Cardiomyopathy Dilated 2H

Mendelian MONDO:0859358 Pathograph 19 Show in embeddings browser hereditary disease familial isolated dilated cardiomyopathy

Dilated cardiomyopathy 2H (CMD2H) is an autosomal recessive, early infantile-onset cardiomyopathy caused by biallelic variants in GET3 (long known as ASNA1, and also called TRC40). It is mechanistically unlike most familial dilated cardiomyopathy: the causal gene encodes no sarcomeric or cytoskeletal protein but the central ATP-dependent chaperone of the GET/TRC pathway, which inserts tail-anchored proteins post-translationally into the endoplasmic reticulum membrane. Loss of that targeting factor destabilizes the pre-targeting complex, depletes a broad set of tail-anchored substrates, and disrupts membrane trafficking and cardiomyocyte proteostasis. The clinical course is rapidly progressive dilated cardiomyopathy with death in early infancy. It was the first evidence that the tail-anchored protein insertion pathway causes human disease.

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1
Inheritance
5
Pathophys.
3
Histopath.
8
Phenotypes
3
Gaps
19
Pathograph
2
Genes
4
Medical Actions
2
Models
3
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Compound heterozygous GET3 variants inherited in trans, identified in a sibling pair by family-based exome sequencing.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"We identified compound heterozygous variants in the highly conserved ASNA1 gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins."
Compound heterozygous inheritance of two GET3/ASNA1 alleles establishes the recessive mode.
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Discussions and Knowledge Gaps

3
Which tail-anchored protein substrates, among the many depleted by GET3 loss, actually account for the cardiac phenotype?
KNOWLEDGE GAP which_ta_substrate_drives_the_heart_phenotype
Attached to
pathophysiology#Impaired Tail-Anchored Protein Insertion pathophysiology#Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
The index paper narrows this considerably: inspecting the predicted human tail-anchored proteome it names seven already associated with human cardiomyopathy - DMPK, DYSF, EMD, JPH2, PLN (printed as PPLA in the source), SYNE1 and SYNE2. So the gap is not that no candidates exist but which of that shortlist is rate-limiting. There is also a partial negative result to work against: emerin localized correctly to the nuclear membrane in patient myocardium, though nuclei were irregularly shaped, which argues against emerin mislocalization being the proximate lesion. Tail-anchored proteins are roughly 5% of integral membrane proteins and the mouse work reports reduced expression of multiple substrates collectively, so the shortlist is where the question becomes tractable.
Show evidence (2 references)
PMID:31461301 SUPPORT Human Clinical
"revealed 7 proteins of interest that have been associated with cardiomyopathy in humans: DMPK (myotonin-protein kinase; Q09013), DYSF (dysferlin; O75923), EMD (emerin; P50402), JPH2 (junctophilin-2; Q9BR39), PPLA (cardiac phospholamban; P26678), SYNE1 (nesprin-1; Q8NF91), and SYNE2 (nesprin-2; Q8WXH0)."
Names the candidate tail-anchored substrates, which is what makes this gap actionable rather than open-ended.
PMID:31461301 REFUTE Human Clinical
"Emerin correctly localized to the nuclear membrane."
Refutes emerin mislocalization as the proximate lesion, narrowing the candidate shortlist.
Why does loss of a ubiquitously expressed chaperone present as isolated dilated cardiomyopathy rather than a multisystem disorder?
KNOWLEDGE GAP cardiac_selectivity_of_a_ubiquitous_chaperone
Attached to
pathophysiology#Biallelic GET3 Loss of Function
Only two patients, siblings, have been reported, and both died in early infancy — so the apparent cardiac selectivity may be real tissue vulnerability or may simply reflect that the heart fails first. There is a concrete mechanistic proposal to test: the endoplasmic reticulum membrane complex provides an alternative insertion route for moderately hydrophobic tail-anchored substrates, so tissues could differ in how much they depend on GET3 specifically. Against pure cardiac selectivity, model organisms show extra-cardiac deficits including visual, touch, otoferlin-dependent hearing and insulin-secretion phenotypes; the two siblings passed newborn hearing screening, but neither survived long enough for later-onset deficits to declare themselves. Additional patients surviving longer would resolve it.
Do complete-null animal models over-represent the severity of the human compound heterozygous genotype, in which one allele is a missense that leaves misfolded protein present?
HUMAN MODEL MISMATCH human_model_severity_mismatch
Attached to
animal_models#Mouse animal_models#Zebrafish pathophysiology#Biallelic GET3 Loss of Function
Both the zebrafish and mouse models are effectively null and both are lethal, whereas the human genotype pairs a nonsense allele with a p.(Val163Ala) missense allele that still produces protein, albeit misfolded and insertion-deficient. Whether residual hypomorphic activity modifies the human course cannot be addressed in a null model, and no patient with a milder allele combination has been reported to test it against.
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Pathophysiology

5
Biallelic GET3 Loss of Function
Three variants across two alleles, not two. The paternal allele carries c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*) in cis; the maternal allele carries c.488T>C p.(Val163Ala). The cis pairing matters mechanistically: Cys289 is part of an essential zinc-binding site, so the paternal allele is doubly compromised rather than simply truncated. Reduced protein abundance was demonstrated directly in patient myocardium and skin fibroblasts. The maternal missense allele leaves protein present but misfolded. Notably the premature stop codon does not trigger nonsense-mediated decay - wild-type and mutant transcripts were present in equal amounts - so the truncated protein is made.
Genetic context allele_type: nonsense and missense variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Three variants across two alleles: c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*) in cis on the paternal allele, c.488T>C p.(Val163Ala) on the maternal. The premature stop escapes nonsense-mediated decay, so truncated protein is made rather than cleared.
ATP hydrolysis activity GO:0016887 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves ATP hydrolysis activity (GO:0016887), qualified as loss of function. GO:0016887 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Tail-Anchored Protein Insertion Both alleles converge on the same functional endpoint, which was measured directly in an in vitro tail-anchored protein insertion assay.
Show evidence (3 references)
PMID:31461301 SUPPORT Human Clinical
"The c.913C>T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts."
Documents reduced GET3/ASNA1 protein in patient heart and fibroblasts attributable to the nonsense allele.
PMID:31461301 SUPPORT Human Clinical
"2 variants c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*) in cis configuration on the paternal allele, and a missense variant c.488T>C p.(Val163Ala) on the maternal allele"
Establishes that the paternal allele carries two variants in cis, not one, which the earlier description omitted.
PMID:31461301 SUPPORT Human Clinical
"Reverse transcription-polymerase chain reaction analysis showed equal amounts of wild-type and mutant products. Hence, no evidence was found for nonsense-mediated decay."
A non-obvious negative result given a premature stop codon - the truncated transcript escapes decay, so truncated protein is produced.
Impaired Tail-Anchored Protein Insertion
GET3/ASNA1 is the central ATP-dependent chaperone that receives tail-anchored proteins from the BAG6/UBL4A/TRC35 pre-targeting complex and delivers them to the WRB/CAML receptor in the endoplasmic reticulum membrane. Losing it both destabilizes that pre-targeting complex and reduces the expression of multiple tail-anchored substrates. Tail-anchored proteins are roughly 5% of integral membrane proteins, which is why a single chaperone defect has such broad downstream consequences.
tail-anchored membrane protein insertion into ER membrane GO:0071816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tail-anchored membrane protein insertion into ER membrane (GO:0071816). GO:0071816 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis Depletion of tail-anchored substrates impairs the vesicular transport machinery those substrates constitute.
Show evidence (1 reference)
PMID:41370295 SUPPORT Model Organism
"ASNA1 (also known as TRC40 or GET3) serves as the central ATP-dependent chaperone delivering TA proteins to the endoplasmic reticulum (ER) membrane."
Identifies the specific molecular role that is lost.
Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
In cardiomyocytes the consequence is disrupted vesicular transport and proteostasis, with compensatory transcriptional upregulation of protein trafficking and Golgi-to-ER transport genes — a maladaptive response rather than a successful rescue.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
vesicle-mediated transport GO:0016192 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vesicle-mediated transport (GO:0016192). GO:0016192 is a biological process from the Gene Ontology. ↓ DECREASED intracellular protein transport GO:0006886 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intracellular protein transport (GO:0006886). GO:0006886 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Cardiomyocyte-specific Asna1 knockout mouse Mouse recapitulates Establishes the cell-autonomous cardiomyocyte mechanism — destabilized pre-targeting complex, depleted tail-anchored substrates, impaired trafficking — that patient tissue could not resolve.
Downstream
Cardiomyocyte Structural Disorganization Failure to insert tail-anchored proteins is expressed structurally, at the intercalated disc and the myofibrillar apparatus.
Impaired Cardiac Contractility and Ventricular Remodeling Loss of cardiomyocyte proteostasis translates into contractile failure and pathological chamber remodeling.
Show evidence (1 reference)
PMID:41370295 SUPPORT Model Organism
"Transcriptomic analyses revealed compensatory upregulation of genes involved in protein trafficking and Golgi-to-ER transport, reflecting maladaptive responses to disrupted vesicular transport."
Documents the disrupted vesicular transport and the maladaptive compensatory response in cardiomyocytes.
Cardiomyocyte Structural Disorganization
The tissue-level correlate of the trafficking defect, and the step the entry previously asserted without one. Intercalated discs are irregular with increased intercellular space on N-cadherin labelling and electron microscopy, desmin staining shows myofibrillar disorganization, and the myocardium carries prominent subendothelial fibrosis. The authors tie the intercalated disc lesion to the same finding in wrb-deficient models and in phospholamban disease, which is what makes it mechanistically specific rather than a non-specific end-stage change.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired Cardiac Contractility and Ventricular Remodeling Disorganized intercalated discs and myofibrils are the structural basis of the contractile failure.
Ventricular septal defect The septal defects are a developmental malformation rather than a sequela of the cardiomyopathy - both were present at birth, before ventricular function declined - so they are drawn from the structural node. How loss of tail-anchored protein targeting disturbs septation is not established.
Atrial septal defect As for the ventricular defect: present at birth and developmental in origin.
Show evidence (2 references)
PMID:31461301 SUPPORT Human Clinical
"Desmin staining confirmed myofibrillar disorganization"
Documents myofibrillar disorganization in patient myocardium.
PMID:31461301 SUPPORT Human Clinical
"Microscopic examination of the myocardium showed prominent subendothelial fibrosis."
Documents the fibrotic change accompanying the structural disorganization.
Impaired Cardiac Contractility and Ventricular Remodeling
Ventricular dilatation with impaired systolic function, documented echocardiographically in both siblings. The developmental requirement is a separate claim and is carried by the mouse model entry rather than folded in here: constitutive cardiomyocyte deletion causes myocardial thinning by embryonic day 16.5, while inducible adult deletion causes dilation without it.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
asna1 loss-of-function zebrafish Zebrafish recapitulates Reproduces the reduced cardiac contractility and lethality of the human disorder, and discriminates patient alleles from wild type: wild-type mRNA rescues the phenotype while either mutant mRNA fails to.
Downstream
Dilated cardiomyopathy
Show evidence (2 references)
PMID:31461301 SUPPORT Model Organism
"Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality."
Establishes reduced cardiac contractility as the organ-level consequence of losing the gene.
PMID:31461301 SUPPORT Human Clinical
"Echocardiography revealed a small muscular ventricular septal defect, an ostium secundum atrial septal defect, and impaired left ventricular (LV) contractility"
The human counterpart of the zebrafish finding, so this node no longer rests on model-organism evidence alone.
✶

Histopathology

3
Prominent subendothelial fibrosis VERY_FREQUENT
Found on microscopic examination of the myocardium at postmortem, alongside increased heart weight relative to body size and severe left ventricular dilatation.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"Microscopic examination of the myocardium showed prominent subendothelial fibrosis."
Reports the fibrotic change in patient myocardium at postmortem.
Irregular intercalated discs with increased intercellular space VERY_FREQUENT
The structurally load-bearing finding. Demonstrated by N-cadherin labelling and electron microscopy in both patients. The authors connect it to the intercalated disc lesion of wrb-deficient models and of phospholamban disease, which makes it the tissue-level correlate of the tail-anchored protein targeting defect rather than a non-specific end-stage change.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"in both patients, intercalated discs were irregular in appearance and intercellular space was increased"
Documents the intercalated disc abnormality in both patients by two independent methods.
Myofibrillar disorganization VERY_FREQUENT
Confirmed by desmin staining in patient myocardium.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"Desmin staining confirmed myofibrillar disorganization"
Records the myofibrillar disorganization on desmin immunostaining.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiomyopathy Dilated 2H Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Blood 1
Left ventricular thrombus FREQUENT HP:0040412 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular thrombus (HP:0040412). HP:0040412 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"a large LV thrombus developed refractory to medical therapy"
Records the intracardiac thrombus and its refractoriness to treatment.
Cardiovascular 5
Dilated cardiomyopathy VERY_FREQUENT HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as course progressive. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Tachypnea Feeding difficulties Left ventricular thrombus Prolonged QRS complex Cardiac arrest
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy."
Reports rapidly progressive dilated cardiomyopathy as the presenting phenotype.
Ventricular septal defect VERY_FREQUENT HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"echocardiography was performed at the first day postpartum showing a small midmuscular ventricular septal defect"
Documents the septal defect in the second sibling on day-one imaging.
Atrial septal defect FREQUENT Secundum atrial septal defect HP:0001684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ostium secundum atrial septal defect, annotated with Secundum atrial septal defect (HP:0001684). HP:0001684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"Echocardiography revealed a small muscular ventricular septal defect, an ostium secundum atrial septal defect, and impaired left ventricular (LV) contractility"
Reports both septal defects together with the contractile impairment in the proband.
Prolonged QRS complex FREQUENT HP:0006677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad QRS complexes, annotated with Prolonged QRS complex (HP:0006677). HP:0006677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"ECG recordings showed sinus rhythm with broad QRS complexes (range 124–264 ms; Figure IVA in the Data Supplement)."
Documents the conduction abnormality on ECG.
Cardiac arrest VERY_FREQUENT HP:0001695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac arrest (HP:0001695). HP:0001695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"After rapid clinical deterioration with brief circulatory arrest, she was transferred to a tertiary referral hospital for extracorporeal membrane oxygenation."
Records the circulatory arrest in the proband.
Digestive 1
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"At age 2 weeks, she presented with severe tachypnea and feeding difficulties."
Records feeding difficulty at presentation.
Respiratory 1
Tachypnea VERY_FREQUENT HP:0002789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachypnea (HP:0002789). HP:0002789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"At age 2 weeks, she presented with severe tachypnea and feeding difficulties."
Records tachypnea as a presenting feature.
🧬

Genetic Associations

2
GET3
Gene: GET3 hgnc:752 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GET3 (hgnc:752). hgnc:752 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"The c.488T>C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala)."
Specifies the maternal missense allele in the index sibship.
GET3 heterozygous modifier candidate
Gene: GET3 hgnc:752 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GET3 (hgnc:752). hgnc:752 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31461301 SUPPORT INDIRECT Human Clinical
"it cannot be excluded that this ASNA1 variant acted as a modifier of the LMNA-related cardiomyopathy"
The authors' own hedged statement. Indirect and deliberately weak - the variant is predicted benign and the claim is a non-exclusion, not a finding.
💊

Medical Actions

4
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Autosomal recessive inheritance carries a 25% recurrence risk for the parents, which is not hypothetical here: the second affected child was identified because of the family history, with echocardiography performed on the first day of life. Preimplantation or prenatal testing and cascade carrier testing follow from the molecular diagnosis.
Show evidence (2 references)
PMID:31461301 SUPPORT Human Clinical
"Because of the family history, echocardiography was performed at the first day postpartum"
Shows the recurrence risk being acted on clinically - the sibling was screened at birth on the strength of the family history.
PMID:20301486 SUPPORT Other
"relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome"
States the purpose of genetic risk assessment of at-risk relatives, which is the cascade-testing and surveillance limb of the counselling offered here.
Supportive Heart Failure Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
No disease-directed therapy exists. Management is the standard supportive care of infantile dilated cardiomyopathy - diuretics, inotropes and mechanical support. Both reported patients died in early infancy.
Mechanism Target:
Impaired Cardiac Contractility and Ventricular Remodeling — Diuretics and inotropes act on the consequences of contractile failure; nothing available addresses the targeting defect upstream of it.
Extracorporeal Membrane Oxygenation
Action: extracorporeal membrane oxygenationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is extracorporeal membrane oxygenation (NCIT:C171507). NCIT:C171507 is a clinical intervention from the NCI Thesaurus. Ontology label: Extracorporeal Membrane Oxygenation NCIT:C171507
Platform: Device
The proband was transferred for ECMO after rapid deterioration with brief circulatory arrest. It did not alter the course: left ventricular function remained poor, a refractory intracardiac thrombus developed, and she died at seven weeks. Recorded because it was actually administered and because its failure is part of the prognosis.
Mechanism Target:
Impaired Cardiac Contractility and Ventricular Remodeling — Mechanical circulatory support substitutes for failing contractility; it does not address the underlying targeting defect.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"she was transferred to a tertiary referral hospital for extracorporeal membrane oxygenation. LV function remained poor without any signs of improvement"
Records that ECMO was administered and that ventricular function did not improve on it.
Heart Transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Platform: Surgery
The definitive option for end-stage infantile dilated cardiomyopathy and the endpoint that mechanical support bridges to. Recorded as the escalation target for this entry's terminal node, not as a therapy either reported patient received: the proband died at seven weeks on ECMO having never reached candidacy, and her sister died at twelve days. Whether transplant is reachable in GET3 disease is therefore genuinely unknown rather than answered negatively - the two known patients deteriorated too fast to test it.
Mechanism Target:
Impaired Cardiac Contractility and Ventricular Remodeling — Replaces the failing myocardium outright; the only option here that removes the diseased tissue rather than compensating for its loss of function.
🔬

Biochemical Markers

1
Serum transferrin and apolipoprotein C-III isoelectric focusing (Slightly abnormal)
Pathograph Readouts
Correlates With Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis Present Absent
A combined N- and O-linked glycosylation pattern, which the authors suggest may report on defective membrane targeting of tail-anchored proteins involved in vesicular trafficking and exocytosis - though they are explicit that the profiles were only slightly abnormal and should not necessarily be considered pathogenic.
Show evidence (1 reference)
PMID:31461301 SUPPORT INDIRECT Human Clinical
"slightly abnormal serum transferrin and apolipoprotein C-III isoelectric focusing profiles, indicative of a combined defect in N-linked and O-linked glycosylation"
The measurement itself; indirect as a readout of the trafficking node because the authors present the link as possible rather than established.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"slightly abnormal serum transferrin and apolipoprotein C-III isoelectric focusing profiles, indicative of a combined defect in N-linked and O-linked glycosylation"
Reports the glycosylation abnormality in both siblings.
🔬

Diagnosis

1
Negative targeted cardiomyopathy gene panel followed by exome sequencing
Clinically actionable and stated outright in the source: a 48-gene targeted cardiomyopathy panel returned no deleterious variants, and the diagnosis was made only on subsequent trio exome sequencing. A negative panel in infantile dilated cardiomyopathy should therefore prompt exome or genome sequencing rather than closing the workup.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31461301 SUPPORT Human Clinical
"Targeted next-generation sequencing of 48 genes implicated in cardiomyopathy revealed no potentially deleterious variants."
Establishes that the standard cardiomyopathy panel does not detect this disorder.
PMID:20301486 SUPPORT Other
"Provide the evaluation strategy of a proband with nonsyndromic DCM"
The GeneReviews overview sets out the proband evaluation strategy for nonsyndromic dilated cardiomyopathy, which is the workup CMD2H presents into and which the negative panel here interrupts.
📈

Progression

1
Early infancy
Age: first year of life
Rapidly progressive dilated cardiomyopathy from early infancy to death within the first year in both reported siblings. No survivor beyond infancy has been described.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy"
Establishes the tempo and outcome of the disease course.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Two siblings in one family. The authors screened 70 children with idiopathic cardiomyopathy and a 19,144-patient diagnostic database and found no further biallelic cases, so the entity is genuinely vanishingly rare rather than merely newly described.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"However, no additional patients were identified"
Records the negative result of the large-cohort search for further cases.
⚖️

Clinical Burden

High
Uniformly fatal in early infancy in the only reported patients, with no disease-directed therapy available.
Show evidence (1 reference)
PMID:31461301 SUPPORT Human Clinical
"Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death."
States the severity and outcome underpinning this burden level.
🐁

Animal Models

2
asna1 loss-of-function zebrafish
Loss of asna1 in zebrafish, used both to establish that the gene is required for cardiac function and, through mRNA rescue, to prove that the patient alleles are functionally deficient.
Species
Zebrafish
Genotype
asna1 loss of function
Publication
PMID:31461301
Pathograph links
Impaired Cardiac Contractility and Ventricular Remodeling recapitulates fidelity: moderate Reproduces the reduced cardiac contractility and lethality of the human disorder, and discriminates patient alleles from wild type: wild-type mRNA rescues the phenotype while either mutant mRNA fails to.
Limitations: A whole-organism knockdown/knockout rather than the human compound heterozygous state, and the zebrafish heart is two-chambered, so ventricular dilatation as seen in human DCM is not directly modeled.
Readouts
Cardiac contractility after mutant versus wild-type mRNA injection
Direction: DECREASED
Interpretation: Wild-type mRNA rescues contractility and lethality; neither patient allele does, which is the functional evidence that both alleles are pathogenic.
Show evidence (1 reference)
PMID:31461301 SUPPORT Model Organism
"In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype."
Reports the rescue experiment discriminating patient alleles from wild type.
Show evidence (1 reference)
PMID:31461301 SUPPORT Model Organism
"Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality."
Establishes the zebrafish model as informative for the cardiac contractility node.
Cardiomyocyte-specific Asna1 knockout mouse
Constitutive and inducible cardiomyocyte-restricted Asna1 deletion. The pair separates a developmental requirement from a maintenance requirement: constitutive deletion causes perinatal lethality with ventricular myocardial thinning by E16.5, while inducible deletion in the adult heart causes rapid dilation and functional decline.
Species
Mouse
Genotype
Cardiomyocyte-specific Asna1 knockout (constitutive and inducible)
Publication
PMID:41370295
Pathograph links
Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis recapitulates fidelity: high Establishes the cell-autonomous cardiomyocyte mechanism — destabilized pre-targeting complex, depleted tail-anchored substrates, impaired trafficking — that patient tissue could not resolve.
Limitations: A complete cardiomyocyte-restricted null rather than the human compound heterozygous genotype, one allele of which is a hypomorphic missense, so the model is more severe than the human lesion and says nothing about residual GET3 function.
Readouts
Ventricular myocardial wall thickness at E16.5
Direction: DECREASED
Interpretation: Marked ventricular myocardial thinning during embryogenesis shows the pathway is required for normal myocardial development.
Show evidence (1 reference)
PMID:41370295 SUPPORT Model Organism
"Constitutive Asna1 deletion during embryogenesis caused perinatal lethality with marked ventricular myocardial thinning by embryonic day 16.5"
Reports the developmental myocardial measurement in the constitutive knockout.
Show evidence (1 reference)
PMID:41370295 SUPPORT Model Organism
"we generated constitutive and inducible cardiomyocyte-specific Asna1 knockout mouse models"
Identifies the model system used to establish the cardiomyocyte-autonomous mechanism.
{ }

Source YAML

click to show 
name: Cardiomyopathy Dilated 2H
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  Dilated cardiomyopathy 2H (CMD2H) is an autosomal recessive, early
  infantile-onset cardiomyopathy caused by biallelic variants in GET3 (long
  known as ASNA1, and also called TRC40). It is mechanistically unlike most
  familial dilated cardiomyopathy: the causal gene encodes no sarcomeric or
  cytoskeletal protein but the central ATP-dependent chaperone of the GET/TRC
  pathway, which inserts tail-anchored proteins post-translationally into the
  endoplasmic reticulum membrane. Loss of that targeting factor destabilizes the
  pre-targeting complex, depletes a broad set of tail-anchored substrates, and
  disrupts membrane trafficking and cardiomyocyte proteostasis. The clinical
  course is rapidly progressive dilated cardiomyopathy with death in early
  infancy. It was the first evidence that the tail-anchored protein insertion
  pathway causes human disease.
synonyms:
- CMD2H
- ASNA1-related cardiomyopathy
- GET3-related dilated cardiomyopathy
parents:
- hereditary disease
- familial isolated dilated cardiomyopathy
disease_term:
  preferred_term: cardiomyopathy, dilated, 2H
  term:
    id: MONDO:0859358
    label: cardiomyopathy, dilated, 2H

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Compound heterozygous GET3 variants inherited in trans, identified in a
    sibling pair by family-based exome sequencing.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified compound heterozygous variants in the highly conserved ASNA1 gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins."
    explanation: Compound heterozygous inheritance of two GET3/ASNA1 alleles establishes the recessive mode.

pathophysiology:
- name: Biallelic GET3 Loss of Function
  description: >-
    Three variants across two alleles, not two. The paternal allele carries
    c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*) in cis; the maternal allele
    carries c.488T>C p.(Val163Ala). The cis pairing matters mechanistically:
    Cys289 is part of an essential zinc-binding site, so the paternal allele is
    doubly compromised rather than simply truncated. Reduced protein abundance
    was demonstrated directly in patient myocardium and skin fibroblasts. The
    maternal missense allele leaves protein present but misfolded. Notably the
    premature stop codon does not trigger nonsense-mediated decay - wild-type
    and mutant transcripts were present in equal amounts - so the truncated
    protein is made.
  biological_scale: MOLECULAR
  downstream:
  - target: Impaired Tail-Anchored Protein Insertion
    causal_link_type: DIRECT
    description: >-
      Both alleles converge on the same functional endpoint, which was measured
      directly in an in vitro tail-anchored protein insertion assay.
    evidence:
    - reference: PMID:31461301
      reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies showed that this variant leads to protein misfolding as well as less effective tail-anchored protein insertion."
      explanation: Directly links the patient missense allele to reduced tail-anchored protein insertion in a functional assay.
  genetic_context:
    zygosity: COMPOUND_HETEROZYGOUS
    variant_origin: GERMLINE
    allele_type: nonsense and missense
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Three variants across two alleles: c.867C>G p.(Cys289Trp) and c.913C>T
      p.(Gln305*) in cis on the paternal allele, c.488T>C p.(Val163Ala) on the
      maternal. The premature stop escapes nonsense-mediated decay, so truncated
      protein is made rather than cleared.
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.913C>T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts."
    explanation: Documents reduced GET3/ASNA1 protein in patient heart and fibroblasts attributable to the nonsense allele.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 variants c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*) in cis configuration on the paternal allele, and a missense variant c.488T>C p.(Val163Ala) on the maternal allele"
    explanation: Establishes that the paternal allele carries two variants in cis, not one, which the earlier description omitted.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reverse transcription-polymerase chain reaction analysis showed equal amounts of wild-type and mutant products. Hence, no evidence was found for nonsense-mediated decay."
    explanation: A non-obvious negative result given a premature stop codon - the truncated transcript escapes decay, so truncated protein is produced.

- name: Impaired Tail-Anchored Protein Insertion
  description: >-
    GET3/ASNA1 is the central ATP-dependent chaperone that receives tail-anchored
    proteins from the BAG6/UBL4A/TRC35 pre-targeting complex and delivers them to
    the WRB/CAML receptor in the endoplasmic reticulum membrane. Losing it both
    destabilizes that pre-targeting complex and reduces the expression of
    multiple tail-anchored substrates. Tail-anchored proteins are roughly 5% of
    integral membrane proteins, which is why a single chaperone defect has such
    broad downstream consequences.
  biological_scale: MOLECULAR
  downstream:
  - target: Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
    causal_link_type: DIRECT
    description: >-
      Depletion of tail-anchored substrates impairs the vesicular transport
      machinery those substrates constitute.
    evidence:
    - reference: PMID:41370295
      reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ASNA1 deficiency destabilized the pre-targeting complex and reduced the expression of multiple TA protein substrates, impairing membrane trafficking and protein transport."
      explanation: States the causal step from lost targeting factor to impaired membrane trafficking.
  biological_processes:
  - preferred_term: tail-anchored membrane protein insertion into ER membrane
    term:
      id: GO:0071816
      label: tail-anchored membrane protein insertion into ER membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:41370295
    reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ASNA1 (also known as TRC40 or GET3) serves as the central ATP-dependent chaperone delivering TA proteins to the endoplasmic reticulum (ER) membrane."
    explanation: Identifies the specific molecular role that is lost.

- name: Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
  description: >-
    In cardiomyocytes the consequence is disrupted vesicular transport and
    proteostasis, with compensatory transcriptional upregulation of protein
    trafficking and Golgi-to-ER transport genes — a maladaptive response rather
    than a successful rescue.
  biological_scale: CELLULAR
  downstream:
  - target: Cardiomyocyte Structural Disorganization
    causal_link_type: DIRECT
    description: >-
      Failure to insert tail-anchored proteins is expressed structurally, at the
      intercalated disc and the myofibrillar apparatus.
    evidence:
    - reference: PMID:31461301
      reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in both patients, intercalated discs were irregular in appearance and intercellular space was increased"
      explanation: The structural lesion observed in patient myocardium, downstream of the trafficking defect.
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Loss of cardiomyocyte proteostasis translates into contractile failure and
      pathological chamber remodeling.
    evidence:
    - reference: PMID:41370295
      reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "inducible deletion in adult cardiomyocytes led to rapid ventricular dilation, impaired cardiac function, pathological remodeling, and early mortality"
      explanation: Cardiomyocyte-restricted deletion is sufficient to produce dilation and contractile failure, establishing the cell-autonomous link.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: vesicle-mediated transport
    term:
      id: GO:0016192
      label: vesicle-mediated transport
    modifier: DECREASED
  - preferred_term: intracellular protein transport
    term:
      id: GO:0006886
      label: intracellular protein transport
    modifier: DECREASED
  evidence:
  - reference: PMID:41370295
    reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transcriptomic analyses revealed compensatory upregulation of genes involved in protein trafficking and Golgi-to-ER transport, reflecting maladaptive responses to disrupted vesicular transport."
    explanation: Documents the disrupted vesicular transport and the maladaptive compensatory response in cardiomyocytes.

- name: Cardiomyocyte Structural Disorganization
  description: >-
    The tissue-level correlate of the trafficking defect, and the step the
    entry previously asserted without one. Intercalated discs are irregular with
    increased intercellular space on N-cadherin labelling and electron
    microscopy, desmin staining shows myofibrillar disorganization, and the
    myocardium carries prominent subendothelial fibrosis. The authors tie the
    intercalated disc lesion to the same finding in wrb-deficient models and in
    phospholamban disease, which is what makes it mechanistically specific
    rather than a non-specific end-stage change.
  biological_scale: TISSUE
  downstream:
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Disorganized intercalated discs and myofibrils are the structural basis of
      the contractile failure.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The septal defects are a developmental malformation rather than a sequela
      of the cardiomyopathy - both were present at birth, before ventricular
      function declined - so they are drawn from the structural node. How loss
      of tail-anchored protein targeting disturbs septation is not established.
  - target: Atrial septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      As for the ventricular defect: present at birth and developmental in
      origin.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Desmin staining confirmed myofibrillar disorganization"
    explanation: Documents myofibrillar disorganization in patient myocardium.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microscopic examination of the myocardium showed prominent subendothelial fibrosis."
    explanation: Documents the fibrotic change accompanying the structural disorganization.

- name: Impaired Cardiac Contractility and Ventricular Remodeling
  description: >-
    Ventricular dilatation with impaired systolic function, documented
    echocardiographically in both siblings. The developmental requirement is a
    separate claim and is carried by the mouse model entry rather than folded in
    here: constitutive cardiomyocyte deletion causes myocardial thinning by
    embryonic day 16.5, while inducible adult deletion causes dilation without
    it.
  biological_scale: ORGANISM
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality."
    explanation: Establishes reduced cardiac contractility as the organ-level consequence of losing the gene.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography revealed a small muscular ventricular septal defect, an ostium secundum atrial septal defect, and impaired left ventricular (LV) contractility"
    explanation: >-
      The human counterpart of the zebrafish finding, so this node no longer
      rests on model-organism evidence alone.

phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Rapidly progressive dilated cardiomyopathy with onset in early infancy —
    ventricular dilatation with impaired systolic function.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Tachypnea
    description: >-
      Presenting symptom of the heart failure in both siblings.
  - target: Feeding difficulties
    description: >-
      Accompanied the tachypnea at presentation.
  - target: Left ventricular thrombus
    description: >-
      Developed in the dilated, poorly contractile ventricle during ECMO and was
      refractory to medical therapy.
  - target: Prolonged QRS complex
    description: >-
      Conduction abnormality accompanying the cardiomyopathy.
  - target: Cardiac arrest
    description: >-
      The proband arrested during the rapid deterioration that took her to ECMO.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy."
    explanation: Reports rapidly progressive dilated cardiomyopathy as the presenting phenotype.

- category: Cardiovascular
  name: Ventricular septal defect
  description: >-
    Present in both siblings - a small muscular VSD in the proband and a small
    midmuscular VSD in her sister, detected on day-one echocardiography.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "echocardiography was performed at the first day postpartum showing a small midmuscular ventricular septal defect"
    explanation: Documents the septal defect in the second sibling on day-one imaging.

- category: Cardiovascular
  name: Atrial septal defect
  description: >-
    An ostium secundum atrial septal defect in the proband, alongside the
    ventricular septal defect and impaired left ventricular contractility.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ostium secundum atrial septal defect
    term:
      id: HP:0001684
      label: Secundum atrial septal defect
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography revealed a small muscular ventricular septal defect, an ostium secundum atrial septal defect, and impaired left ventricular (LV) contractility"
    explanation: Reports both septal defects together with the contractile impairment in the proband.

- category: Respiratory
  name: Tachypnea
  description: >-
    Presenting symptom in both siblings - at two weeks in the proband, and at one
    week in her sister.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 2 weeks, she presented with severe tachypnea and feeding difficulties."
    explanation: Records tachypnea as a presenting feature.

- category: Gastrointestinal
  name: Feeding difficulties
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 2 weeks, she presented with severe tachypnea and feeding difficulties."
    explanation: Records feeding difficulty at presentation.

- category: Cardiovascular
  name: Prolonged QRS complex
  description: >-
    Broad QRS complexes ranging 124-264 ms on ECG in the proband.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Broad QRS complexes
    term:
      id: HP:0006677
      label: Prolonged QRS complex
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECG recordings showed sinus rhythm with broad QRS complexes (range 124–264 ms; Figure IVA in the Data Supplement)."
    explanation: Documents the conduction abnormality on ECG.

- category: Cardiovascular
  name: Cardiac arrest
  description: >-
    Documented in both siblings - a brief circulatory arrest in the proband
    preceding transfer for ECMO, and a terminal cardiorespiratory arrest in her
    sister after which resuscitation was stopped at twenty minutes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After rapid clinical deterioration with brief circulatory arrest, she was transferred to a tertiary referral hospital for extracorporeal membrane oxygenation."
    explanation: Records the circulatory arrest in the proband.

- category: Cardiovascular
  name: Left ventricular thrombus
  description: >-
    A large left ventricular thrombus developed in the proband during
    extracorporeal membrane oxygenation and was refractory to medical therapy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Left ventricular thrombus
    term:
      id: HP:0040412
      label: Left ventricular thrombus
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a large LV thrombus developed refractory to medical therapy"
    explanation: Records the intracardiac thrombus and its refractoriness to treatment.

biochemical:
- name: Serum transferrin and apolipoprotein C-III isoelectric focusing
  biomarker_term:
    preferred_term: combined N-linked and O-linked glycosylation defect
    term:
      id: HP:0003160
      label: Abnormal isoelectric focusing of serum transferrin
  presence: Slightly abnormal
  readouts:
  - target: Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
    relationship: CORRELATES_WITH
    direction: PRESENT_ABSENT
    description: >-
      Serum transferrin and apolipoprotein C-III isoelectric focusing profile.
    interpretation: >-
      A combined N- and O-linked glycosylation pattern, which the authors
      suggest may report on defective membrane targeting of tail-anchored
      proteins involved in vesicular trafficking and exocytosis - though they
      are explicit that the profiles were only slightly abnormal and should not
      necessarily be considered pathogenic.
    evidence:
    - reference: PMID:31461301
      reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "slightly abnormal serum transferrin and apolipoprotein C-III isoelectric focusing profiles, indicative of a combined defect in N-linked and O-linked glycosylation"
      explanation: The measurement itself; indirect as a readout of the trafficking node because the authors present the link as possible rather than established.
  notes: >-
    Both siblings had slightly abnormal transferrin and apolipoprotein C-III
    isoelectric focusing profiles, indicating a combined N- and O-linked
    glycosylation defect. The authors suggest this may be a readout of the same
    lesion the pathograph describes - several trafficking and exocytosis
    components are tail-anchored proteins that depend on GET3 for membrane
    insertion - but they are explicit that because the profiles were only
    slightly abnormal, the results should not necessarily be considered
    pathogenic. Recorded at that strength. Note that a combined N- and O-linked
    pattern is not the type I profile of an N-glycan assembly defect, which is
    why the binding is the general transferrin isoelectric focusing term rather
    than a type I one.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "slightly abnormal serum transferrin and apolipoprotein C-III isoelectric focusing profiles, indicative of a combined defect in N-linked and O-linked glycosylation"
    explanation: Reports the glycosylation abnormality in both siblings.

histopathology:
- name: Prominent subendothelial fibrosis
  finding_term:
    preferred_term: prominent subendothelial fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  description: >-
    Found on microscopic examination of the myocardium at postmortem, alongside
    increased heart weight relative to body size and severe left ventricular
    dilatation.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microscopic examination of the myocardium showed prominent subendothelial fibrosis."
    explanation: Reports the fibrotic change in patient myocardium at postmortem.

- name: Irregular intercalated discs with increased intercellular space
  description: >-
    The structurally load-bearing finding. Demonstrated by N-cadherin labelling
    and electron microscopy in both patients. The authors connect it to the
    intercalated disc lesion of wrb-deficient models and of phospholamban
    disease, which makes it the tissue-level correlate of the tail-anchored
    protein targeting defect rather than a non-specific end-stage change.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in both patients, intercalated discs were irregular in appearance and intercellular space was increased"
    explanation: Documents the intercalated disc abnormality in both patients by two independent methods.

- name: Myofibrillar disorganization
  description: >-
    Confirmed by desmin staining in patient myocardium.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Desmin staining confirmed myofibrillar disorganization"
    explanation: Records the myofibrillar disorganization on desmin immunostaining.

diagnosis:
- name: Negative targeted cardiomyopathy gene panel followed by exome sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Clinically actionable and stated outright in the source: a 48-gene targeted
    cardiomyopathy panel returned no deleterious variants, and the diagnosis was
    made only on subsequent trio exome sequencing. A negative panel in infantile
    dilated cardiomyopathy should therefore prompt exome or genome sequencing
    rather than closing the workup.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted next-generation sequencing of 48 genes implicated in cardiomyopathy revealed no potentially deleterious variants."
    explanation: Establishes that the standard cardiomyopathy panel does not detect this disorder.
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews overview sets out the proband evaluation strategy for
      nonsyndromic dilated cardiomyopathy, which is the workup CMD2H presents
      into and which the negative panel here interrupts.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two siblings in one family. The authors screened 70 children with idiopathic
    cardiomyopathy and a 19,144-patient diagnostic database and found no further
    biallelic cases, so the entity is genuinely vanishingly rare rather than
    merely newly described.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, no additional patients were identified"
    explanation: Records the negative result of the large-cohort search for further cases.

progression:
- phase: Early infancy
  age_range: first year of life
  notes: >-
    Rapidly progressive dilated cardiomyopathy from early infancy to death
    within the first year in both reported siblings. No survivor beyond infancy
    has been described.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy"
    explanation: Establishes the tempo and outcome of the disease course.

clinical_burden:
  burden_level: HIGH
  rationale: >-
    Uniformly fatal in early infancy in the only reported patients, with no
    disease-directed therapy available.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death."
    explanation: States the severity and outcome underpinning this burden level.

genetic:
- name: GET3
  notes: >-
    Biallelic variants in GET3 (HGNC-approved symbol; long known as ASNA1 and
    also called TRC40), encoding the central ATP-dependent targeting factor of
    the GET/TRC tail-anchored protein insertion pathway. The reported genotype is
    three variants across two alleles, not two: c.867C>G p.(Cys289Trp) and
    c.913C>T p.(Gln305*) in cis on the paternal allele, and c.488T>C
    p.(Val163Ala) on the maternal allele. The cis pairing matters - Cys289 is
    part of an essential zinc-binding site, so the paternal allele is doubly
    compromised rather than simply truncated. All three were absent from gnomAD
    v2.0.2, and the index paper cites a pLI of 0.92 from that release as evidence
    of loss-of-function intolerance. Treat that number as version-bound: current
    gnomAD gives a much lower pLI for this gene, so the constraint estimate has
    moved between releases and only the v2.0.2 value should be attributed to the
    paper. Note that the entire published human literature uses the ASNA1 symbol.
  gene_term:
    preferred_term: GET3
    term:
      id: hgnc:752
      label: GET3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.488T>C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala)."
    explanation: Specifies the maternal missense allele in the index sibship.

- name: GET3 heterozygous modifier candidate
  notes: >-
    A single heterozygous c.547G>A p.(Val183Met) ASNA1 variant was found in an
    unrelated patient with LMNA-related dilated cardiomyopathy who needed
    transplantation at 16. In-silico predictors call it tolerated or likely
    benign and no second allele was found, so this is not a second case of
    CMD2H. The authors raise it only as a possible modifier of the LMNA disease,
    and it is recorded here at that strength and no more.
  gene_term:
    preferred_term: GET3
    term:
      id: hgnc:752
      label: GET3
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "it cannot be excluded that this ASNA1 variant acted as a modifier of the LMNA-related cardiomyopathy"
    explanation: >-
      The authors' own hedged statement. Indirect and deliberately weak - the
      variant is predicted benign and the claim is a non-exclusion, not a
      finding.

animal_models:
- name: asna1 loss-of-function zebrafish
  species: Zebrafish
  genotype: asna1 loss of function
  publication: PMID:31461301
  description: >-
    Loss of asna1 in zebrafish, used both to establish that the gene is required
    for cardiac function and, through mRNA rescue, to prove that the patient
    alleles are functionally deficient.
  modeled_mechanisms:
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the reduced cardiac contractility and lethality of the human
      disorder, and discriminates patient alleles from wild type: wild-type mRNA
      rescues the phenotype while either mutant mRNA fails to.
    limitations: >-
      A whole-organism knockdown/knockout rather than the human compound
      heterozygous state, and the zebrafish heart is two-chambered, so ventricular
      dilatation as seen in human DCM is not directly modeled.
    readouts:
    - name: Cardiac contractility after mutant versus wild-type mRNA injection
      target: Impaired Cardiac Contractility and Ventricular Remodeling
      direction: DECREASED
      interpretation: >-
        Wild-type mRNA rescues contractility and lethality; neither patient
        allele does, which is the functional evidence that both alleles are
        pathogenic.
      evidence:
      - reference: PMID:31461301
        reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype."
        explanation: Reports the rescue experiment discriminating patient alleles from wild type.
    evidence:
    - reference: PMID:31461301
      reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality."
      explanation: Establishes the zebrafish model as informative for the cardiac contractility node.

- name: Cardiomyocyte-specific Asna1 knockout mouse
  species: Mouse
  genotype: Cardiomyocyte-specific Asna1 knockout (constitutive and inducible)
  publication: PMID:41370295
  description: >-
    Constitutive and inducible cardiomyocyte-restricted Asna1 deletion. The pair
    separates a developmental requirement from a maintenance requirement:
    constitutive deletion causes perinatal lethality with ventricular myocardial
    thinning by E16.5, while inducible deletion in the adult heart causes rapid
    dilation and functional decline.
  modeled_mechanisms:
  - target: Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Establishes the cell-autonomous cardiomyocyte mechanism — destabilized
      pre-targeting complex, depleted tail-anchored substrates, impaired
      trafficking — that patient tissue could not resolve.
    limitations: >-
      A complete cardiomyocyte-restricted null rather than the human compound
      heterozygous genotype, one allele of which is a hypomorphic missense, so
      the model is more severe than the human lesion and says nothing about
      residual GET3 function.
    readouts:
    - name: Ventricular myocardial wall thickness at E16.5
      target: Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
      direction: DECREASED
      interpretation: >-
        Marked ventricular myocardial thinning during embryogenesis shows the
        pathway is required for normal myocardial development.
      evidence:
      - reference: PMID:41370295
        reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Constitutive Asna1 deletion during embryogenesis caused perinatal lethality with marked ventricular myocardial thinning by embryonic day 16.5"
        explanation: Reports the developmental myocardial measurement in the constitutive knockout.
    evidence:
    - reference: PMID:41370295
      reference_title: "ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we generated constitutive and inducible cardiomyocyte-specific Asna1 knockout mouse models"
      explanation: Identifies the model system used to establish the cardiomyocyte-autonomous mechanism.

treatments:
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance carries a 25% recurrence risk for the
    parents, which is not hypothetical here: the second affected child was
    identified because of the family history, with echocardiography performed on
    the first day of life. Preimplantation or prenatal testing and cascade
    carrier testing follow from the molecular diagnosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the family history, echocardiography was performed at the first day postpartum"
    explanation: >-
      Shows the recurrence risk being acted on clinically - the sibling was
      screened at birth on the strength of the family history.
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome
    explanation: >-
      States the purpose of genetic risk assessment of at-risk relatives, which
      is the cascade-testing and surveillance limb of the counselling offered
      here.

- name: Supportive Heart Failure Management
  description: >-
    No disease-directed therapy exists. Management is the standard supportive
    care of infantile dilated cardiomyopathy - diuretics, inotropes and
    mechanical support. Both reported patients died in early infancy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    description: >-
      Diuretics and inotropes act on the consequences of contractile failure;
      nothing available addresses the targeting defect upstream of it.

- name: Extracorporeal Membrane Oxygenation
  description: >-
    The proband was transferred for ECMO after rapid deterioration with brief
    circulatory arrest. It did not alter the course: left ventricular function
    remained poor, a refractory intracardiac thrombus developed, and she died at
    seven weeks. Recorded because it was actually administered and because its
    failure is part of the prognosis.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: extracorporeal membrane oxygenation
    term:
      id: NCIT:C171507
      label: Extracorporeal Membrane Oxygenation
  target_mechanisms:
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    description: >-
      Mechanical circulatory support substitutes for failing contractility; it
      does not address the underlying targeting defect.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she was transferred to a tertiary referral hospital for extracorporeal membrane oxygenation. LV function remained poor without any signs of improvement"
    explanation: Records that ECMO was administered and that ventricular function did not improve on it.

- name: Heart Transplantation
  therapeutic_modality: SURGERY
  description: >-
    The definitive option for end-stage infantile dilated cardiomyopathy and the
    endpoint that mechanical support bridges to. Recorded as the escalation
    target for this entry's terminal node, not as a therapy either reported
    patient received: the proband died at seven weeks on ECMO having never
    reached candidacy, and her sister died at twelve days. Whether transplant is
    reachable in GET3 disease is therefore genuinely unknown rather than
    answered negatively - the two known patients deteriorated too fast to test
    it.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Impaired Cardiac Contractility and Ventricular Remodeling
    description: >-
      Replaces the failing myocardium outright; the only option here that
      removes the diseased tissue rather than compensating for its loss of
      function.
  notes: >-
    Deliberately unevidenced; no GET3/ASNA1-specific transplantation outcomes
    are reported. Follows the convention used by the numbered-series peers
    Dilated_Cardiomyopathy_1EE and Dilated_Cardiomyopathy_1A.

discussions:
- discussion_id: which_ta_substrate_drives_the_heart_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which tail-anchored protein substrates, among the many depleted by GET3
    loss, actually account for the cardiac phenotype?
  attaches_to:
  - pathophysiology#Impaired Tail-Anchored Protein Insertion
  - pathophysiology#Disrupted Cardiomyocyte Membrane Trafficking and Proteostasis
  rationale: >-
    The index paper narrows this considerably: inspecting the predicted human
    tail-anchored proteome it names seven already associated with human
    cardiomyopathy - DMPK, DYSF, EMD, JPH2, PLN (printed as PPLA in the source),
    SYNE1 and SYNE2. So the gap is
    not that no candidates exist but which of that shortlist is rate-limiting.
    There is also a partial negative result to work against: emerin localized
    correctly to the nuclear membrane in patient myocardium, though nuclei were
    irregularly shaped, which argues against emerin mislocalization being the
    proximate lesion. Tail-anchored proteins are roughly 5% of integral membrane
    proteins and the mouse work reports reduced expression of multiple substrates
    collectively, so the shortlist is where the question becomes tractable.
  evidence:
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed 7 proteins of interest that have been associated with cardiomyopathy in humans: DMPK (myotonin-protein kinase; Q09013), DYSF (dysferlin; O75923), EMD (emerin; P50402), JPH2 (junctophilin-2; Q9BR39), PPLA (cardiac phospholamban; P26678), SYNE1 (nesprin-1; Q8NF91), and SYNE2 (nesprin-2; Q8WXH0)."
    explanation: Names the candidate tail-anchored substrates, which is what makes this gap actionable rather than open-ended.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Emerin correctly localized to the nuclear membrane."
    explanation: Refutes emerin mislocalization as the proximate lesion, narrowing the candidate shortlist.

- discussion_id: cardiac_selectivity_of_a_ubiquitous_chaperone
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does loss of a ubiquitously expressed chaperone present as isolated
    dilated cardiomyopathy rather than a multisystem disorder?
  attaches_to:
  - pathophysiology#Biallelic GET3 Loss of Function
  rationale: >-
    Only two patients, siblings, have been reported, and both died in early
    infancy — so the apparent cardiac selectivity may be real tissue
    vulnerability or may simply reflect that the heart fails first. There is a
    concrete mechanistic proposal to test: the endoplasmic reticulum membrane
    complex provides an alternative insertion route for moderately hydrophobic
    tail-anchored substrates, so tissues could differ in how much they depend on
    GET3 specifically. Against pure cardiac selectivity, model organisms show
    extra-cardiac deficits including visual, touch, otoferlin-dependent hearing
    and insulin-secretion phenotypes; the two siblings passed newborn hearing
    screening, but neither survived long enough for later-onset deficits to
    declare themselves. Additional patients surviving longer would resolve it.

- discussion_id: human_model_severity_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do complete-null animal models over-represent the severity of the human
    compound heterozygous genotype, in which one allele is a missense that
    leaves misfolded protein present?
  attaches_to:
  - animal_models#Mouse
  - animal_models#Zebrafish
  - pathophysiology#Biallelic GET3 Loss of Function
  rationale: >-
    Both the zebrafish and mouse models are effectively null and both are
    lethal, whereas the human genotype pairs a nonsense allele with a
    p.(Val163Ala) missense allele that still produces protein, albeit misfolded
    and insertion-deficient. Whether residual hypomorphic activity modifies the
    human course cannot be addressed in a null model, and no patient with a
    milder allele combination has been reported to test it against.

notes: >-
  GeneReviews scope. The applicable GeneReviews resource is the disease-level
  "Dilated Cardiomyopathy Overview" (PMID:20301486). There is no ASNA1/GET3-specific
  chapter, and there is unlikely to be one: CMD2H is a single two-patient report
  from 2019, and GeneReviews chapters in this space are gene-specific. The cached
  PubMed record is content_type abstract_only, so the Clinical Characteristics,
  Management and Genetic Counseling sections are not available to mine - but the
  purpose statement that is cached carries two propositions that do apply here,
  and both are quoted: the proband evaluation strategy, on the exome-sequencing
  diagnosis entry, and the genetic risk assessment of at-risk relatives, on
  genetic counselling. An earlier draft of this note concluded from the
  abstract-only cache that nothing was minable, which was wrong, and cited
  Cardiomyopathy_Dilated_100 as precedent for not mining it when that entry mines
  the same two strings. Cardiomyopathy_Dilated_2G tags without mining and remains
  the accurate half of that comparison. The clinical baseline for everything the
  overview does not cover is the primary ASNA1 report, PMID:31461301.

  Histopathology term binding. Only the first of the three findings is bound.
  NCIT:C3044 (Fibrosis) covers prominent subendothelial fibrosis, following
  Arrhythmogenic_Right_Ventricular_Cardiomyopathy. NCIT was searched for the
  other two and has nothing usable: for irregular intercalated discs there is no
  finding term at all, and for myofibrillar disorganization the only near hit is
  Myofibrillar Myopathy, which is a disease rather than a histological finding.
  Both are left unbound under no term beats a bad one; the search does not need
  repeating.

  A published correction exists on the sole clinical source. PMID:32543991 is a
  Published Erratum on PMID:31461301, the paper behind almost every snippet in
  this entry. Its content is not retrievable - PubMed returns no abstract or
  body text for it, so `just fetch-reference` yields an empty record - and it is
  therefore cited nowhere here and contributed no snippet. Recorded rather than
  left implicit: a reader relying on this entry should know a correction to its
  primary source exists and that its substance has not been checked. Anyone with
  journal access should read it and confirm none of the curated claims are
  affected.

  Do not confuse CMD2H with CMD2D. Both are autosomal recessive,
  neonatal/infantile-onset, rapidly progressive dilated cardiomyopathies with
  early death, and their OMIM numbers sit one letter apart, but they are
  different diseases with different genes:

    CMD2H  OMIM:620203  MONDO:0859358  GET3 (ASNA1)  Verhagen et al. 2019
    CMD2D  OMIM:619371  MONDO:0030300  RPL3L         Ganapathi et al. 2020

  This entry is CMD2H (GET3), and the confusion is not hypothetical. The first
  openscientist deep-research run for this entry produced a report about CMD2D
  instead - 44 mentions of RPL3L, zero of ASNA1 or GET3 - because the run was
  dispatched with a disease name and no identifier. The committed report is a
  later run that received MONDO:0859358 and is correct. That report documents
  the same hazard from the other side: it records that early iterations
  followed the GATAD1 literature, which is CMD2B (OMIM:614672), and that
  identifier cross-referencing through MONDO and OLS is what corrected it.

  So this disease name sits between at least two decoys, CMD2D/RPL3L and
  CMD2B/GATAD1, and the MONDO identifier is what separates them. See issue
  #10495 and the justfile fix in #10696.

  Naming: HGNC has renamed ASNA1 to GET3, and this entry binds hgnc:752 (GET3)
  accordingly, but every published human report uses ASNA1 — search both symbols
  when looking for further cases. TRC40 is a third name for the same protein.

references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:31461301
  title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
- reference: PMID:41370295
  title: ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes.
📚

References & Deep Research

References

3
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:31461301
Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.
No top-level findings curated for this source.
PMID:41370295
ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes.
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 (6)

Record notes

GeneReviews scope. The applicable GeneReviews resource is the disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486). There is no ASNA1/GET3-specific chapter, and there is unlikely to be one: CMD2H is a single two-patient report from 2019, and GeneReviews chapters in this space are gene-specific. The cached PubMed record is content_type abstract_only, so the Clinical Characteristics, Management and Genetic Counseling sections are not available to mine - but the purpose statement that is cached carries two propositions that do apply here, and both are quoted: the proband evaluation strategy, on the exome-sequencing diagnosis entry, and the genetic risk assessment of at-risk relatives, on genetic counselling. An earlier draft of this note concluded from the abstract-only cache that nothing was minable, which was wrong, and cited Cardiomyopathy_Dilated_100 as precedent for not mining it when that entry mines the same two strings. Cardiomyopathy_Dilated_2G tags without mining and remains the accurate half of that comparison. The clinical baseline for everything the overview does not cover is the primary ASNA1 report, PMID:31461301. Histopathology term binding. Only the first of the three findings is bound. NCIT:C3044 (Fibrosis) covers prominent subendothelial fibrosis, following Arrhythmogenic_Right_Ventricular_Cardiomyopathy. NCIT was searched for the other two and has nothing usable: for irregular intercalated discs there is no finding term at all, and for myofibrillar disorganization the only near hit is Myofibrillar Myopathy, which is a disease rather than a histological finding. Both are left unbound under no term beats a bad one; the search does not need repeating. A published correction exists on the sole clinical source. PMID:32543991 is a Published Erratum on PMID:31461301, the paper behind almost every snippet in this entry. Its content is not retrievable - PubMed returns no abstract or body text for it, so `just fetch-reference` yields an empty record - and it is therefore cited nowhere here and contributed no snippet. Recorded rather than left implicit: a reader relying on this entry should know a correction to its primary source exists and that its substance has not been checked. Anyone with journal access should read it and confirm none of the curated claims are affected. Do not confuse CMD2H with CMD2D. Both are autosomal recessive, neonatal/infantile-onset, rapidly progressive dilated cardiomyopathies with early death, and their OMIM numbers sit one letter apart, but they are different diseases with different genes: CMD2H OMIM:620203 MONDO:0859358 GET3 (ASNA1) Verhagen et al. 2019 CMD2D OMIM:619371 MONDO:0030300 RPL3L Ganapathi et al. 2020 This entry is CMD2H (GET3), and the confusion is not hypothetical. The first openscientist deep-research run for this entry produced a report about CMD2D instead - 44 mentions of RPL3L, zero of ASNA1 or GET3 - because the run was dispatched with a disease name and no identifier. The committed report is a later run that received MONDO:0859358 and is correct. That report documents the same hazard from the other side: it records that early iterations followed the GATAD1 literature, which is CMD2B (OMIM:614672), and that identifier cross-referencing through MONDO and OLS is what corrected it. So this disease name sits between at least two decoys, CMD2D/RPL3L and CMD2B/GATAD1, and the MONDO identifier is what separates them. See issue #10495 and the justfile fix in #10696. Naming: HGNC has renamed ASNA1 to GET3, and this entry binds hgnc:752 (GET3) accordingly, but every published human report uses ASNA1 — search both symbols when looking for further cases. TRC40 is a third name for the same protein.

Mine the GeneReviews overview, connect Cardiac arrest, bind fibrosis, add transplantation · 2026-09-06T05:15:38Z · View source

Third review round on PR #10494. Three blocking items and four suggestions; all seven addressed. GeneReviews. The entry tagged PMID:20301486 and mined nothing from it, justifying that on the abstract-only cache and citing Cardiomyopathy_Dilated_2G and Cardiomyopathy_Dilated_100 as precedent. The reviewer checked and CMD100 mines the same abstract-only cache in two places. The note was half wrong: CMD2G does tag without mining and is a real precedent, CMD100 is not. Both minable strings from the cached purpose statement are now quoted where they apply - the proband evaluation strategy on the exome-sequencing diagnosis entry, and the genetic risk assessment of at-risk relatives on genetic counselling - graded OTHER, matching CMD100. The note now records that the earlier conclusion was wrong rather than silently dropping it. Cardiac arrest was the one phenotype never named as a target, so it rendered as a disconnected node. It is now a sequela of Dilated cardiomyopathy, as a bare name. Histopathology. Prominent subendothelial fibrosis is bound to NCIT:C3044 Fibrosis, following Arrhythmogenic_Right_Ventricular_Cardiomyopathy. NCIT was searched for the other two findings and has nothing usable - no finding term for irregular intercalated discs, and for myofibrillar disorganization only Myofibrillar Myopathy, which is a disease. Both left unbound under no term beats a bad one, with the search recorded in notes so it is not repeated. Heart transplantation added, reversing a decline I made twice. My objection was that the two reported patients died at seven weeks and twelve days having never been transplant candidates, so asserting the therapy would go beyond the source. That objection was about evidence, and the repo already has a convention for exactly this case: Dilated_Cardiomyopathy_1EE and Dilated_Cardiomyopathy_1A carry Heart Transplantation with notes reading Deliberately unevidenced, no gene-specific outcomes are reported. That is the honest shape and I should have found it rather than declining twice. Bound to NCIT:C15246 Heart Transplantation, the cached term the sibling DCM entries use, not the NCIT:C15326 the research report suggested. The description says explicitly that neither patient reached candidacy and that whether transplant is reachable in GET3 disease is unknown rather than answered negatively. Two snippets that stopped short of a character now carry the full phrase - the QRS range through its en-dash, and the tail-anchored substrate list through all seven proteins with their identifiers. Neither truncation was folded-scalar corruption, which is the thing worth avoiding; both were just weaker quotes than the source offered. PLN in the substrate discussion is now marked as printed PPLA in the source, so a reader can find the string in the paper. PLN remains the correct HGNC symbol. The PR description was stale and said the committed deep-research report is about RPL3L. It is not - the committed artifact carries mondo_id MONDO:0859358 and zero RPL3L mentions, because the run was repeated after the recipe fix in #10696. I said in the previous round that I was updating the description and did not. Rewritten now and verified by re-reading it from the API. Validation: just validate passes; 43/43 snippets verified, up from 41. All per-file offline gates green. The three whole-KB snippet gates report pre-existing findings on this branch's base, none in this file.

Tag the GeneReviews baseline; add genetic counselling and genetic_context · 2026-09-05T19:17:03Z · View source

Response to the review on PR #10494. One blocking item, three of five suggestions taken. GeneReviews baseline. PMID:20301486 'Dilated Cardiomyopathy Overview' was already in references_cache and both nearest siblings tag it, but this entry did not. Now tagged in references and covered by a GeneReviews scope paragraph in notes, following the pattern in Cardiomyopathy_Dilated_2G: there is no ASNA1/GET3-specific chapter and unlikely ever to be one, the cached record is abstract_only so section-by-section mining is not possible, and no snippet is quoted from it. Two earlier reviews and I had all recorded GeneReviews as 'unverified, probably absent'; the reviewer is right that the disease-level overview is the applicable resource and that the siblings show the accepted handling. Running just tag-references to check the tagging modified 332 other KB files. All were reverted - only Cardiomyopathy_Dilated_2H.yaml is staged. Worth recording because that recipe rewrites the whole corpus rather than the file passed to it, so it cannot be run casually inside a curation branch. Suggestions taken: genetic_context on the molecular node, carrying zygosity COMPOUND_HETEROZYGOUS, variant_origin GERMLINE, functional_impact_category LOSS_OF_FUNCTION and the three-variant description, so the variant detail is queryable rather than prose-only; and a Genetic Counseling treatment, which is not a formality here - the second affected child was echocardiographed on the first day of life because of the family history, and that sentence is the evidence. Suggestion declined, with reasons. Heart transplantation stays out of treatments. An earlier review on this same PR examined this and concluded omitting it was correct rather than a gap: the only transplant in the primary paper is an unrelated LMNA patient transplanted at 16, and neither CMD2H patient was ever a candidate, having died at 7 weeks and 12 days. The deep-research report does describe transplantation as the definitive option for infantile DCM generally, but adding it on that basis would be asserting a therapy for this disease that its only two patients were never offered. Flagging the disagreement between the two reviews rather than silently switching. Congestive heart failure as a separate phenotype is also left out: the entry already carries dilated cardiomyopathy with its sequelae of tachypnea, feeding difficulties and cardiac arrest, and the source describes the course rather than diagnosing heart failure as a distinct finding, so a separate HP:0001635 node would restate what the existing chain already says. The PR description was stale, still describing the committed research report as the wrong-disease RPL3L one; corrected separately. Validation: just validate passes; 41/41 snippets verified, up from 40/40. All offline gates green, scope clean.

Replace the wrong-disease research report with a correct one; MONDO ID confirmed as the cause · 2026-09-03T13:41:07Z · View source

Replaces the committed deep-research report with a correct one, and settles the question of what caused the original to be about the wrong disease. The reviewer on PR #10494 traced the wrong-disease report to an empty mondo_id in its frontmatter and asked for a re-run with the identifier supplied. Doing that produced a clean controlled result, because the only variable that changed between runs was the identifier - same provider, same disease name, same prompt template: run 1, mondo_id '': RPL3L 44 mentions, ASNA1/GET3 0 run 2, trailing --var override, '': RPL3L 44 mentions, ASNA1/GET3 0 run 3, patched recipe, MONDO:0859358: RPL3L 0 mentions, ASNA1/GET3 49 Run 2 is worth recording because it was my error and I reported it as a test when it was not one. I passed --var mondo_id=MONDO:0859358 as a trailing argument assuming it would override the hardcoded empty value in the recipe; it does not, and the report came back with mondo_id '' and reproduced the original failure exactly. I posted corrections on PR #10494 and PR #10696 rather than leave the claim standing. The practical consequence is that the hardcoded empty value cannot be worked around from the command line at all, which makes the justfile fix in #10696 the only route. Run 3 was produced with that fix applied locally and uncommitted in this worktree; the local patch was reverted immediately afterwards, and project.justfile is unmodified on this branch. The corrected report independently confirms the mechanism of the failure from the other side. It records that early iterations of the investigation followed the GATAD1 literature - which is CMD2B, OMIM:614672, a third recessive dilated cardiomyopathy - and that cross-referencing MONDO:0859358 to OMIM:620203 to GET3/ASNA1 is what corrected it. So the provider used the identifier to disambiguate, and this disease name sits between at least two decoys rather than one. The corrected report validates cleanly: 14/14 references resolved, 0 unresolved, 0 off topic, 8/8 quoted claims found in source. It cites PMID:31461301 and PMID:41370295, the two primary papers this entry is already built from, so it corroborates the entry rather than adding new claims. No entry content was changed on the strength of it; the entry remains built from the primary literature. The wrong-disease report is not retained. When it was the only report, keeping it annotated was the right call and that is what the reviewer advised; now that a correct report exists, keeping a CMD2D report under a filename naming CMD2H would be a trap for the next curator with no compensating value. Its content is regenerable in one command for the disease it actually describes, which is still queued as stubs/Cardiomyopathy_Dilated_2D.yaml. The mix-up itself is documented in the entry notes, in this history, in issue #10495 and in the PR discussion. Entry notes rewritten accordingly - they previously described the committed report as being about CMD2D, which is no longer true - and now name both decoys, CMD2D/RPL3L and CMD2B/GATAD1. Validation unchanged: just validate passes, 37/37 snippets verified.

Address PR #10494 review: mine the primary full text properly · 2026-09-03T13:06:21Z · View source

Response to the automated review on PR #10494. All six blocking items accepted; all five suggestions taken. The reviewer's core criticism was correct and is the one that generalizes: the entry drew 16 snippets from a cached full text carrying several times that much modelable content, and the reason was that I had treated the deep-research report as the research artifact and, on finding it was about the wrong disease, effectively proceeded without one instead of mining the primary paper as the substitute. 1. Phenotypes. The entry carried one phenotype for a disease with two deeply phenotyped patients. Added ventricular septal defect (2/2), atrial septal defect, tachypnea (2/2), feeding difficulties, prolonged QRS complex, and left ventricular thrombus. 2. histopathology: section added - subendothelial fibrosis, irregular intercalated discs with increased intercellular space, and myofibrillar disorganization on desmin staining. The intercalated disc finding is marked diagnostic: the authors tie it to the same lesion in wrb-deficient models and in phospholamban disease, which makes it mechanistically specific rather than end-stage change. 3. The paternal allele carries two variants in cis, c.867C>G p.(Cys289Trp) with c.913C>T p.(Gln305*), not one. This changes the mechanistic story because Cys289 is part of an essential zinc-binding site, so the paternal allele is doubly compromised rather than simply truncated. Also captured: no nonsense-mediated decay was found, equal wild-type and mutant transcript, which is a non-obvious negative given a premature stop codon and means the truncated protein is actually made. 4. Both knowledge gaps claimed the evidence was silent where it is not. which_ta_substrate_drives_the_heart_phenotype said 'the current evidence does not name one' - the paper names seven cardiomyopathy-associated tail-anchored candidates and reports a partial negative, correct emerin localization, which narrows the shortlist further. That negative is curated as a REFUTE item. cardiac_selectivity_of_a_ubiquitous_chaperone now engages with the EMC alternative-insertion proposal and with the extra-cardiac deficits reported across model organisms. 5. therapeutic_modality BEHAVIORAL on supportive heart failure management corrected to OTHER, and ECMO added as its own DEVICE treatment with target_mechanisms. It was actually administered and its failure is part of the prognosis. 6. prevalence: and diagnosis: added. The prevalence record carries the negative large-cohort search - 70 idiopathic cardiomyopathy children and a 19,144-patient database with no further biallelic cases - which establishes genuine rarity rather than mere recency. The diagnosis entry records that a 48-gene cardiomyopathy panel was negative and the diagnosis came only from exome, which is clinically actionable. Suggestions taken. The bundled contractility node was split: a new TISSUE-scale node, Cardiomyocyte Structural Disorganization, now sits between the cellular trafficking node and the organ-level contractility node, which gives the histopathology a natural attachment point and removes a bare assertion from the chain. Rather than retagging the contractility node TISSUE as suggested, the split puts a real TISSUE node in and leaves contractility at ORGANISM, which seemed the better resolution of the same observation. Synonyms added. The transferrin and apolipoprotein C-III isoelectric focusing abnormality added as a biochemical entry, with notes explaining it is a readout of the entry's own trafficking node rather than an incidental result. The heterozygous p.(Val183Met) modifier candidate added as a MODIFIER genetic entry, deliberately weak: the variant is predicted benign, no second allele was found, and the authors' claim is a non-exclusion. Root cause of the wrong-disease report, and it is repo-wide. The reviewer traced it to the report frontmatter carrying an empty mondo_id. Checking the recipe confirms the cause is upstream of any one run: justfile hardcodes --var mondo_id= for every research-disorder invocation, so every deep-research run in this repository has been dispatched with a disease name and no identifier. That is being handled as a separate change rather than folded into a curation PR. A corrected openscientist run for this disease with --var mondo_id=MONDO:0859358 was launched and will be added when it lands. Validation after changes: just validate passes; 37/37 snippets verified, up from 16/16. All offline gates green. Compliance 91.2% global / 91.8% weighted.

Create: Cardiomyopathy_Dilated_2H (GET3/ASNA1) · 2026-09-02T03:25:40Z · View source

De novo curation of dilated cardiomyopathy 2H (MONDO:0859358, OMIM:620203), autosomal recessive infantile-lethal DCM caused by biallelic GET3 (ASNA1/TRC40) variants. The deep-research report for this entry curated the wrong disease, and nothing was taken from it. This is the most important thing to record about this session. openscientist was run on 'Cardiomyopathy Dilated 2H' and returned a well-structured, internally consistent report naming RPL3L as the causal gene. RPL3L appears 44 times in it; ASNA1 and GET3 appear zero times; its entire mechanism section is built on muscle-specific ribosome biogenesis, RPL3/RPL3L paralog balance, and nucleolar protein aggregation. That is CMD2D, not CMD2H. Resolution, verified through NCBI rather than assumed: CMD2H OMIM:620203 MONDO:0859358 MedGen 1824069 gene 439 GET3 defined by Verhagen et al. 2019 CMD2D OMIM:619371 MONDO:0030300 MedGen 1782612 gene 6123 RPL3L defined by Ganapathi et al. 2020 MedGen elink from concept to gene is 1:1 in both directions, and MedGen's own definition of CMD2H cites Verhagen et al. 2019, which is PMID:31461301, the ASNA1 paper. The repository's stub queue already separates the two correctly: stubs/Cardiomyopathy_Dilated_2H.yaml carries MONDO:0859358 and stubs/Cardiomyopathy_Dilated_2D.yaml carries MONDO:0030300 with hgnc:10351 RPL3L. So the entry is right and the report is wrong. Why the report's own validation did not catch it. Reference validation returned 19/19 resolved, 0 unresolved, 0 off topic. That is exactly the failure mode documented in the initiate-new-disorder-creation skill: relevance is scored against the report's own vocabulary, so a report built around the wrong disease has wrong-disease vocabulary throughout and scores all of its wrong-disease citations as on topic. The only signal was a single quote-match failure, on PMID:35323613, whose text turned out to be about biallelic RPL3L variants. That one line is what prompted the check. The report is committed for provenance with the misidentification flagged in three places a curator would look: the entry's notes block, this history record, and the pull request body. Its RPL3L reference cache files were deliberately not staged, since they belong to a different disease. Issue filed to point the report at the CMD2D stub, where its content would actually apply. Entry content is therefore built entirely from primary literature identified independently of the report: PMID:31461301 (Verhagen 2019, the index sibship and the tail-anchored protein insertion assay), PMID:32543991 (its correction), and PMID:41370295 (2025 cardiomyocyte-specific Asna1 knockout mouse work). Pathograph: four nodes from biallelic GET3 loss of function through impaired tail-anchored protein insertion and disrupted cardiomyocyte membrane trafficking and proteostasis to impaired cardiac contractility and ventricular remodeling. Two animal models are curated with ModelMechanismLink readouts. The zebrafish asna1 model carries the mRNA rescue experiment, which is what discriminates the patient alleles from wild type. The mouse model pairs constitutive and inducible cardiomyocyte-restricted deletion, separating a developmental requirement from a maintenance requirement. A HUMAN_MODEL_MISMATCH discussion records that both models are effectively null while the human genotype pairs a nonsense allele with a p.(Val163Ala) missense that still produces protein, so neither model can speak to residual hypomorphic activity. HP:0001522 'Death in infancy' could not be used as a phenotype because it sits outside the PhenotypeTerm dynamic enum; early death is recorded through progression and clinical_burden instead. Validation: just validate passes (schema, terms, references); 16/16 snippets verified. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all pass. No datasets: block.

OpenScientist ▸
Cardiomyopathy Dilated 2H (CMD2H) — Comprehensive Disease Report
openscientist-autonomous 13 citations 2026-09-03T09:23:13.953610

Cardiomyopathy Dilated 2H (CMD2H) — Comprehensive Disease Report

Disease: Cardiomyopathy, Dilated, 2H (CMD2H) MONDO ID: MONDO:0859358 OMIM (phenotype): 620203 Causal gene: GET3 / ASNA1 (TRC40), 19p13.13 Category: Mendelian (autosomal recessive)

Summary

Cardiomyopathy Dilated 2H (CMD2H; MONDO:0859358, OMIM 620203) is an ultra-rare, autosomal recessive, infantile-onset, rapidly progressive dilated cardiomyopathy caused by biallelic loss-of-function variants in GET3/ASNA1 (TRC40; NCBI Gene 439; 19p13.13). GET3/ASNA1 encodes the cytosolic ATPase that recognizes the transmembrane domain of tail-anchored (TA) membrane proteins and delivers them to the endoplasmic reticulum (ER) for post-translational insertion via the GET/TRC pathway. Reduced GET3 function impairs TA-protein insertion and cardiomyocyte proteostasis, producing ventricular dilation, heart failure, and death in early infancy.

A critical disambiguation underpins this report. The disease name "Cardiomyopathy Dilated 2H" and MONDO:0859358 map to OMIM 620203 and are caused by GET3/ASNA1, not by GATAD1. GATAD1 causes a different recessive dilated cardiomyopathy, CMD2B (OMIM 614672). Early iterations of this investigation initially followed the GATAD1 literature; identifier cross-referencing through Monarch/OLS4 established that MONDO:0859358 → OMIM:620203 → GET3/ASNA1, and the report was corrected accordingly. GATAD1/CMD2B findings are retained below only as an explicitly labeled contrast, to prevent future confusion, and should not be attributed to CMD2H.

The molecular and clinical picture of CMD2H is supported by a coherent evidence chain: the index human family (compound heterozygous ASNA1 variants p.Gln305 and p.Val163Ala in two siblings with fatal infantile DCM; Verhagen et al. 2019), an in vitro TA-protein insertion assay demonstrating reduced function of the missense allele, zebrafish rescue experiments confirming both variants are deleterious, and cardiomyocyte-specific Asna1*-knockout mice (Feng et al. 2025) that recapitulate ventricular dilation, myocardial thinning, and disrupted TA-protein proteostasis. There is currently no disease-specific or targeted therapy; management follows standard guideline-directed heart-failure care, with transplantation as the definitive option.

Section 1 — Disease Information

Overview. CMD2H is a Mendelian, autosomal recessive form of dilated cardiomyopathy (DCM) — a cardiac muscle disorder defined by left-ventricular (or biventricular) dilation and systolic dysfunction in the absence of abnormal loading conditions or coronary disease sufficient to explain it. CMD2H is distinguished from common idiopathic DCM by its monogenic recessive etiology (biallelic GET3/ASNA1 variants), its very early (infantile) onset, and its rapid, frequently fatal course.

Key identifiers.

Resource Identifier
MONDO MONDO:0859358 ("cardiomyopathy, dilated, 2H")
OMIM (phenotype) 620203
OMIM (gene, GET3/ASNA1) 601913
MedGen C5774296
UMLS C5774296
GARD 0026714
NCBI Gene 439 (GET3; aliases ASNA1, TRC40, ASNA-I, ARSA1, CMD2H)
Ensembl (gene) ENSG00000198356
HGNC symbol GET3 (previously ASNA1)

Cross-references were verified via Monarch and OLS4. Note that "CMD2H" is itself listed among the official gene aliases for GET3 in NCBI Gene.

Synonyms / alternative names. Dilated cardiomyopathy 2H; DCM 2H; CMD2H; (gene-based) ASNA1-related / GET3-related dilated cardiomyopathy; ASNA1-related infantile dilated cardiomyopathy.

Information source. Disease-level, aggregated Mendelian resources (OMIM, MONDO, MedGen) combined with a small number of primary case reports and functional studies. The clinical description derives from a single index family (two siblings) plus supporting model-organism and in vitro data — it is not derived from large EHR cohorts, reflecting the ultra-rare nature of the disorder.

Section 2 — Etiology

Primary cause: genetic. CMD2H is caused by biallelic (compound heterozygous or homozygous) loss-of-function variants in GET3/ASNA1. It is a monogenic, autosomal recessive disorder with no established environmental or infectious primary cause.

"We identified compound heterozygous variants in the highly conserved ASNA1 gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins." — Verhagen et al. 2019, PMID: 31461301

"Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death." — Verhagen et al. 2019, PMID: 31461301

Genetic risk factors. The causal risk factor is inheritance of two damaging GET3/ASNA1 alleles. Consistent with a recessive mechanism, gnomAD shows GET3/ASNA1 is constrained but tolerant of heterozygous loss of function (pLI = 0.05; LoF observed/expected = 15/32.4; oe_lof = 0.46, 90% CI 0.31–0.71; lof_z = 2.59; mis_z = 2.51). This constraint profile — tolerant of one null allele but depleted overall — is exactly what is expected for a gene in which heterozygous carriers are healthy and disease requires biallelic hits.

Environmental risk / protective factors / gene–environment interactions. No environmental risk factors, protective factors, or gene–environment interactions specific to CMD2H have been reported. Given the severe, near-fully-penetrant recessive genotype, environmental modifiers are unlikely to be dominant contributors, though data are too sparse to exclude modifiers of severity. (For DCM broadly, "second-hit" models — inflammation, clonal hematopoiesis, environmental triggers layered on genetic susceptibility — are increasingly recognized [PMID: 41898170], but these apply to common/idiopathic DCM, not specifically CMD2H.)

Section 3 — Phenotypes

The CMD2H phenotype, as documented in the index sibling pair, is a severe, rapidly progressive, infantile-onset dilated cardiomyopathy:

Phenotype Type Onset Severity / course HPO suggestion
Dilated cardiomyopathy Clinical sign (imaging) Infantile / early Severe, rapidly progressive HP:0001644
Ventricular systolic dysfunction Clinical sign Infantile Severe HP:0001635 (congestive heart failure)
Ventricular dilation Structural Infantile Severe HP:0001711 (abnormal LV morphology)
Heart failure Clinical syndrome Infantile Severe, fatal HP:0001635
Death in infancy Outcome Early infancy Fatal HP:0001522

Phenotype characteristics. Age of onset: neonatal/infantile. Severity: severe. Progression: rapidly progressive. Frequency among affected individuals: in the reported family, both biallelic siblings were affected and died in early infancy (high penetrance for the severe biallelic genotype), though the total number of reported patients is very small (n ≈ 2 index cases), limiting frequency estimates.

Quality-of-life impact. Not formally measured with instruments (EQ-5D, SF-36, PROMIS) given infantile lethality. The practical impact is maximal — the disease is life-limiting in infancy in reported cases.

Section 4 — Genetic / Molecular Information

Causal gene. GET3 / ASNA1 (TRC40). NCBI Gene 439; 19p13.13; Ensembl ENSG00000198356; OMIM gene 601913.

Pathogenic variants (index family). Verhagen et al. 2019 identified compound heterozygous ASNA1/GET3 variants in two affected siblings:

Variant (cDNA) Protein Parental origin Class Functional consequence
c.913C>T p.(Gln305*) Paternal Nonsense / premature termination codon Decreased protein in myocardium and skin fibroblasts (null / LoF)
c.488T>C p.(Val163Ala) Maternal Missense Protein misfolding; less effective tail-anchored protein insertion (hypomorphic LoF)

"Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy." — PMID: 31461301

Variant classification. Both variants segregate with disease in a recessive pattern and are supported by functional evidence (reduced protein/insertion activity; failure to rescue zebrafish). They are consistent with pathogenic/likely-pathogenic classification under ACMG/AMP criteria (functional evidence PS3; recessive segregation; predicted null variant PVS1 for p.Gln305*).

Variant type/class. One nonsense/PTC allele (loss of protein) and one missense/misfolding allele. Origin: germline, biallelic (autosomal recessive). Population frequency: rare, consistent with an ultra-rare Mendelian disorder. Functional consequence: loss of function for both alleles (one null, one hypomorphic).

Modifier genes / epigenetics / chromosomal abnormalities. No CMD2H-specific modifier genes, epigenetic marks, or chromosomal abnormalities have been reported. This is a single-gene, small-variant disorder; no aneuploidy/translocation involvement is described.

Section 5 — Environmental Information

No environmental factors, lifestyle factors, or infectious agents are implicated in CMD2H. It is a purely genetic (Mendelian recessive) disorder. This contrasts with acquired/inflammatory DCM (e.g., viral myocarditis progressing to DCM [PMID: 42415986]; inflammatory cardiomyopathy [PMID: 41747776]), which is mechanistically distinct and not part of the CMD2H entity.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in GET3/ASNA1 (e.g., p.Gln305 null + p.Val163Ala misfolding) result in* reduced GET3/ASNA1 protein level and/or ATPase/chaperone activity in cardiomyocytes.
  2. Reduced GET3 activity leads to destabilization of the cytosolic pre-targeting complex and impaired recognition/delivery of tail-anchored (TA) membrane proteins to the ER membrane (GET/TRC pathway failure). (Demonstrated in vitro via a TA-insertion assay for p.Val163Ala.)
  3. Failed TA-protein insertion results in reduced expression/mistargeting of multiple TA-protein substrates (SNAREs, ER/Golgi trafficking components, apoptosis regulators), impairing membrane trafficking and organelle proteostasis. (Demonstrated in Asna1-KO mouse cardiomyocytes.)
  4. Disrupted cardiomyocyte proteostasis and membrane-protein homeostasis lead to a maladaptive compensatory transcriptional response (upregulation of protein-trafficking and Golgi-to-ER transport genes) and impaired cardiomyocyte function/contractility. (Transcriptomics + zebrafish contractility data.)
  5. Cardiomyocyte dysfunction results in ventricular myocardial thinning (developmental) and/or ventricular dilation with reduced systolic function (postnatal/adult).
  6. Progressive ventricular dilation and pump failure lead to heart failure and, in reported human cases, death in early infancy.

Steps 1–3 are directly demonstrated (human protein data, in vitro insertion assay, mouse molecular data). Steps 4–6 are supported by convergent zebrafish (contractility, lethality) and mouse (dilation, thinning, mortality) evidence; the precise identity of the critical cardiac TA-protein substrate(s) whose loss is rate-limiting for the heart phenotype remains inferred rather than fully demonstrated.

Detail by category

Molecular pathway — the GET/TRC (guided-entry of tail-anchored proteins) pathway. GET3/ASNA1 (yeast Get3; mammalian TRC40) is the central cytosolic ATPase that binds the C-terminal transmembrane domain of TA proteins and delivers them to an ER membrane receptor formed by WRB (=GET1) and CAML/CAMLG (=GET2) (PMID: 21444755, PMID: 27226539). This is a post-translational, ATP-dependent targeting cycle.

Cellular processes. Membrane-protein biogenesis, ER-targeted protein trafficking, proteostasis, and (indirectly) apoptosis regulation (many apoptotic/BCL-2-family and SNARE proteins are TA proteins). ASNA1's ATPase activity is required for cell survival and ER homeostasis in other tissues (pancreatic progenitors [PMID: 29180572]; β-cell ER homeostasis [PMID: 26438609]), underscoring the pathway's general importance to proteostasis.

Protein dysfunction. p.Gln305* → truncation/loss of protein (reduced abundance in patient myocardium and fibroblasts). p.Val163Ala → misfolding and reduced TA-insertion efficiency (hypomorph). Net effect: loss of function.

"Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish." — PMID: 31461301

Downstream molecular profiling (mouse). In cardiomyocyte-specific Asna1-KO mice, ASNA1 deficiency destabilized the pre-targeting complex and reduced expression of multiple TA-protein substrates, impairing membrane trafficking. Transcriptomics revealed compensatory (maladaptive) upregulation of protein-trafficking and Golgi-to-ER transport genes.

"ASNA1 deficiency destabilized the pre-targeting complex and reduced the expression of multiple TA protein substrates, impairing membrane trafficking and protein transport." — Feng et al. 2025, PMID: 41370295

Tissue-damage mechanisms. Impaired proteostasis → cardiomyocyte dysfunction → myocardial thinning (embryonic) or dilation and pathological remodeling (postnatal). Fibrosis/oxidative stress are downstream remodeling features common to DCM but not specifically characterized in CMD2H.

Upstream vs downstream. Upstream: GET3/ASNA1 LoF → GET/TRC pathway failure. Downstream: TA-substrate depletion → cardiomyocyte proteostatic stress → contractile dysfunction → ventricular dilation → heart failure.

Suggested ontology terms. - GO biological process: tail-anchored membrane protein insertion into ER membrane (GO:0071816); post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620); protein insertion into ER membrane (GO:0045048). - GO cellular component: cytosol (GO:0005829); endoplasmic reticulum membrane (GO:0005789); TRC/GET complex. - CL cell type: cardiac muscle cell / cardiomyocyte (CL:0000746); regular ventricular cardiac myocyte (CL:2000046).

Section 7 — Anatomical Structures Affected

Organ level. Primary organ: heart (UBERON:0000948), specifically the ventricular myocardium — left ventricle (UBERON:0002084) and, in mouse, biventricular. Body system: cardiovascular system (UBERON:0004535). Secondary involvement: systemic congestion / heart-failure sequelae (pulmonary, hepatic, renal hypoperfusion) as in any severe infantile DCM.

Tissue and cell level. Tissue: cardiac muscle tissue / myocardium (UBERON:0002349). Target cell: cardiomyocyte (CL:0000746; ventricular cardiac myocyte CL:2000046). GET3/ASNA1 is broadly expressed, but the disease phenotype is myocardium-predominant.

Subcellular level. Compartments: cytosol (GO:0005829, site of GET3 targeting complex) and ER membrane (GO:0005789, destination of TA-protein insertion). Membrane trafficking machinery (Golgi-to-ER transport) is transcriptionally perturbed.

Localization / lateralization. Cardiac, bilateral/biventricular (mouse); left-ventricular predominant description in human DCM. No focal or asymmetric lateralization is characteristic.

Section 8 — Temporal Development

Onset. Congenital/infantile. In the index human family, disease was evident and rapidly progressive in early infancy. In constitutive Asna1-KO mice, myocardial thinning appears by embryonic day 16.5 with perinatal lethality, indicating a developmental component.

Progression. Rapid. Human course: rapidly progressive DCM with death in early infancy. Inducible adult-cardiomyocyte Asna1 deletion in mice caused rapid ventricular dilation, impaired function, remodeling, and early mortality — indicating that GET3/ASNA1 is required for both cardiac development and ongoing adult cardiomyocyte maintenance.

"Constitutive Asna1 deletion during embryogenesis caused perinatal lethality with marked ventricular myocardial thinning by embryonic day 16.5, whereas inducible deletion in adult cardiomyocytes led to rapid ventricular dilation, impaired cardiac function, pathological remodeling, and early mortality." — Feng et al. 2025, PMID: 41370295

Course pattern. Progressive, non-remitting, fatal in reported cases. No spontaneous remission described. Critical period: perinatal/infancy is the window of vulnerability; there is no established intervention window beyond supportive heart-failure care and transplantation.

Section 9 — Inheritance and Population

Inheritance. Autosomal recessive (biallelic GET3/ASNA1 LoF). Heterozygous carriers are unaffected — consistent with gnomAD constraint showing tolerance of a single LoF allele.

Penetrance / expressivity. In the single reported family both biallelic siblings were severely affected (apparently high penetrance for the severe biallelic genotype), but the extremely small case count precludes robust penetrance/expressivity estimates.

Epidemiology. Ultra-rare. Only a single index family (two siblings) is definitively reported for CMD2H, plus supporting functional data; prevalence/incidence are not established. For context, idiopathic DCM overall has an approximate historical prevalence near 1:2500 and is "the most common cardiomyopathy worldwide" (PMID: 42511685), but CMD2H represents a vanishingly small monogenic subset.

Carrier frequency / founder effects / consanguinity. Not established; no founder effect reported. Sex ratio: no sex bias expected for an autosomal recessive gene; not established given tiny sample. Geographic distribution: not established.

gnomAD constraint (ENSG00000198356; chr19:12,737,139–12,748,323, GRCh38): pLI = 0.05; LoF o/e = 15/32.4 (oe_lof = 0.46, 90% CI 0.31–0.71); lof_z = 2.59; mis_z = 2.51 — supports a recessive, loss-of-function model with healthy heterozygous carriers.

Section 10 — Diagnostics

Genetic testing is the definitive diagnostic modality. Because CMD2H is clinically indistinguishable from other infantile DCM on imaging alone, molecular diagnosis rests on identifying biallelic GET3/ASNA1 variants.

  • Recommended approach: trio exome sequencing (WES) or genome sequencing (WGS), or a comprehensive cardiomyopathy gene panel that includes ASNA1/GET3, with segregation testing of parents to confirm compound heterozygosity/biallelic status. Exome sequencing was the method that discovered the disease gene.
  • Single-gene testing: targeted ASNA1/GET3 sequencing (with deletion/duplication analysis) is appropriate once the diagnosis is suspected or in cascade testing.
  • Variant interpretation: classify per ACMG/AMP using ClinVar/ClinGen, incorporating functional evidence (reduced protein, impaired TA-insertion) and recessive segregation.

Clinical/imaging tests (phenotype confirmation, non-specific). Echocardiography and cardiac MRI to document ventricular dilation and reduced ejection fraction; ECG; natriuretic peptides (BNP/NT-proBNP) and troponin as heart-failure biomarkers. Endomyocardial biopsy could show reduced GET3 protein (as in the index case) but is not routinely required.

Differential diagnosis. Other genetic infantile/pediatric DCMs (e.g., TTN, LMNA, sarcomeric and metabolic cardiomyopathies), CTNNA3-related recessive DCM [PMID: 42471840], GATAD1-related CMD2B (see disambiguation), mitochondrial/metabolic cardiomyopathies, and acquired causes (viral myocarditis, inflammatory cardiomyopathy). Genetic testing distinguishes CMD2H.

Screening. Cascade genetic testing of at-risk relatives and carrier testing of parents for reproductive counseling. No population newborn screening exists for this ultra-rare disorder.

Section 11 — Outcome / Prognosis

Prognosis is poor in reported cases — rapidly progressive DCM with death in early infancy in the two index siblings. Mouse models mirror this severity (perinatal lethality with constitutive KO; early mortality with adult inducible KO).

Survival / mortality. Reported human outcome: fatal in infancy. Definitive survival statistics are not available due to the tiny case count.

Morbidity / complications. Severe heart failure, arrhythmia risk, and the sequelae of low cardiac output. For DCM broadly, non-ischaemic DCM confers ~12-fold higher out-of-hospital cardiac arrest incidence versus the general population (532 vs 45 per 100,000 person-years) with higher shockable-rhythm rates [PMID: 42536775] — underscoring arrhythmic risk that informs management of any DCM, though CMD2H's infantile lethality dominates its natural history.

"The incident rate of OHCA was approximately 12 times higher in NIDCM patients compared with the general population (incidence rate 532 vs 45 per 100 000 person years)." — PMID: 42536775

Prognostic factors. Biallelic null genotype and infantile onset predict severe outcome. No CMD2H-specific prognostic biomarkers are established.

Section 12 — Treatment

There is no disease-specific or targeted therapy for CMD2H. Management follows standard guideline-directed heart-failure therapy for pediatric/infantile DCM, with heart transplantation as the definitive option for end-stage disease.

Pharmacotherapy (supportive, standard HF care; NCIT terms in brackets). - Diuretics for congestion (e.g., furosemide) [Loop Diuretic]. - ACE inhibitors / ARBs / ARNI for afterload reduction and remodeling [Angiotensin-Converting Enzyme Inhibitor, NCIT:C776]. - Beta-blockers where tolerated [Beta-Adrenergic Blocker, NCIT:C2568]. - Mineralocorticoid receptor antagonists. - SGLT2 inhibitors are now standard in adult HFrEF; pediatric applicability is individualized. - Inotropic support for acute decompensation.

Device / advanced therapies. ICD for arrhythmic protection in appropriate patients; mechanical circulatory support (VAD) as a bridge; cardiac transplantation [Heart Transplantation, NCIT:C15326] for refractory disease.

Advanced / experimental therapeutics. No approved gene therapy, RNA therapy, or targeted small molecule exists for GET3/ASNA1-related DCM. Because the mechanism is recessive loss of function, gene-replacement / gene-addition strategies (e.g., AAV-delivered ASNA1) are conceptually rational future directions but are entirely preclinical/hypothetical at present.

Pharmacogenomics. None specific to CMD2H.

Section 13 — Prevention

Primary prevention of the disease itself is genetic: carrier identification and reproductive counseling. Options for at-risk couples (both carriers) include prenatal diagnosis and preimplantation genetic testing (PGT-M).

  • Genetic counseling for families with an affected child: 25% recurrence risk per pregnancy for two carrier parents (autosomal recessive).
  • Cascade carrier testing of relatives.
  • Secondary/tertiary prevention for an affected infant is limited to early heart-failure management, arrhythmia surveillance/ICD where appropriate, and timely transplant evaluation.

No immunization, behavioral, or public-health prevention applies to this monogenic disorder.

Section 14 — Other Species / Natural Disease

Evolutionary conservation. GET3/ASNA1 is a highly conserved ATPase. Functional orthologs span yeast (GET3), C. elegans (asna-1), zebrafish (asna1), and mouse (Asna1), all participating in TA-protein insertion. This deep conservation supports the mechanistic model and enables cross-species modeling.

"Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate cardiac function and disease." — Verhagen et al. 2019, PMID: 31461301

Orthologous genes (suggested identifiers to populate): mouse Asna1, zebrafish asna1, C. elegans asna-1, S. cerevisiae GET3. Natural disease in companion animals/wildlife: no OMIA entry for spontaneous ASNA1/GET3 cardiomyopathy is established; the animal data are experimental models rather than naturally occurring disease. Zoonotic potential: not applicable (genetic disorder).

Section 15 — Model Organisms

Zebrafish (Danio rerio, asna1). Loss of asna1 produced reduced cardiac contractility and early lethality; wild-type asna1 mRNA rescued the phenotype, whereas mRNA carrying either patient variant (p.Gln305* or p.Val163Ala) failed to rescue — establishing both human alleles as functionally deleterious and validating the gene–disease relationship in vivo.

Mouse (Mus musculus, Asna1) — cardiomyocyte-specific conditional knockouts (Feng et al. 2025, PMID: 41370295). - Constitutive cardiomyocyte deletion → perinatal lethality with ventricular myocardial thinning by E16.5. - Inducible adult deletion → rapid ventricular dilation, impaired cardiac function, pathological remodeling, and early mortality. - Molecular: destabilized pre-targeting complex, reduced TA-substrate expression, impaired membrane trafficking; compensatory transcriptional upregulation of trafficking genes.

Phenotype recapitulation. Excellent — mouse models reproduce the core human features (ventricular dilation, impaired function, early death) and provide the mechanistic link to TA-protein proteostasis. Zebrafish provide orthogonal in vivo validation and a variant-specific rescue assay.

Model limitations. Species differences in cardiac physiology; conditional models are engineered LoF rather than the exact human compound-heterozygous genotype; human natural-history and therapeutic-response data remain minimal.

Suggested resources: MGI (Asna1), ZFIN (asna1), IMPC/IMSR for mouse alleles.

Key Findings (with evidence)

Finding 1 — CMD2H is caused by biallelic GET3/ASNA1, not GATAD1 (critical disambiguation)

MONDO:0859358 "cardiomyopathy, dilated, 2H" cross-references OMIM:620203, MedGen/UMLS C5774296, and GARD 0026714 (verified via Monarch/OLS4). The causal gene is GET3/ASNA1 (NCBI Gene 439, 19p13.13), whose official aliases include ASNA1, TRC40, ARSA1, and CMD2H. Verhagen et al. 2019 identified compound heterozygous ASNA1 variants in two siblings with fatal infantile DCM. GATAD1 causes a distinct disease, CMD2B (OMIM 614672) — the initial GATAD1 leads in this investigation belong to CMD2B and do not apply to CMD2H.

"Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death." — PMID: 31461301

Finding 2 — Pathogenic variant spectrum: a truncating null plus a misfolding missense, both LoF

Paternal c.913C>T, p.(Gln305*) (null; reduced protein in myocardium/fibroblasts) + maternal c.488T>C, p.(Val163Ala) (misfolding; impaired TA insertion). Both are loss-of-function; zebrafish rescue failed for both. Germline, biallelic, autosomal recessive.

"Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy." — PMID: 31461301

Finding 3 — Mechanism: defective GET/TRC tail-anchored-protein insertion impairs cardiomyocyte function

GET3/ASNA1 (TRC40) is the cytosolic ATPase delivering TA proteins to the ER via the WRB(GET1)/CAML(GET2) receptor. Biallelic LoF reduces TA-insertion capacity (in vitro assay), reducing cardiac contractility (zebrafish) and causing dilation/failure.

"Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish." — PMID: 31461301

Finding 4 — Mouse cardiomyocyte-specific Asna1 KO recapitulates CMD2H

Constitutive KO → perinatal lethality + myocardial thinning by E16.5; inducible adult KO → ventricular dilation, impaired function, remodeling, early death; molecular destabilization of the pre-targeting complex with reduced TA-substrate expression.

"ASNA1 deficiency destabilized the pre-targeting complex and reduced the expression of multiple TA protein substrates, impairing membrane trafficking and protein transport." — PMID: 41370295

Finding 5 — gnomAD constraint supports a recessive LoF model

pLI = 0.05; oe_lof = 0.46 (90% CI 0.31–0.71); lof_z = 2.59; mis_z = 2.51 — constrained but heterozygous-LoF-tolerant, consistent with unaffected carriers and biallelic disease.

Mechanistic Model / Interpretation

 Biallelic GET3/ASNA1 LoF          [p.Gln305* (null) + p.Val163Ala (misfolding)]
    |
    v
 Reduced GET3/ASNA1 protein & ATPase activity in cardiomyocytes
    |
    v
 Destabilized cytosolic pre-targeting (TRC/GET) complex
    |
    v
 Impaired delivery of tail-anchored (TA) proteins to ER
 (via WRB=GET1 / CAML=GET2 receptor)  -- in vitro TA-insertion assay down
    |
    v
 Reduced expression / mistargeting of multiple TA-protein substrates
 (SNAREs, trafficking & apoptosis regulators) -> impaired membrane trafficking
    |
    v
 Cardiomyocyte proteostatic stress + maladaptive compensatory transcription
    |
      +-----+---------------------------+
      v                                 v
 (embryonic) myocardial          (postnatal/adult) ventricular
 thinning by E16.5               dilation + systolic dysfunction
      |                                 |
      +----------------+----------------+
               v
Heart failure -> death in early infancy

Upstream driver: GET/TRC pathway failure. Downstream effectors: TA-substrate depletion → cardiomyocyte dysfunction → dilation → pump failure. The identity of the single most rate-limiting cardiac TA substrate remains inferred.

Evidence Base

PMID Title (abbrev.) Role Support / Challenge
31461301 Biallelic Variants in ASNA1... (Verhagen 2019) Index human family; gene discovery; in vitro + zebrafish Core support — establishes GET3/ASNA1 causation, variants, mechanism
41370295 Cardiomyocyte-specific Asna1 KO mice (Feng 2025) Mouse model Core support — recapitulates dilation/thinning; molecular mechanism
Monarch / OLS4 MONDO:0859358 ↔ OMIM:620203 ↔ GET3/ASNA1 Identifier verification Core support — disease/gene mapping; disambiguation from CMD2B
gnomAD (ENSG00000198356) Constraint metrics Population genetics Support — recessive LoF model
21444755, 27226539 WRB/CAML TA-insertion receptor Pathway biology Support — GET/TRC receptor machinery
29180572, 26438609 ASNA1 in pancreas / β-cell ER homeostasis Pathway importance Support — ASNA1 ATPase essential for survival/proteostasis
42536775 OHCA risk in non-ischaemic DCM Clinical context Context — DCM arrhythmic risk (broad)
42511685 Geographical/ethnic heterogeneity in genetic DCM Epidemiology context Context — DCM epidemiology framing
41898170 Emerging mechanisms/therapies in DCM Therapy context Context — general DCM management
21965549 GATAD1 in AR DCM (Theis 2011) Disambiguation Belongs to CMD2B, not CMD2H

Limitations and Knowledge Gaps

  1. Extremely small human evidence base. The core clinical description rests on a single family (two siblings). Prevalence, penetrance, expressivity, carrier frequency, sex ratio, and geographic/ethnic distribution are essentially unknown.
  2. Substrate specificity unresolved. It is not established which cardiac TA-protein substrate(s) are most critically depleted; the link from "reduced TA insertion" to "cardiomyocyte failure" is mechanistically plausible and model-supported but the rate-limiting node is inferred.
  3. No natural-history or therapeutic-response data specific to CMD2H; treatment recommendations are extrapolated from general DCM/heart-failure care.
  4. Historical disambiguation risk. Much online and literature content conflates "Dilated Cardiomyopathy 2H" with GATAD1; this report explicitly corrects that — CMD2H = GET3/ASNA1; GATAD1 = CMD2B.
  5. No CMD2H-specific biomarkers, modifiers, or epigenetic data are available.

Proposed Follow-up Experiments / Actions

  1. Expand the case series. Query GeneMatcher, DECIPHER, and large cardiomyopathy registries (e.g., the Dutch Cardiomyopathy Registry [PMID: 42573902]) for additional biallelic ASNA1/GET3 patients to define phenotypic range and penetrance.
  2. Define the critical cardiac TA-substrate(s). Proteomics/TA-substrate profiling in Asna1-KO cardiomyocytes and patient-derived iPSC-cardiomyocytes to pinpoint the rate-limiting insertion defect.
  3. iPSC-CM disease modeling. Generate patient-derived iPSC-cardiomyocytes (and isogenic corrected controls) to characterize contractility, ER stress, and trafficking, and to serve as a therapeutic-screening platform.
  4. Genotype–phenotype and rescue studies. Systematic in vitro insertion assays across additional ASNA1 variants to build an ACMG-grade functional evidence base (PS3) for clinical variant interpretation.
  5. Preclinical gene-replacement proof of concept. Test AAV-mediated ASNA1 restoration in the inducible Asna1-KO mouse as a rational strategy for a recessive LoF disorder.
  6. Curate identifiers. Ensure knowledge-base entries link MONDO:0859358 → OMIM 620203 → GET3/ASNA1 (gene OMIM 601913) and flag the GATAD1/CMD2B distinction to prevent propagation of the historical error.

Evidence source legend: human clinical (Verhagen 2019, index family), in vitro (TA-insertion assay), model organism (zebrafish asna1; mouse Asna1 conditional KO), computational/population genetics (gnomAD constraint), and database/ontology cross-referencing (Monarch/OLS4, OMIM, MONDO, NCBI Gene).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 8
Quoted claims found in source 8
Quoted claims not found in source 0
References weighed for topical relevance 14
On topic 4
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 20
Resolved 19
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 10
Terms named correctly 2
Terms named as a different term 5
Terms whose name is worth a second look 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:0859358 (9 mentions) - the report calls it "if available", "cardiomyopathy, dilated, 2H"; MONDO calls it cardiomyopathy, dilated, 2H
  • HP:0001644 (1 mention) - the report calls it "Severe, rapidly progressive"; HP calls it Dilated cardiomyopathy
  • HP:0001635 (2 mentions) - the report calls it "congestive heart failure", "Severe, fatal"; HP calls it Congestive heart failure
  • HP:0001522 (1 mention) - the report calls it "Fatal"; HP calls it Death in infancy
  • GO:0005829 (2 mentions) - the report calls it "GO cellular component: cytosol"; GO calls it cytosol

Terms whose name is worth a second look

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

  • HP:0001711 (1 mention) - the report calls it "abnormal LV morphology"; HP calls it Abnormal left ventricle morphology
  • CL:0000746 (2 mentions) - the report calls it "CL cell type: cardiac muscle cell / cardiomyocyte"; CL calls it cardiac muscle cell
  • UBERON:0002349 (1 mention) - the report calls it "cardiac muscle tissue / myocardium"; UBERON calls it myocardium, and lists "cardiac muscle" among its other names

Terms named inconsistently

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

  • MONDO:0859358 - called "if available", "cardiomyopathy, dilated, 2H"
  • HP:0001635 - called "congestive heart failure", "Severe, fatal"

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: OMIM.