH2 disease.

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"Currently, ClinGen considers JPH2 to have moderate evidence for association with HCM in an autosomal dominant inheritance pattern, and moderate evidence for association with DCM in a semidominant inheritance pattern."

The curated gene-disease validity position for both phenotypes. Note the word for the DCM relationship is semidominant rather than recessive, which is a weaker claim than this entry's title makes and is why it is quoted rather than paraphrased.

PMID:30384889 SUPPORT Human Clinical

"The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP)"

Places JPH2 among the calcium-signalling causes of severe childhood cardiomyopathy in a countrywide cohort. This abstract does not describe the JPH2 kindred's allele; that detail is in the full text and is therefore not curated here.

Variants (1)

c.1920dupT, p.E641*

A homozygous single-nucleotide insertion producing a stop codon, found in consanguineous Iranian families with neonatal dilated cardiomyopathy and confirmed by segregation analysis. The first loss-of-function JPH2 allele described in disease.

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Medical Actions

2

Guideline-directed paediatric heart failure management

Action: supportive care for heart failure Ontology label: Supportive Care NCIT:C15747

Platform: Other

Standard heart failure care. There is no CMD2E-specific therapy, and the entry does not name individual agents because no source located reports a drug regimen in a genotyped CMD2E patient.

Mechanism Target:

Congestive heart failure — Manages the failing circulation. It does not address the dyadic defect.

Show evidence (1 reference)

PMID:31227780 SUPPORT Human Clinical

"A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure."

The outcome without disease-modifying treatment, which is what supportive management is measured against here.

Cardiac transplantation

Action: cardiac transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

Transplantation is a realistic endpoint in severe childhood-onset cardiomyopathy: 17 of 66 children in the Finnish countrywide cohort were transplanted. That figure is for the cohort, not for JPH2 patients.

Mechanism Target:

Impaired Cardiac Contractility — Replaces the failing heart, and with it the cardiomyocytes that lack junctophilin-2. It is the only intervention that removes the mechanism.

Show evidence (2 references)

PMID:30384889 SUPPORT Human Clinical

"The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation."

The transplantation count in the childhood cardiomyopathy cohort that includes JPH2 patients. It is a cohort figure and is labelled as one.

PMID:30384889 SUPPORT Human Clinical

"Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment."

The authors' argument that the genetic diagnosis itself informs the transplant decision, which is why molecular diagnosis is curated as consequential in a disease with no specific therapy.

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Diagnosis

1

Genetic testing for biallelic JPH2 loss-of-function variants

Next-generation sequencing, with segregation analysis in the family. Two features of this disease shape the testing strategy: the phenotype is not distinguishable on imaging from any other paediatric dilated cardiomyopathy, and loss-of-function JPH2 alleles are enriched in Greater Middle Eastern populations, so consanguinity raises the prior.

Show evidence (1 reference)

PMID:31227780 SUPPORT Human Clinical

"In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants."

The population-genetic finding that raises the pre-test probability in a specific group, which is the actionable part of that study.

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Progression

1

Neonatal or early childhood presentation with systolic failure

Onset is in the neonatal period or early childhood, and the course is rapidly progressive. In the Iranian kindred the second family lost two children in childhood to cardiac failure before the variant was identified.

Show evidence (2 references)

PMID:31227780 SUPPORT Human Clinical

"A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure."

The outcome in an affected sibship. Note the sentence describes the parents as heterozygous carriers of the variant that was homozygous in the affected children.

PMID:30384889 SUPPORT Human Clinical

"The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation."

The severity and transplantation rate of the Finnish childhood cardiomyopathy cohort in which JPH2 appears. It describes the whole cohort of 66 children rather than the JPH2 patients specifically.

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Prevalence

2

Published JPH2 variant-positive individuals, systematic review to 2021

Cases In Literature Ultra Rare

The systematic review identified 61 individuals carrying a JPH2 variant, of whom about 80% had cardiac disease and 18% had dilated cardiomyopathy. That 18% is the DCM share of all JPH2 disease, dominant and recessive together, and is not a prevalence of CMD2E: the analysis that separates recessive from dominant was done on 24 probands, not on the 61.

Show evidence (1 reference)

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD."

The published JPH2 case count with its phenotype breakdown. The breakdown is across both inheritance modes, which is why no CMD2E-specific figure is curated from it.

Greater Middle East population and variome cohorts

Carrier Frequency 21.0 per 100,000 <1 in 1,000,000 (carriers)

Loss-of-function JPH2 variants are carried by 0.21% of Greater Middle Eastern individuals against 0.04% worldwide, a fivefold enrichment that the authors attribute to population structure and consanguinity. The recorded rate is the GME carrier frequency; the prevalence_class band refers to the resulting homozygote frequency, which is what the disease requires, and is therefore far below the carrier rate.

Show evidence (1 reference)

PMID:31227780 SUPPORT Human Clinical

"Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%)."

The carrier frequencies for rare and loss-of-function JPH2 variants, given separately for the worldwide and Greater Middle Eastern populations. The loss-of-function figure is the one that bears on this disease, because missense alleles cause the dominant one.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 2E:

Hypertrophic Cardiomyopathy 17

Overlapping Features The dominant JPH2 disease, curated separately. Same gene, different allele class and different inheritance: heterozygous missense variants acting through altered regulation of the ryanodine receptor, rather than biallelic loss of the protein. Genetic testing distinguishes them; the phenotypes are opposite in ventricular geometry.

Distinguishing Features

Heterozygous missense rather than biallelic loss-of-function alleles.
Ventricular hypertrophy rather than dilation, with a wider associated range including arrhythmia, sudden cardiac death and conduction disease.

Show evidence (1 reference)

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and..."

The two diseases contrasted in one sentence, by allele class and inheritance rather than by phenotype alone.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 2E
creation_date: "2026-09-17T16:17:48Z"
description: >-
  CMD2E is the autosomal recessive dilated cardiomyopathy caused by biallelic
  loss-of-function variants in JPH2, the gene for junctophilin-2. It is the
  recessive counterpart of the dominant JPH2 disease already curated here as
  Hypertrophic_Cardiomyopathy_17, and the two are separated by mechanism as well
  as by inheritance: the dominant disease runs on missense alleles that alter
  how junctophilin-2 regulates the ryanodine receptor, while this one removes
  the protein.

  The mechanism is architectural rather than biochemical. Junctophilin-2 tethers
  the t-tubule sarcolemma to the junctional sarcoplasmic reticulum and so holds
  the dyadic cleft at the width that places L-type calcium channels opposite
  ryanodine receptors. Calcium-induced calcium release depends on that geometry,
  not on any catalytic step, so losing the tether degrades excitation-contraction
  coupling by moving two channels apart. The mouse genetics are unusually clean
  on this point: germline Jph2-null embryos die with deficient junctional
  membrane complexes and abnormal calcium transients, and acute cardiac-specific
  knockdown in adults produces loss of junctional membrane complexes, increased
  variability in the plasmalemma-to-sarcoplasmic-reticulum distance, and heart
  failure.

  Clinically it presents in the neonatal period or early childhood with rapidly
  progressive systolic failure, and transplantation is a realistic outcome.
  There is no disease-specific therapy. AAV9-mediated JPH2 delivery rescues
  contractility in a mouse pressure-overload model, which is a rationale rather
  than a treatment.
synonyms:
- CMD2E
- cardiomyopathy, dilated, 2E
- JPH2 dilated cardiomyopathy
- junctophilin-2 dilated cardiomyopathy
- autosomal recessive dilated cardiomyopathy due to JPH2 deficiency
category: Mendelian
disease_term:
  preferred_term: cardiomyopathy, dilated, 2E
  term:
    id: MONDO:0030366
    label: cardiomyopathy, dilated, 2E
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030366
      label: cardiomyopathy, dilated, 2E
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic JPH2 loss of function. The inheritance mode is the axis that
    separates this disease from the dominant JPH2 hypertrophic cardiomyopathy,
    and the separation is not merely nosological: the systematic review of JPH2
    cardiac disease found that recessive loss-of-function alleles give severe
    early-onset dilated cardiomyopathy while dominant missense alleles give a
    wider range of disease including hypertrophic cardiomyopathy and arrhythmia.
  evidence:
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In analyzing the 24 probands described in the studies, we found that
      autosomal recessive, loss-of-function variants are associated with severe,
      early onset DCM, while autosomal dominant missense variants are associated
      with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and
      cardiac conduction disease.
    explanation: >-
      The genotype-inheritance-phenotype split across all published JPH2
      probands, and the sentence that justifies curating CMD2E separately from
      CMH17 rather than as one JPH2 entry.
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This conclusion is supported by the identification of a novel JPH2 LOF
      variant confirmed by segregation analysis resulting in autosomal recessive
      pediatric DCM due to presumptive JPH2 truncation.
    explanation: >-
      A segregation-confirmed recessive allele, which is the direct evidence for
      the inheritance mode in a specific kindred.
prevalence:
- population: Published JPH2 variant-positive individuals, systematic review to 2021
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The systematic review identified 61 individuals carrying a JPH2 variant, of
    whom about 80% had cardiac disease and 18% had dilated cardiomyopathy. That
    18% is the DCM share of all JPH2 disease, dominant and recessive together,
    and is not a prevalence of CMD2E: the analysis that separates recessive from
    dominant was done on 24 probands, not on the 61.
  evidence:
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We identified a total of 61 variant-positive individuals, approximately 80%
      of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and
      14% arrhythmia/SCD.
    explanation: >-
      The published JPH2 case count with its phenotype breakdown. The breakdown
      is across both inheritance modes, which is why no CMD2E-specific figure is
      curated from it.
- population: Greater Middle East population and variome cohorts
  measure_type: CARRIER_FREQUENCY
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 21.0
  notes: >-
    Loss-of-function JPH2 variants are carried by 0.21% of Greater Middle Eastern
    individuals against 0.04% worldwide, a fivefold enrichment that the authors
    attribute to population structure and consanguinity. The recorded rate is the
    GME carrier frequency; the prevalence_class band refers to the resulting
    homozygote frequency, which is what the disease requires, and is therefore
    far below the carrier rate.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a
      significantly higher proportion among GME individuals (4.45%); LOF variants
      were rare overall (0.04%) yet were most prevalent in GME (0.21%).
    explanation: >-
      The carrier frequencies for rare and loss-of-function JPH2 variants, given
      separately for the worldwide and Greater Middle Eastern populations. The
      loss-of-function figure is the one that bears on this disease, because
      missense alleles cause the dominant one.
progression:
- phase: Neonatal or early childhood presentation with systolic failure
  notes: >-
    Onset is in the neonatal period or early childhood, and the course is
    rapidly progressive. In the Iranian kindred the second family lost two
    children in childhood to cardiac failure before the variant was identified.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second Iranian family with consanguineous parents hosting an identical
      heterozygous variant had 2 children die in childhood from cardiac failure.
    explanation: >-
      The outcome in an affected sibship. Note the sentence describes the parents
      as heterozygous carriers of the variant that was homozygous in the affected
      children.
  - reference: PMID:30384889
    reference_title: Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The KidCMP cohort presents remarkable early-onset and severe disorders: the
      median age of diagnosis was 0.33 years, and 17 patients underwent cardiac
      transplantation.
    explanation: >-
      The severity and transplantation rate of the Finnish childhood
      cardiomyopathy cohort in which JPH2 appears. It describes the whole cohort
      of 66 children rather than the JPH2 patients specifically.
pathophysiology:
- name: JPH2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function JPH2 alleles remove junctophilin-2. The reported
    recessive alleles are truncating: a homozygous single-nucleotide insertion
    producing p.E641* in consanguineous Iranian families, and a nonsense allele
    in a Finnish childhood cardiomyopathy kindred. This is the axis that
    separates CMD2E from the dominant JPH2 disease, which runs on missense
    alleles that alter the protein's regulation of the ryanodine receptor rather
    than removing it.
  genes:
  - preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of Junctional Membrane Complex Assembly
    causal_link_type: DIRECT
    description: >-
      Junctophilin-2 is the structural protein of the complex, so removing it
      prevents the complex from forming. Demonstrated in the germline null mouse,
      whose cardiomyocytes show deficient junctional membrane complexes.
    evidence:
    - reference: PMID:10949023
      reference_title: "Junctophilins: a novel family of junctional membrane complex proteins."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiac myocytes from the mutant mice showed deficiency of the junctional
        membrane complexes and abnormal Ca2+ transients.
      explanation: >-
        The structural and functional consequence of losing JP-2, in the same
        cells, which is what this edge asserts.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family-based genetic analysis of GME individuals with cardiomyopathic
      disease identified an Iranian patient with dilated cardiomyopathy (DCM) as
      a carrier of a novel, homozygous single nucleotide insertion in JPH2
      resulting in a stop codon (JPH2-p.E641*).
    explanation: >-
      The recessive allele and its consequence, named precisely. The same paper
      notes that loss-of-function JPH2 variants had not previously been described
      in disease, only missense ones.
- name: Failure of Junctional Membrane Complex Assembly
  biological_scale: CELLULAR
  description: >-
    Without junctophilin-2 the t-tubule sarcolemma and the junctional
    sarcoplasmic reticulum are not held together, so the dyad does not assemble
    and the distance between the two membranes becomes variable. The lesion is
    geometric: nothing about either channel is altered, they are simply no longer
    reliably apposed.
  cellular_components:
  - preferred_term: T-tubule
    modifier: ABNORMAL
    term:
      id: GO:0030315
      label: T-tubule
  - preferred_term: sarcoplasmic reticulum
    term:
      id: GO:0016529
      label: sarcoplasmic reticulum
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Failure of Calcium-Induced Calcium Release
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21339484
    reference_title: Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      JPH2 deficiency resulted in loss of excitation-contraction coupling gain,
      precipitated by a reduction in the number of junctional membrane complexes
      and increased variability in the plasmalemma-sarcoplasmic reticulum
      distance.
    explanation: >-
      The geometric lesion measured directly: fewer complexes and a more variable
      membrane separation, with the functional consequence named in the same
      sentence.
  - reference: PMID:27760414
    reference_title: Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Junctophilin-2 (JPH2) is the primary structural protein for the coupling of
      transverse (T)-tubule associated cardiac L-type Ca channels and type-2
      ryanodine receptors on the sarcoplasmic reticulum within junctional
      membrane complexes (JMCs) in cardiomyocytes.
    explanation: >-
      States the protein's structural role and what it couples. It is the
      introduction to a gene-therapy study rather than that study's finding,
      which is why it is marked as background.
- name: Failure of Calcium-Induced Calcium Release
  biological_scale: CELLULAR
  description: >-
    With the dyad disassembled, calcium entering through the L-type channel no
    longer reliably reaches a ryanodine receptor, so the amplification step of
    excitation-contraction coupling fails. The measurable consequences are
    abnormal and asynchronous calcium transients and a loss of
    excitation-contraction coupling gain.
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DECREASED
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
  downstream:
  - target: Impaired Cardiac Contractility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21339484
    reference_title: Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Excitation-contraction coupling in striated muscle requires proper
      communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+
      release channels on sarcoplasmic reticulum within junctional membrane
      complexes.
    explanation: >-
      The requirement this node's failure violates. It is the paper's background
      statement of the physiology rather than its result.
    quote_role: BACKGROUND
  - reference: PMID:10949023
    reference_title: "Junctophilins: a novel family of junctional membrane complex proteins."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiac myocytes from the mutant mice showed deficiency of the junctional
      membrane complexes and abnormal Ca2+ transients.
    explanation: >-
      The calcium handling defect measured in null cardiomyocytes, alongside the
      structural defect that causes it.
- name: Impaired Cardiac Contractility
  biological_scale: ORGANISM
  description: >-
    Systolic dysfunction with ventricular dilation and progression to heart
    failure. In the acute knockdown mouse this is a direct and rapid consequence
    of losing junctophilin-2 in the adult heart, which matters for interpreting
    the human disease: it shows the protein is required continuously for
    contractile function, not only for building the dyad during development.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Congestive heart failure
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21339484
    reference_title: Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiac-specific JPH2 knockdown resulted in impaired cardiac
      contractility, which caused heart failure and increased mortality.
    explanation: >-
      Contractile failure and its outcome from an adult-onset, cardiac-restricted
      loss of the protein, which is the closest experimental analogue of the
      human recessive disease.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Ventricular dilation with systolic dysfunction, presenting in the neonatal
    period or early childhood. It is the defining phenotype of the entry.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family-based genetic analysis of GME individuals with cardiomyopathic
      disease identified an Iranian patient with dilated cardiomyopathy (DCM) as
      a carrier of a novel, homozygous single nucleotide insertion in JPH2
      resulting in a stop codon (JPH2-p.E641*).
    explanation: >-
      The phenotype in the index patient, tied to the homozygous allele.
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In analyzing the 24 probands described in the studies, we found that
      autosomal recessive, loss-of-function variants are associated with severe,
      early onset DCM, while autosomal dominant missense variants are associated
      with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and
      cardiac conduction disease.
    explanation: >-
      Dilated cardiomyopathy as the phenotype of the recessive loss-of-function
      group specifically, which is what makes OBLIGATE defensible here: the
      genotype is defined by the phenotype it produces in this review's analysis.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Progressive systolic heart failure, the clinical expression of the
    contractile defect and the cause of death in untreated affected children.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second Iranian family with consanguineous parents hosting an identical
      heterozygous variant had 2 children die in childhood from cardiac failure.
    explanation: >-
      Cardiac failure as the cause of death in two affected children of a second
      family carrying the same allele.
genetic:
- name: JPH2
  gene_term:
    preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  relationship_type: CAUSATIVE
  notes: >-
    JPH2 encodes junctophilin-2, the structural protein of the cardiac dyad. One
    gene, two inheritance modes: biallelic loss of function causes this disease,
    and heterozygous missense variants cause hypertrophic cardiomyopathy, curated
    separately as Hypertrophic_Cardiomyopathy_17. ClinGen's position at the time
    of the systematic review was moderate evidence for JPH2 in hypertrophic
    cardiomyopathy with autosomal dominant inheritance and moderate evidence for
    dilated cardiomyopathy with semidominant inheritance.

    A caution for anyone re-deriving this binding from a deep-research report:
    the OpenScientist run for this entry offered HGNC:14179 for JPH2. That
    identifier is CIAO3. The correct one, used here, is hgnc:14202, confirmed
    against the HGNC REST API. HGNC is skipped by the report's own term
    validator, so nothing in the pipeline would have caught it.
  variants:
  - name: c.1920dupT, p.E641*
    description: >-
      A homozygous single-nucleotide insertion producing a stop codon, found in
      consanguineous Iranian families with neonatal dilated cardiomyopathy and
      confirmed by segregation analysis. The first loss-of-function JPH2 allele
      described in disease.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously, missense variants in JPH2 have been linked to hypertrophic
      cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have
      not been described.
    explanation: >-
      States what was known before this report and what it added, which is the
      distinction between this entry and the dominant JPH2 disease.
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Currently, ClinGen considers JPH2 to have moderate evidence for association
      with HCM in an autosomal dominant inheritance pattern, and moderate
      evidence for association with DCM in a semidominant inheritance pattern.
    explanation: >-
      The curated gene-disease validity position for both phenotypes. Note the
      word for the DCM relationship is semidominant rather than recessive, which
      is a weaker claim than this entry's title makes and is why it is quoted
      rather than paraphrased.
  - reference: PMID:30384889
    reference_title: Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2,
      HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2),
      development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and
      the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP)
    explanation: >-
      Places JPH2 among the calcium-signalling causes of severe childhood
      cardiomyopathy in a countrywide cohort. This abstract does not describe the
      JPH2 kindred's allele; that detail is in the full text and is therefore not
      curated here.
diagnosis:
- name: Genetic testing for biallelic JPH2 loss-of-function variants
  description: >-
    Next-generation sequencing, with segregation analysis in the family. Two
    features of this disease shape the testing strategy: the phenotype is not
    distinguishable on imaging from any other paediatric dilated cardiomyopathy,
    and loss-of-function JPH2 alleles are enriched in Greater Middle Eastern
    populations, so consanguinity raises the prior.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, we report ethnic-specific differences in JPH2 rare variants,
      with GME individuals being at higher risk of hosting homozygous LOF
      variants.
    explanation: >-
      The population-genetic finding that raises the pre-test probability in a
      specific group, which is the actionable part of that study.
differential_diagnoses:
- name: Hypertrophic Cardiomyopathy 17
  description: >-
    The dominant JPH2 disease, curated separately. Same gene, different allele
    class and different inheritance: heterozygous missense variants acting
    through altered regulation of the ryanodine receptor, rather than biallelic
    loss of the protein. Genetic testing distinguishes them; the phenotypes are
    opposite in ventricular geometry.
  distinguishing_features:
  - Heterozygous missense rather than biallelic loss-of-function alleles.
  - Ventricular hypertrophy rather than dilation, with a wider associated range
    including arrhythmia, sudden cardiac death and conduction disease.
  evidence:
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In analyzing the 24 probands described in the studies, we found that
      autosomal recessive, loss-of-function variants are associated with severe,
      early onset DCM, while autosomal dominant missense variants are associated
      with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and
      cardiac conduction disease.
    explanation: >-
      The two diseases contrasted in one sentence, by allele class and
      inheritance rather than by phenotype alone.
treatments:
- name: Guideline-directed paediatric heart failure management
  description: >-
    Standard heart failure care. There is no CMD2E-specific therapy, and the
    entry does not name individual agents because no source located reports a
    drug regimen in a genotyped CMD2E patient.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care for heart failure
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Congestive heart failure
    description: >-
      Manages the failing circulation. It does not address the dyadic defect.
  evidence:
  - reference: PMID:31227780
    reference_title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second Iranian family with consanguineous parents hosting an identical
      heterozygous variant had 2 children die in childhood from cardiac failure.
    explanation: >-
      The outcome without disease-modifying treatment, which is what supportive
      management is measured against here.
- name: Cardiac transplantation
  description: >-
    Transplantation is a realistic endpoint in severe childhood-onset
    cardiomyopathy: 17 of 66 children in the Finnish countrywide cohort were
    transplanted. That figure is for the cohort, not for JPH2 patients.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Impaired Cardiac Contractility
    description: >-
      Replaces the failing heart, and with it the cardiomyocytes that lack
      junctophilin-2. It is the only intervention that removes the mechanism.
  evidence:
  - reference: PMID:30384889
    reference_title: Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The KidCMP cohort presents remarkable early-onset and severe disorders: the
      median age of diagnosis was 0.33 years, and 17 patients underwent cardiac
      transplantation.
    explanation: >-
      The transplantation count in the childhood cardiomyopathy cohort that
      includes JPH2 patients. It is a cohort figure and is labelled as one.
  - reference: PMID:30384889
    reference_title: Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic diagnoses may suggest intervention strategies and predict
      prognosis, offering valuable tools for prioritization of patients for
      transplantation versus conservative treatment.
    explanation: >-
      The authors' argument that the genetic diagnosis itself informs the
      transplant decision, which is why molecular diagnosis is curated as
      consequential in a disease with no specific therapy.
discussions:
- discussion_id: gap_cmd2e_gene_therapy_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does AAV9-mediated JPH2 delivery, which rescues a pressure-overload mouse,
    address the defect in a patient who has never had junctophilin-2?
  attaches_to:
  - "pathophysiology#Failure of Junctional Membrane Complex Assembly"
  rationale: >-
    The gene therapy result is real and striking: AAV9-JPH2 rescues contractility
    and preserves t-tubule structure in mice after transverse aortic
    constriction. But the model is not this disease. In transverse aortic
    constriction, junctophilin-2 falls secondarily as the heart fails, so the
    experiment restores a protein the animal once had, in a heart whose dyads
    were built normally. A CMD2E patient is a constitutive null whose dyads were
    never assembled, and whose myocardium has remodelled around their absence
    since before birth. Whether delivering junctophilin-2 to such a heart
    reassembles dyads, or arrives too late to reorganise a t-tubule system that
    never formed, is untested. The report treats this result as a strong
    preclinical rationale for CMD2E; that is a reasonable hope and it is not
    evidence, and the distinction matters because the patients are infants for
    whom transplantation is the alternative.
  proposed_experiments:
  - experiment_id: exp_cmd2e_aav9_in_constitutive_null
    name: AAV9-JPH2 in a cardiac Jph2 conditional null rather than a pressure-overload model
    description: >-
      Deliver AAV9-JPH2 to mice in which Jph2 has been deleted in cardiomyocytes
      from before dyad assembly, and measure junctional membrane complex number,
      plasmalemma-to-sarcoplasmic-reticulum distance and contractility against
      the pressure-overload rescue. A rescue in that model would support
      translation; a failure would locate the problem in dyad assembly rather
      than in protein supply.
- discussion_id: gap_cmd2e_semidominant_boundary
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the JPH2 dilated cardiomyopathy relationship recessive or semidominant,
    and do heterozygous loss-of-function carriers have cardiac disease?
  attaches_to:
  - "genetic#JPH2"
  - "inheritance#Autosomal recessive inheritance"
  rationale: >-
    This entry is titled and curated as autosomal recessive, and the segregation
    evidence in the Iranian kindred supports that. But ClinGen's curated position
    at the time of the systematic review was "semidominant" for the JPH2-dilated
    cardiomyopathy relationship, which is a different claim: it implies
    heterozygous carriers are not simply unaffected. Loss-of-function JPH2
    variants are carried by 0.21% of Greater Middle Eastern individuals, so the
    carrier population is large enough to answer this, and none of the published
    work reports systematic cardiac phenotyping of heterozygous relatives. The
    stake is cascade screening: if carriers are at risk, the families already
    identified contain many people who should be under surveillance and are not.
  proposed_experiments:
  - experiment_id: exp_cmd2e_heterozygote_phenotyping
    name: Echocardiographic phenotyping of obligate heterozygous JPH2 LOF carriers
    description: >-
      Systematically image the obligate carrier parents and heterozygous
      relatives in the published consanguineous kindreds, and compare ventricular
      dimensions and systolic function against matched controls, to test whether
      one functional JPH2 allele is sufficient.
notes: >-
  Scope and lump/split. MONDO:0030366 was bound nowhere in kb/. JPH2 appears as a
  gene in the broad Dilated_Cardiomyopathy entry and in the hypertrophic
  entries, and Hypertrophic_Cardiomyopathy_17 is the dominant JPH2 disease. This
  entry is the recessive counterpart, curated separately because the systematic
  review separates them by allele class and inheritance rather than by phenotype
  alone. Sibling per-type entries already exist (Cardiomyopathy_Dilated_2G, _2H,
  _2J), so the naming and granularity follow them. Neither the broad DCM entry
  nor CMH17 is edited here.

  A wrong gene identifier in the deep-research report. The OpenScientist run
  offered HGNC:14179 for JPH2 throughout. That identifier is CIAO3, cytosolic
  iron-sulfur assembly component 3. The correct one is hgnc:14202, which is what
  this entry binds, confirmed against the HGNC REST API and matching the stub.
  Nothing in the pipeline would have caught this: the research recipe passes
  --term-skip-prefix HGNC, so gene CURIEs are unchecked where they are emitted,
  and on the KB side `just validate-terms` checks only that a CURIE's label
  matches that CURIE, which a wrong-but-consistent pair would pass. This is the
  failure mode CLAUDE.md documents under "A gene binding only has to be
  self-consistent", reproduced live.

  Whose cohort a number comes from. Three denominators appear and none is a
  CMD2E frequency. The systematic review's 61 variant-positive individuals and
  its 18% DCM share span both inheritance modes. The Finnish KidCMP figures,
  median diagnosis age 0.33 years and 17 of 66 transplanted, are for a
  countrywide childhood cardiomyopathy cohort in which JPH2 is one of many
  genes. The Greater Middle East carrier frequencies are population genetics,
  not disease frequency. Each record says which, and the carrier-frequency
  prevalence record explains in its notes why its band and its rate refer to
  different quantities.

  Two phenotypes only. Dilated cardiomyopathy and congestive heart failure. The
  temptation with a cardiac entry is to add arrhythmia, sudden cardiac death and
  conduction disease from the JPH2 literature, and those belong to the dominant
  missense disease: the systematic review assigns them to that group explicitly.
  Importing them here would merge the two entities the same review separates.

  The gene therapy result, and why it is a discussion rather than a treatment.
  AAV9-JPH2 rescues contractility and t-tubule structure after transverse aortic
  constriction, where junctophilin-2 falls secondarily in a heart whose dyads
  formed normally. A CMD2E patient never had the protein. Curated as a
  HUMAN_MODEL_MISMATCH with a proposed experiment rather than as a treatment
  with a rationale, because the model and the disease differ in the one variable
  the therapy depends on.

  ClinGen says semidominant, this entry says recessive. That disagreement is
  quoted rather than smoothed: the ClinGen position is curated verbatim on the
  gene record and a KNOWLEDGE_GAP asks whether heterozygous loss-of-function
  carriers have cardiac disease, which nothing published has systematically
  tested.

  Deep research. One OpenScientist run, committed; reference validation reports
  17 of 17 references resolved, with 9 of 17 assessed as on topic, which is low
  and consistent with a report that ranges across the whole junctophilin
  literature. `just preflight-dr` returned SKIP, which means unchecked, because
  MONDO records no causal gene for MONDO:0030366. That is four of five entries in
  this run. Manual fallback: JPH2 dominates the report's gene mentions and its
  OMIM #619492 is CMD2E's.

  What is deliberately absent. No animal_models: block, despite three mouse
  studies being central to the mechanism. They are curated as evidence on the
  pathophysiology nodes instead, because none of them is a model of CMD2E: the
  germline null is embryonic lethal, the knockdown is an acute adult
  intervention, and the gene therapy study uses pressure overload. Recording any
  of them as an animal model of this disease would assert a fidelity claim none
  of the papers makes. No datasets: block, no clinical_trials: block, no
  environmental: block. No GeneReviews chapter exists; `just check-genereviews`
  reports NO_CHAPTER.
references:
- reference: PMID:31227780
  title: Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.
- reference: PMID:34861382
  title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
- reference: PMID:21339484
  title: Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
- reference: PMID:27760414
  title: Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release.
- reference: PMID:30384889
  title: Genetic Basis of Severe Childhood-Onset Cardiomyopathies.
datasets: []

📚

References & Deep Research

References

5

PMID:31227780

Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:34861382

One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.

No top-level findings curated for this source.

PMID:21339484

Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.

No top-level findings curated for this source.

PMID:27760414

Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release.

No top-level findings curated for this source.

PMID:30384889

Genetic Basis of Severe Childhood-Onset Cardiomyopathies.

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 (2)

Record notes

Scope and lump/split. MONDO:0030366 was bound nowhere in kb/. JPH2 appears as a gene in the broad Dilated_Cardiomyopathy entry and in the hypertrophic entries, and Hypertrophic_Cardiomyopathy_17 is the dominant JPH2 disease. This entry is the recessive counterpart, curated separately because the systematic review separates them by allele class and inheritance rather than by phenotype alone. Sibling per-type entries already exist (Cardiomyopathy_Dilated_2G, _2H, _2J), so the naming and granularity follow them. Neither the broad DCM entry nor CMH17 is edited here. A wrong gene identifier in the deep-research report. The OpenScientist run offered HGNC:14179 for JPH2 throughout. That identifier is CIAO3, cytosolic iron-sulfur assembly component 3. The correct one is hgnc:14202, which is what this entry binds, confirmed against the HGNC REST API and matching the stub. Nothing in the pipeline would have caught this: the research recipe passes --term-skip-prefix HGNC, so gene CURIEs are unchecked where they are emitted, and on the KB side `just validate-terms` checks only that a CURIE's label matches that CURIE, which a wrong-but-consistent pair would pass. This is the failure mode CLAUDE.md documents under "A gene binding only has to be self-consistent", reproduced live. Whose cohort a number comes from. Three denominators appear and none is a CMD2E frequency. The systematic review's 61 variant-positive individuals and its 18% DCM share span both inheritance modes. The Finnish KidCMP figures, median diagnosis age 0.33 years and 17 of 66 transplanted, are for a countrywide childhood cardiomyopathy cohort in which JPH2 is one of many genes. The Greater Middle East carrier frequencies are population genetics, not disease frequency. Each record says which, and the carrier-frequency prevalence record explains in its notes why its band and its rate refer to different quantities. Two phenotypes only. Dilated cardiomyopathy and congestive heart failure. The temptation with a cardiac entry is to add arrhythmia, sudden cardiac death and conduction disease from the JPH2 literature, and those belong to the dominant missense disease: the systematic review assigns them to that group explicitly. Importing them here would merge the two entities the same review separates. The gene therapy result, and why it is a discussion rather than a treatment. AAV9-JPH2 rescues contractility and t-tubule structure after transverse aortic constriction, where junctophilin-2 falls secondarily in a heart whose dyads formed normally. A CMD2E patient never had the protein. Curated as a HUMAN_MODEL_MISMATCH with a proposed experiment rather than as a treatment with a rationale, because the model and the disease differ in the one variable the therapy depends on. ClinGen says semidominant, this entry says recessive. That disagreement is quoted rather than smoothed: the ClinGen position is curated verbatim on the gene record and a KNOWLEDGE_GAP asks whether heterozygous loss-of-function carriers have cardiac disease, which nothing published has systematically tested. Deep research. One OpenScientist run, committed; reference validation reports 17 of 17 references resolved, with 9 of 17 assessed as on topic, which is low and consistent with a report that ranges across the whole junctophilin literature. `just preflight-dr` returned SKIP, which means unchecked, because MONDO records no causal gene for MONDO:0030366. That is four of five entries in this run. Manual fallback: JPH2 dominates the report's gene mentions and its OMIM #619492 is CMD2E's. What is deliberately absent. No animal_models: block, despite three mouse studies being central to the mechanism. They are curated as evidence on the pathophysiology nodes instead, because none of them is a model of CMD2E: the germline null is embryonic lethal, the knockdown is an acute adult intervention, and the gene therapy study uses pressure overload. Recording any of them as an animal model of this disease would assert a fidelity claim none of the papers makes. No datasets: block, no clinical_trials: block, no environmental: block. No GeneReviews chapter exists; `just check-genereviews` reports NO_CHAPTER.

Create: Cardiomyopathy_Dilated_2E (MONDO:0030366, JPH2) · 2026-09-17T17:14:22Z · View source

De novo curation of MONDO:0030366, biallelic JPH2 loss-of-function dilated cardiomyopathy, as the recessive counterpart of the existing Hypertrophic_Cardiomyopathy_17. Deep research: one OpenScientist run, reference validation 17/17 resolved with 9/17 on topic. preflight-dr returned SKIP; MONDO records no causal gene for this term, which is the fourth of five entries in this run where that check could not discriminate. The most important finding is a wrong gene identifier in the report: it offered HGNC:14179 for JPH2 throughout, and HGNC:14179 is CIAO3. The correct identifier, hgnc:14202, was confirmed against the HGNC REST API and matches the stub; it is what the entry binds. Nothing in the pipeline would have caught this, because the research recipe passes --term-skip-prefix HGNC so gene CURIEs are unchecked where emitted, and just validate-terms on the KB side only checks that a CURIE's label matches that CURIE, which a wrong-but-consistent pair passes. This is the failure mode CLAUDE.md documents under 'A gene binding only has to be self-consistent', reproduced live; just list-gene-term-mismatches reports zero findings on the finished entry. Three mouse studies carry the mechanism but no animal_models block is recorded, because none of them models CMD2E: the germline null is embryonic lethal, the knockdown is an acute adult intervention, and the AAV9 gene-therapy study uses pressure overload where junctophilin-2 falls secondarily in a heart whose dyads formed normally. That last mismatch is curated as a HUMAN_MODEL_MISMATCH discussion rather than as a treatment rationale. ClinGen's curated position calls the JPH2-DCM relationship semidominant where this entry says recessive; the disagreement is quoted verbatim on the gene record and a second KNOWLEDGE_GAP asks whether heterozygous loss-of-function carriers have cardiac disease. Arrhythmia, sudden cardiac death and conduction disease were deliberately not imported, because the systematic review assigns them to the dominant missense group. Validation: just validate 24/24 snippets verified, validate-terms, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-genereviews NO_CHAPTER, list-gene-term-mismatches clean.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 17 citations 2026-09-17T17:04:26.586737

1. Disease Information

Overview. CMD2E is a Mendelian, gene-defined subtype of dilated cardiomyopathy (DCM). DCM is characterized by left ventricular (or biventricular) dilation and systolic dysfunction not explained by abnormal loading conditions or coronary disease. CMD2E is the specific entity attributable to biallelic JPH2 loss-of-function.

Key identifiers.

Resource	Identifier
OMIM (phenotype)	#619492 (CARDIOMYOPATHY, DILATED, 2E; CMD2E)
OMIM (gene)	*605267 (JPH2)
MONDO	MONDO:0030366
HGNC	HGNC:14179 (JPH2)
NCBI Gene	57158
Ensembl	ENSG00000149596
UniProt	Q9BR39
Cytoband	20q13.12 (GRCh38 chr20:44,106,590–44,187,188)
ICD-10 (parent DCM)	I42.0
ICD-11 (parent DCM)	BC43.0
MeSH (parent DCM)	D002311
Orphanet	Under familial isolated DCM (ORPHA:154)

Synonyms / alternative names. "Dilated cardiomyopathy 2E"; "CMD2E"; "JPH2-related dilated cardiomyopathy"; "junctophilin-2-related recessive dilated cardiomyopathy." Note that "CMD2E" (with numeric-letter suffix) denotes the OMIM molecular-genetic subtype and should not be confused with dominant JPH2 disease.

Information source type. Evidence is derived from aggregated disease-level resources (OMIM, MONDO, gnomAD) combined with individual-patient case reports and small kindreds (two founding families plus subsequent case reports), and from model-organism and in vitro mechanistic studies. There is no large EHR-derived cohort specific to CMD2E owing to its rarity.

2. Etiology

Primary cause — genetic. CMD2E is caused by homozygous or compound heterozygous loss-of-function variants in JPH2. Two independent recessive kindreds established causality (Finding F001):

p.Q428X (c.1282C>T), homozygous nonsense, Finnish family — proband diagnosed at age 3, transplanted at age 4 (PMID: 30384889). The paper identifies JPH2 among calcium-signaling genes in a severe childhood cardiomyopathy cohort: "calcium signaling (JPH2, CALM1, CACNA1C)."
p.E641* (c.1920dupT), homozygous 1-bp insertion creating a premature stop, consanguineous Iranian families on a shared founder haplotype (PMID: 31227780): "identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*)."

Genetic risk factors. The obligate risk factor is inheritance of two LOF JPH2 alleles. Consanguinity and founder effects substantially elevate risk (the Iranian p.E641* variant on a shared haplotype). Heterozygous carriers are asymptomatic (see §9), consistent with a recessive mechanism.

Environmental risk factors. No specific environmental trigger is established as causal for CMD2E; the disease is monogenic. General DCM environmental modifiers (viral myocarditis, toxins, alcohol) are not implicated in the biallelic-JPH2 entity, though they could theoretically aggravate any myocardial reserve deficit.

Protective factors. No genetic or environmental protective factors are specifically documented for CMD2E. By inference, retention of even one functional JPH2 allele is "protective" (carriers are unaffected), reflecting haplosufficiency.

Gene–environment interactions. None specifically documented. The dominant driver is genotype (biallelic LOF); environmental contribution appears minimal relative to the primary lesion.

3. Phenotypes

CMD2E presents with the core phenotype of dilated cardiomyopathy: left ventricular dilation and impaired systolic function (reduced ejection fraction) producing congestive heart failure, with arrhythmia risk and risk of premature death (Finding F006). Progression is rapid, frequently to transplant-dependent end-stage failure.

Phenotype	Type	HPO term (suggested)	Onset	Severity / progression	Frequency
Dilated cardiomyopathy	Clinical sign (imaging)	HP:0001644	Neonatal–early childhood	Severe, progressive	Defining (all patients)
Left ventricular systolic dysfunction / reduced EF	Laboratory/imaging abnormality	HP:0005162 / HP:0012664	Neonatal–early childhood	Severe, progressive	Very frequent
Congestive heart failure	Clinical sign	HP:0001635	Neonatal–early childhood	Severe	Very frequent
Ventricular arrhythmia / arrhythmia	Clinical sign	HP:0004308 / HP:0011675	Childhood	Variable	Reported risk
Sudden cardiac death / premature death	Outcome	HP:0001645 / HP:0001663	Childhood	—	Reported

Phenotype characteristics. Age of onset: neonatal to early childhood (congenital/pediatric). Severity: severe. Progression: rapid and progressive. Frequency: the DCM/systolic-failure phenotype is fully penetrant in reported biallelic patients. Supporting quote (PMID: 31227780): "A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure."

Quality-of-life impact. Not formally measured with standardized instruments (EQ-5D/SF-36/PROMIS) in this rare disease, but the burden is profound: infants/children experience heart-failure symptoms (feeding difficulty, failure to thrive, dyspnea, exercise intolerance), hospitalization, need for mechanical support, and transplantation with lifelong immunosuppression.

4. Genetic / Molecular Information

Causal gene. JPH2 — junctophilin-2 (OMIM *605267; HGNC:14179; NCBI Gene 57158; Ensembl ENSG00000149596; UniProt Q9BR39; 20q13.12). Finding F007 verified these identifiers via mygene.info.

Pathogenic variants (CMD2E, recessive).

Variant (protein)	cDNA	Type	Zygosity	Population	Reference
p.Q428X	c.1282C>T	Nonsense (LOF)	Homozygous	Finnish	PMID: 30384889
p.E641*	c.1920dupT	Frameshift/stop-gain (LOF)	Homozygous (founder)	Iranian / Greater Middle East	PMID: 31227780

Variant classification. Both founding variants are truncating loss-of-function alleles (nonsense / frameshift-stopgain) and are consistent with Pathogenic classification under ACMG/AMP (null variant in a gene where LOF is a known disease mechanism, segregation, rarity/absence in controls). Additional recessive frameshift cases have subsequently been reported in pediatric DCM (e.g., PMID: 41919412).

Variant type/class. Truncating (nonsense, frameshift → premature termination codon); predicted to trigger nonsense-mediated decay or produce truncated non-functional protein → loss of function.

Allele frequency (population databases). gnomAD constraint for JPH2 (Finding F004): pLI ≈ 3.9×10⁻⁹, LOEUF (oe_lof upper) = 0.89, observed/expected LOF = 38/55.9 (oe_lof 0.68) — i.e., heterozygous LOF is tolerated, consistent with unaffected carriers and a recessive disease requiring biallelic loss. LOF variants are rare overall (0.04%) but enriched in Greater Middle Eastern (GME) individuals (0.21%) (PMID: 31227780): "Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%)."

Somatic vs germline. Germline (inherited). No somatic mechanism is relevant.

Functional consequences. Loss of function (haploinsufficiency is tolerated; biallelic loss is pathogenic). This contrasts sharply with the dominant missense JPH2 variants causing hypertrophic cardiomyopathy/arrhythmia (e.g., A405S — PMID: 28393127; E169K causing atrial fibrillation via impaired RyR2 stabilization — PMID: 23973696), which act by altered/reduced RyR2 regulation rather than complete protein loss.

Modifier genes. None specifically established for CMD2E. Other calcium-handling/dyadic genes (RYR2, CACNA1C, CALM1, BIN1, CMYA5) are biologically plausible modifiers but unproven in this disorder.

Epigenetic information / chromosomal abnormalities. No disease-specific DNA-methylation, histone-modification, or large-scale chromosomal abnormality (aneuploidy/translocation) is documented for CMD2E. The disease is a small-scale sequence (point/indel) disorder.

5. Environmental Information

CMD2E is a monogenic recessive disorder; no environmental, lifestyle, or infectious agents are established as causal. Unlike acquired DCM (viral myocarditis, alcohol, chemotherapy toxins), the biallelic-JPH2 entity arises from the genetic lesion. Consanguinity is the principal non-molecular contributor to disease occurrence at the population level, by increasing the probability of biallelic inheritance of rare founder LOF alleles (§9). Environmental cardiac stressors are, at most, plausible aggravators of already-compromised myocardial reserve, not initiators.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic JPH2 loss-of-function mutation (e.g., p.Q428X, p.E641*) leads to absence/severe reduction of functional junctophilin-2 protein in cardiomyocytes (loss of function; both alleles null).
Loss of junctophilin-2 results in failure to tether the T-tubule sarcolemma to the junctional sarcoplasmic reticulum, so the cardiac dyad / junctional membrane complex cannot assemble or be maintained (the ~12–15 nm dyadic cleft is lost or disordered). Demonstrated in mouse Jph2-null myocytes (PMID: 10949023).
Without an intact dyad, L-type Ca²⁺ channels (CACNA1C/LTCC) are no longer recruited to and juxtaposed with RyR2 — the JPH2 "joining region" that directly binds the LTCC α1C subunit is lost (PMID: 33092464), which leads to loss of the tight spatial coupling required for CICR.
Disrupted LTCC–RyR2 coupling results in impaired/asynchronous calcium-induced calcium release and reduced EC-coupling gain — abnormal, spatially and temporally desynchronized Ca²⁺ transients (demonstrated in null and knockdown myocytes; PMID: 10949023, PMID: 21339484).
Deficient Ca²⁺ transients lead to reduced cardiomyocyte contractility (weak systole).
Chronic contractile insufficiency results in ventricular dilation and systolic heart failure (the DCM phenotype) — inferred progression from cellular to organ level, supported by cardiac-knockdown mice developing heart failure (PMID: 21339484).
Ventricular remodeling and abnormal Ca²⁺ handling lead to arrhythmia risk and premature death (inferred from clinical course and RyR2 dysregulation literature).

Branch (stress-adaptive signaling). In parallel with structural loss, proteolytic cleavage of JPH2 (by calpain, PMID: 30409805; by MMP-2, PMID: 31506724) generates an N-terminal fragment (JP2NT) that translocates to the nucleus as a stress-adaptive transcriptional regulator. This branch is most relevant to acquired heart failure, but it underscores that JPH2 has both a structural (dyad-tethering) and a signaling role; in CMD2E, complete germline loss abolishes both. Supporting quote (PMID: 30409805): "After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression."

Category detail

Molecular pathways. Cardiac excitation–contraction coupling and calcium-induced calcium release (CICR) at the dyad; LTCC (CACNA1C) → RyR2 signaling axis. GO biological processes: GO:0006942 (regulation of striated muscle contraction), GO:0055117 (regulation of cardiac muscle contraction), GO:0010881 (regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion), GO:0051209 (release of sequestered calcium ion into cytosol). Supporting quote (PMID: 33092464): "The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes."
Cellular processes. Impaired myocyte contraction; disrupted junctional membrane complex biogenesis; abnormal intracellular Ca²⁺ homeostasis. In the acquired/proteolysis branch: stress-adaptive transcriptional reprogramming.
Protein dysfunction. Loss of function — truncated/absent junctophilin-2; loss of the membrane-tethering MORN motifs and the LTCC-binding "joining region."
Metabolic changes. No primary metabolic defect; secondary bioenergetic strain accompanies heart failure (not specific to CMD2E).
Immune involvement. Not a primary feature; CMD2E is not autoimmune/inflammatory in origin.
Tissue-damage mechanisms. Progressive myocardial dysfunction and dilation; interstitial/collagen remodeling accompanies advanced failure (t-tubule/dyad disorganization associated with collagen deposition in failing human myocardium — PMID: 34690801).
Biochemical abnormality. Defective calcium-channel coupling (LTCC–RyR2 microdomain failure) — an ion-handling/microdomain defect rather than an enzyme deficiency.
Cell types & GO cellular components. Cell type: ventricular cardiac muscle cell (CL:0002131) / cardiac muscle cell (CL:0000746). Cellular components: cardiac dyad, T-tubule (GO:0033268 / GO:0014801), junctional sarcoplasmic reticulum membrane (GO:0014701) / sarcoplasmic reticulum (GO:0016529), Z-disc (GO:0030018).

Mechanistic schematic

Biallelic JPH2 LOF (p.Q428X / p.E641*)
│  (loss of function)
▼
No functional junctophilin-2
│  (cannot tether T-tubule ↔ jSR)
▼
Dyad / junctional membrane complex fails to form
│  (LTCC not recruited opposite RyR2)
▼
LTCC (CACNA1C) — RyR2 coupling lost
│
▼
Impaired calcium-induced calcium release
(asynchronous, low-gain Ca2+ transients)
│
▼
Reduced cardiomyocyte contractility
│
▼
LV dilation + systolic heart failure (DCM)  ──► arrhythmia / premature death

7. Anatomical Structures Affected

Organ level (primary). Heart (UBERON:0000948), specifically the ventricular myocardium / cardiac ventricle (UBERON:0002349 / UBERON:0002082); left ventricle predominant with possible biventricular involvement. Body system: cardiovascular.
Secondary organ involvement. Downstream congestive effects of heart failure (pulmonary congestion, hepatic congestion, systemic hypoperfusion) — complications rather than primary sites.
Tissue/cell level. Cardiac (striated) muscle tissue; ventricular cardiac muscle cells / cardiomyocytes (CL:0002131 / CL:0000746).
Subcellular level. The cardiac dyad — the junction of T-tubule (GO:0033268) and junctional sarcoplasmic reticulum (GO:0014701 / GO:0016529); the Z-disc (GO:0030018); sarcolemma–SR contact microdomain.
Localization / lateralization. Bilateral/global ventricular process (not lateralized); a diffuse cardiomyocyte-autonomous defect rather than a focal lesion.

8. Temporal Development

Onset. Neonatal to early-childhood (congenital/pediatric). Onset pattern is early and can be insidious to subacute, progressing to overt decompensated heart failure. In the founding kindreds, the Finnish proband was diagnosed at age 3 (PMID: 30384889) and Iranian children died in childhood from cardiac failure (PMID: 31227780).
Progression. Rapid and progressive, advancing to end-stage systolic failure. Disease course is progressive (not relapsing-remitting), typically culminating in transplant dependence within a few years of diagnosis (Finnish proband transplanted at age 4).
Duration. Chronic and lifelong from a genetic standpoint; without transplantation the natural course is early fatal.
Patterns / remission. No spontaneous remission is expected; "remission" is achieved only via transplantation (replacement of the affected organ). Critical intervention window is early — before irreversible ventricular remodeling and end-organ compromise.

9. Inheritance and Population

Inheritance pattern. Autosomal recessive (biallelic LOF required). Established by homozygous variants segregating with disease in two independent consanguineous/founder kindreds (Finding F001).

Penetrance / expressivity. In reported biallelic individuals, penetrance of the DCM/heart-failure phenotype appears complete/high; heterozygous carriers are unaffected. Expressivity within biallelic patients is severe with early onset; the small number of families limits precise estimates.

Carrier frequency & founder effects. gnomAD shows JPH2 tolerates heterozygous LOF (LOEUF 0.89; oe_lof 0.68), consistent with silent carriers (Finding F004). Worldwide ~1.45% of healthy individuals carry a rare JPH2 variant, rising to 4.45% in GME populations; LOF alleles are rare (0.04%) but most prevalent in GME (0.21%) (PMID: 31227780). The Iranian p.E641* allele arose on a shared founder haplotype.

Consanguinity. A major contributor — recessive disease manifests when consanguineous unions bring together two copies of a rare founder LOF allele.

Anticipation / mosaicism. No evidence of genetic anticipation (not a repeat-expansion disorder). Germline mosaicism not specifically reported.

Epidemiology. CMD2E is very rare (an ultra-rare Mendelian subtype of DCM); precise prevalence/incidence figures are not established given the small number of reported families. It falls under the Orphanet umbrella of familial isolated DCM (ORPHA:154). Enrichment is expected in consanguineous populations, particularly the Greater Middle East.

Demographics. No strong sex bias is established (recessive, autosomal). Affected individuals are infants/children. Geographic clustering follows founder/consanguinity patterns (e.g., Iranian founder for p.E641*).

10. Diagnostics

Clinical/imaging. Diagnosis of the DCM phenotype rests on echocardiography (LV dilation, reduced ejection fraction) and cardiac MRI (chamber dimensions, systolic function, fibrosis on late gadolinium enhancement). ECG and Holter monitoring assess arrhythmia/conduction. Biomarkers: elevated BNP/NT-proBNP (heart-failure severity); troponin may be monitored. Endomyocardial biopsy is not required for diagnosis but would show non-specific myocyte changes/remodeling.

Genetic testing (definitive for CMD2E). Because CMD2E is defined molecularly, genetic testing is the confirmatory diagnostic: - Cardiomyopathy/DCM multigene NGS panels including JPH2 are first-line. - Whole-exome (WES) or whole-genome sequencing (WGS) is highly useful, especially for early-onset/consanguineous pediatric DCM where recessive genes are implicated; the founding CMD2E variants were identified via broad sequencing in severe childhood cardiomyopathy cohorts (PMID: 30384889). - Confirming biallelic status (homozygous vs compound heterozygous, with parental segregation) is essential to distinguish recessive CMD2E from incidental heterozygous carriage. - Chromosomal microarray/karyotype/FISH/mtDNA/repeat-expansion testing are not indicated for this small-scale sequence disorder.

Clinical criteria & differential diagnosis. Standard DCM diagnostic criteria (dilation + systolic dysfunction not explained by loading/coronary disease). Differential: other genetic pediatric DCM (e.g., TTN, LMNA, FLNC, DES, DSP, TNNT2), syndromic/oligogenic DCM (PMID: 42559185), metabolic/mitochondrial cardiomyopathies, myocarditis, and — importantly — dominant JPH2 hypertrophic cardiomyopathy (CMH17), which is phenotypically hypertrophic (not dilated) and mechanistically distinct.

Screening. For affected families: cascade genetic testing of relatives to identify carriers and at-risk future offspring; carrier screening in consanguineous couples with a founder allele; prenatal/preimplantation testing where a familial biallelic risk exists.

11. Outcome / Prognosis

Survival/mortality. Prognosis is poor without transplantation: both founding kindreds illustrate early end-stage disease — transplantation at age 4 in the Finnish proband (PMID: 30384889) and childhood death from cardiac failure in Iranian children (PMID: 31227780). With modern pediatric heart-failure care, outcomes for end-stage DCM are favorable: registry data show adolescents with DCM have excellent 3-year survival with either a HeartMate 3 VAD (94.4%) or transplant (95.6%) (PMID: 42334151): "Adolescents with DCM treated with either HM3 or transplant had excellent 3-year outcomes."

Morbidity/function. High morbidity from heart failure (hospitalizations, activity limitation, feeding/growth impairment in infants), device-related complications in those on mechanical support, and lifelong immunosuppression after transplant.

Complications. Progressive systolic failure, ventricular arrhythmia, thromboembolism, end-organ hypoperfusion, and sequelae of mechanical support/transplant.

Prognostic factors. Age/severity at presentation, degree of ventricular dysfunction, arrhythmia burden, and response to guideline-directed therapy. Recovery of native ventricular function is not expected given the fixed genetic dyadic defect; definitive treatment is organ replacement (or, prospectively, gene replacement).

12. Treatment

No CMD2E-specific approved therapy exists (Finding F005). Management is standard pediatric dilated-cardiomyopathy / heart-failure care:

Pharmacotherapy (guideline-directed medical therapy). ACE inhibitors / ARBs, beta-blockers, mineralocorticoid-receptor antagonists, diuretics; contemporary HFrEF agents as age-appropriate. (Suggested NCIT concept classes: Angiotensin-Converting Enzyme Inhibitor, Beta-Adrenergic Blocker, Diuretic, Aldosterone Antagonist.)
Mechanical circulatory support. Ventricular assist devices (e.g., HeartMate 3) as bridge-to-transplant or longer-term support; pediatric VAD outcomes are well documented (PMID: 42622114, PMID: 42334151). (NCIT: Ventricular Assist Device.)
Orthotopic heart transplantation. The definitive treatment for end-stage disease; the Finnish proband was transplanted at age 4. (NCIT: Heart Transplantation.)
Device therapy / arrhythmia management as indicated (ICD for high arrhythmic risk).

Targeted / advanced therapeutics (investigational rationale). Because CMD2E is a loss-of-function disorder, gene replacement is the mechanistically ideal strategy. AAV9-mediated JPH2 overexpression rescued cardiac contractility, preserved T-tubule structure, and normalized RyR2-mediated Ca²⁺ release in a mouse (transverse aortic constriction) heart-failure model (PMID: 27760414): "AAV9-mediated expression of JPH2 rescued cardiac contractility in mice subjected to TAC. AAV9-JPH2 also preserved T-tubule structure." This provides a strong preclinical rationale for AAV9-JPH2 gene therapy in CMD2E, though no human trial yet exists.

Pharmacogenomics. No gene-specific pharmacogenomic guidance is established for CMD2E.

Treatment outcomes. Supportive/GDMT slows progression but does not correct the primary defect; end-stage disease is managed with VAD/transplant, with excellent short-to-medium-term survival in modern pediatric practice (PMID: 42334151).

13. Prevention

Primary prevention. No population-level primary prevention (monogenic disease). The principal lever is reproductive genetic counseling in families/populations carrying founder LOF alleles — particularly reducing recessive risk in consanguineous unions.
Secondary prevention. Cascade genetic screening of relatives of probands to identify carriers and at-risk offspring; early echocardiographic surveillance in genetically at-risk children enables timely heart-failure therapy.
Tertiary prevention. Optimizing GDMT, arrhythmia risk management, and timely VAD/transplant to prevent complications and death in affected individuals.
Genetic counseling & reproductive options. For couples both carrying a JPH2 LOF allele, recurrence risk is 25% per pregnancy; preimplantation genetic testing and prenatal diagnosis are options. Carrier screening is especially relevant in Greater Middle Eastern / consanguineous populations given founder enrichment (PMID: 31227780).
Immunization / public health / prophylaxis. Not applicable (non-infectious, monogenic).

14. Other Species / Natural Disease

Taxonomy / orthologs (Finding F007). JPH2 is conserved across vertebrates: mouse Jph2 (NCBI Gene 59091; Ensembl ENSMUSG00000017817; UniProt Q9ET78), zebrafish jph2 (NCBI Gene 553333; Ensembl ENSDARG00000028625). The essential role in cardiac dyad/EC-coupling formation is conserved.
Natural disease in other species. No well-characterized naturally occurring biallelic-JPH2 dilated cardiomyopathy is documented in companion animals or wildlife in the reviewed literature; disease knowledge derives from engineered models (§15).
Comparative biology / evolutionary conservation. The dyad is an evolutionarily conserved cardiomyocyte structure, and junctophilin's tethering function is conserved, making cross-species models highly informative. (For background on dyad evolution, see PMID: 36189805.)
Zoonotic potential. Not applicable.

15. Model Organisms

CMD2E biology is strongly supported by mouse genetics (Finding F003):

Model	Manipulation	Key phenotype	Reference
Germline Jph2-null mouse	Global knockout	Embryonic lethal immediately after heartbeat onset; deficient junctional membrane complexes; abnormal, asynchronous Ca²⁺ transients	PMID: 10949023; PMID: 12086916
Cardiac-specific shRNA JPH2 knockdown	Partial (postnatal) loss	Impaired contractility, fewer junctional membrane complexes, increased plasmalemma–SR distance variability, reduced EC-coupling gain, heart failure and increased mortality	PMID: 21339484
AAV9-JPH2 gene delivery (TAC HF model)	Overexpression/rescue	Rescued contractility, preserved T-tubules, normalized RyR2-mediated Ca²⁺ release	PMID: 27760414

Model types available. Mammalian (mouse) knockout, cardiac-specific knockdown, and AAV-based rescue; zebrafish orthologs enable developmental modeling. iPSC-derived cardiomyocytes from patients are a logical (in vitro) system to model biallelic human variants.

Phenotype recapitulation. Mouse models faithfully recapitulate the core mechanism — dyad loss, EC-coupling failure, abnormal Ca²⁺ handling, and contractile/heart failure — validating the human causal chain. Supporting quotes: "JP-2 is abundantly expressed in the heart, and mutant mice lacking JP-2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal Ca2+ transients" (PMID: 10949023); "Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality" (PMID: 21339484).

Model limitations. Germline null is embryonic-lethal, so it cannot model the postnatal human course; knockdown produces partial rather than complete loss; TAC models pressure-overload HF rather than the primary congenital dyadic deficit. A conditional/humanized biallelic-LOF model or patient iPSC-cardiomyocytes would better capture the human CMD2E trajectory.

Mechanistic Model / Interpretation

CMD2E is best understood as a structural dyadopathy of the cardiomyocyte. Junctophilin-2 is the molecular "staple" that holds the T-tubule sarcolemma against the junctional SR; its "joining region" additionally recruits L-type Ca²⁺ channels into the dyad opposite RyR2. Removing both alleles removes the staple, the dyad cannot form, and the exquisitely spatially-organized CICR that powers every heartbeat becomes weak and asynchronous. Because contractility depends on this microdomain, the ventricle cannot generate adequate force, dilates, and fails.

The genetics reinforce the mechanism: heterozygous LOF is tolerated (gnomAD LOEUF 0.89; unaffected carriers), so one functional allele suffices — the disease is unmasked only by biallelic loss, explaining its recessive inheritance and enrichment in consanguineous/founder settings. This is the mirror image of dominant JPH2 missense disease (HCM/AF; PMID: 28393127, PMID: 23973696), where a mutant protein perturbs RyR2 regulation in a dose-dependent, dominant manner. The dichotomy — dominant missense → hypertrophic/arrhythmic vs recessive null → dilated/failing — is a clean genotype–mechanism–phenotype correspondence.

The therapeutic corollary follows directly: a loss-of-function disease is the archetypal target for gene replacement, and AAV9-JPH2 rescue in mice (PMID: 27760414) shows that restoring the protein restores dyad structure and Ca²⁺ handling. Until such therapy is available for humans, the clinical pathway is heart-failure GDMT → mechanical support → transplant, for which contemporary pediatric outcomes are strong (PMID: 42334151).

Evidence Base

PMID	Role	How it supports the findings
30384889	Gene discovery	Identifies JPH2 (homozygous Q428X) in severe childhood cardiomyopathy; establishes CMD2E gene (F001)
31227780	Gene confirmation + population genetics	Homozygous p.E641* recessive DCM; GME carrier/LOF frequencies; founder effect (F001, F004, F006)
33092464	Mechanism	JPH2 joining region binds LTCC to assemble dyad and maintain CICR (F002)
30409805	Mechanism (proteolysis/signaling)	Calpain cleavage disrupts EC-coupling; JP2NT transcription regulator branch (F002)
31506724	Mechanism (proteolysis)	MMP-2 cleaves JPH2, damages dyads in ischemia-reperfusion (F002)
10949023	Model organism	Germline Jph2-null: embryonic lethal, deficient junctional complexes, abnormal Ca²⁺ (F003)
12086916	Model organism	JP-2 and RyR2 knockouts lethal at heartbeat onset; dyad essential for Ca²⁺ homeostasis (F003)
21339484	Model organism	Cardiac JPH2 knockdown → contractile failure, heart failure, mortality (F003)
27760414	Therapeutic rationale	AAV9-JPH2 rescues contractility, T-tubules, RyR2 Ca²⁺ release (F005)
42334151	Clinical management	Excellent 3-yr survival with VAD/transplant in adolescent DCM (F005)
28393127	Contrast (dominant)	JPH2 A405S dominant HCM — distinguishes from recessive CMD2E
23973696	Contrast (dominant)	JPH2 E169K AF via impaired RyR2 stabilization — dominant mechanism
34690801	Human failing heart	RyR2/JPH2 nanoscale disorganization and collagen in failing myocardium

Limitations and Knowledge Gaps

Very small human evidence base. CMD2E rests on a handful of families (Finnish Q428X; Iranian founder E641*; subsequent case reports). Prevalence, incidence, precise penetrance, sex ratio, and natural-history statistics are therefore not robustly quantified.
No standardized QoL or registry data specific to CMD2E; morbidity/QoL is inferred from general pediatric DCM.
Mechanism largely extrapolated from models and dominant-disease studies. Direct functional validation of the specific recessive human LOF variants (e.g., patient iPSC-cardiomyocytes) is limited; the causal chain steps 6–7 (cell → organ; arrhythmia/death) are inferred.
No human gene-therapy data. AAV9-JPH2 rescue is preclinical (mouse pressure-overload HF), not tested in congenital biallelic-LOF disease or in humans.
Modifier genes, epigenetics, and environmental interactions are essentially uncharacterized for CMD2E.
Ontology mappings for the specific CMD2E entity (e.g., exact Orphanet subtype, ICD-11 extension code) are approximate; identifiers here reflect the parent DCM class where a subtype-specific code is unavailable.

Proposed Follow-up Experiments / Actions

Patient-derived iPSC-cardiomyocyte modeling of p.Q428X and p.E641* (and isogenic corrected controls) to directly quantify dyad density, LTCC–RyR2 colocalization (dSTORM), Ca²⁺-transient synchrony, and contractility — closing the inference gap between genotype and cellular phenotype.
Conditional / humanized biallelic-LOF mouse (bypassing embryonic lethality) to establish a postnatal CMD2E model recapitulating the human dilated, progressive course.
Preclinical AAV9-JPH2 gene-replacement trial in a biallelic-LOF model, with dose-finding and durability endpoints, to advance the rational targeted therapy toward first-in-human studies.
International registry / GeneMatcher-style aggregation of biallelic JPH2 DCM cases to define prevalence, penetrance, natural history, and genotype–phenotype correlations.
Targeted carrier screening for JPH2 LOF founder alleles in Greater Middle Eastern / consanguineous populations, with genetic counseling and reproductive-option education.
Cascade testing protocols and early echocardiographic surveillance guidelines for genotype-positive relatives.
Deep clinical phenotyping (arrhythmia burden via Holter/ICD data, cardiac MRI fibrosis) in future cases to refine risk stratification and timing of VAD/transplant.

Evidence source types represented: human clinical (case reports/kindreds, pediatric HF registries), model organism (mouse knockout/knockdown/AAV rescue), in vitro/biochemical (JPH2–LTCC interaction, proteolysis), and computational/population genetics (gnomAD constraint, founder-haplotype analysis).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	17
On topic	9
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	25
Resolved	23
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	3

Terms the report names something else

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

MONDO:0030366 (3 mentions) - the report calls it "MONDO"; MONDO calls it cardiomyopathy, dilated, 2E
HP:0001644 (1 mention) - the report calls it "Clinical sign (imaging)"; HP calls it Dilated cardiomyopathy
HP:0001635 (1 mention) - the report calls it "Clinical sign"; HP calls it Congestive heart failure

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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4. Genetic / Molecular Information

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Mechanistic schematic

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Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver