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Classifications

Harrison's Part

Channelopathy

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Inheritance

1

Autosomal dominant inheritance HP:0000006

The asserted model is autosomal dominant: both founding probands carried a heterozygous ABCC9 variant. The 2004 report additionally describes an affected parent in one family from whom DNA was not available, so the transmission was never genotype-confirmed; that family detail sits in the paper's paywalled body and is recorded here as context rather than as cited evidence. Penetrance and expressivity are unknown from two families, and ClinGen's autosomal dominant classification of the gene-disease relationship is Limited rather than an endorsement of the mode. The contrast with the recessive ABCC9 disorder is load-bearing rather than incidental — in AIMS, heterozygous parents of biallelic probands show no conserved clinical pathology, so a single ABCC9 loss-of-function allele is not on its own sufficient for the AIMS phenotype.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

The founding human genetic observation on which the dominant model rests: heterozygous variants ascertained in affected individuals.

PMID:38217872 SUPPORT INDIRECT Human Clinical

"Heterozygous parents do not show any conserved clinical pathology"

Supports the separation of dominant CMD1O from recessive AIMS by an inference step - carriers of one AIMS allele do not manifest the AIMS phenotype, so any dominant ABCC9 cardiac disease has to be a different claim about a different allele class.

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Mechanistic Hypotheses

1

Failure of KATP metabolic-stress gating as the CMD1O lesion

katp_metabolic_gating_failure EMERGING

The proposed model: a C-terminal ABCC9 variant displaces SUR2A's catalytic cycle, the Kir6.2 pore is consequently mis-gated, the cardiomyocyte cannot match electrical and contractile work to energetic demand under stress, calcium overload follows, and calcineurin-dependent remodeling converts that into a dilated, arrhythmogenic ventricle. The molecular arm is demonstrated in recombinant systems; the myocardial arm is supported by KATP-deficient animals but has never been shown for an ABCC9 catalytic-domain allele in a heart, human or otherwise. It is recorded as EMERGING rather than CANONICAL because the gene-disease relationship it explains is itself classified as Limited.

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Discussions and Knowledge Gaps

3

Is a heterozygous ABCC9 variant sufficient to cause dilated cardiomyopathy in humans, and if so which allele classes do it?

KNOWLEDGE GAP OPEN abcc9_dcm_gene_disease_validity

Attached to

pathophysiology#ABCC9 C-Terminal Catalytic-Domain Variant genetic#ABCC9 variants of limited clinical validity for dilated cardiomyopathy

ClinGen's Dilated Cardiomyopathy GCEP classifies ABCC9-DCM as Limited. The weaknesses are specific rather than general: two probands from a single screen; segregation resting on an affected father from whom no DNA was available; no replication cohort combining independent human genetics with comparable functional characterisation; and a ClinVar spectrum dominated by variants of uncertain significance. The functional work is strong for what it covers - the recombinant catalytic and gating defect is real and quantified - but it does not establish that a heterozygous allele is sufficient to produce the disease in a human heart. Until this is resolved no clinical inference should be drawn from an ABCC9 variant, and this entry curates the mechanism as proposed rather than established.

Proposed experiments

Case-control rare-variant burden test for ABCC9 in dilated cardiomyopathy

exp_cmd1o_case_control_burden

Test whether rare ABCC9 variants, and specifically C-terminal nucleotide-binding-domain variants, are enriched in large sequenced dilated cardiomyopathy cohorts relative to ancestry-matched population controls. This is the analysis that would move the ClinGen classification in either direction and it has not been reported.

Would support

pathophysiology#ABCC9 C-Terminal Catalytic-Domain Variant

Supporting outcome

Significant excess of rare C-terminal ABCC9 variants in DCM cases over ancestry-matched controls after correction for multiple testing.

Refuting outcome

No enrichment, with the observed variant frequency in cases indistinguishable from population background.

Heterozygous knock-in of a human ABCC9 catalytic-domain allele

exp_cmd1o_knockin_heterozygote

Generate a heterozygous knock-in of p.(Ala1513Thr) or p.(Leu1524fs), or the murine equivalent, and test for stress-conditional cardiac disease. This would distinguish a dominant effect of the actual disease alleles from the complete-absence phenotype of the existing null models, which is the distinction the current animal evidence cannot make.

Would support

pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress

Supporting outcome

Heterozygous knock-in animals develop ventricular dilation and reduced systolic function under adrenergic or pressure load while remaining near-normal at baseline.

Refuting outcome

Heterozygous knock-in animals are indistinguishable from wild type under the same imposed stress.

Show evidence (2 references)

CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z SUPPORT Other

The expert-panel classification that defines this gap.

PMID:33947203 SUPPORT Other

"Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only."

Situates ABCC9 in the large limited-evidence tail of the curated DCM gene set, which is why this gap is not unique to this gene.

Why does deleting cardiac SUR2 in the adult mouse myocardium PROTECT the heart, when the human disease model says loss of SUR2A regulatory function causes dilated cardiomyopathy?

HUMAN MODEL MISMATCH OPEN abcc9_adult_deletion_direction_mismatch

Attached to

pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress

This is the sharpest tension in the entry and it is a direction mismatch, not a strength-of-evidence quibble. Adult cardiomyocyte-restricted SUR2 deletion increased glucose uptake and protected against ischemia-reperfusion injury, the opposite sign to what the CMD1O mechanism predicts. Several things could explain it and they have different consequences. Developmental timing may matter, since the same gene deleted earlier produces cardiomyopathy. Allele class may matter: a conditional complete deletion is not a heterozygous catalytic-domain variant, and a receptor that is absent is not the same as a receptor that mis-reports nucleotide state - a mis-gated channel could plausibly be worse than no channel. The stressor may matter, since acute ischemia-reperfusion is not chronic hemodynamic load, and the KATP-null literature is explicit that phenotypes are unmasked by the specific stress imposed. Until this is resolved, the entry does not assert that reducing cardiac SUR2 function is sufficient for dilated cardiomyopathy.

Proposed experiments

Matched comparison of adult conditional deletion, germline null, and catalytic-domain knock-in

exp_cmd1o_timing_and_allele_comparison

Impose the same chronic pressure-overload protocol on adult cardiomyocyte-specific SUR2 deletion, germline SUR2 loss, and a heterozygous catalytic-domain knock-in, with identical imaging and calcium readouts, to separate the timing, allele-class and stressor explanations for the sign reversal.

Would refute

pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress

Supporting outcome

The catalytic-domain knock-in fails under chronic load while the adult conditional deletion does not, isolating allele class as the explanation.

Refuting outcome

All three genotypes are protected under chronic load, which would place the human association rather than the model in question.

Show evidence (2 references)

PMID:31061927 REFUTE Model Organism

"This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury."

The result that creates the mismatch.

PMID:31061927 SUPPORT Model Organism

"SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter."

Identifies the metabolic compensation the authors propose as the reason for protection, which is one of the candidate explanations for the mismatch.

Is there any CMD1O-directed therapy, and can KATP pharmacology be turned on this disease at all?

KNOWLEDGE GAP OPEN abcc9_no_targeted_therapy_or_trials

Attached to

treatments#Guideline-Directed Medical Therapy for HFrEF pathophysiology#Defective Catalysis-Mediated KATP Pore Gating

A ClinicalTrials.gov search performed for this entry on 2026-09-04 returned no interventional trial for dilated cardiomyopathy 1O, CMD1O, or SUR2A-related cardiomyopathy. The single ABCC9-named registered study (NCT04120766) is a nicorandil trial in hippocampal sclerosis and dementia, not a cardiac study, so no `clinical_trials` block is curated here. The pharmacological obstacle is real rather than a matter of neglect: KATP openers and blockers cross-react across Kir6 and SUR subfamilies, so a drug aimed at cardiac SUR2A can produce the pancreatic or vascular version of the opposite pathology. The existing preclinical glibenclamide work addresses gain-of-function Cantu syndrome, which is the wrong direction for CMD1O, and the adult-deletion mouse result means even the intended direction of correction is not settled.

Proposed experiments

Patient-allele iPSC-cardiomyocyte gating and metabolic-stress rescue screen

exp_cmd1o_ipsc_cardiomyocyte_gating_rescue

Build isogenic iPSC-derived cardiomyocytes carrying p.(Ala1513Thr) or p.(Leu1524fs), measure KATP gating and action-potential adaptation under metabolic challenge, and test whether subunit-selective channel modulators restore the adaptation. This would establish both whether the human alleles break stress adaptation in a human cardiomyocyte and whether the defect is pharmacologically addressable.

Would support

pathophysiology#Defective Catalysis-Mediated KATP Pore Gating

Supporting outcome

Variant cardiomyocytes fail to adapt action-potential duration under metabolic challenge and adaptation is restored by a SUR2-selective modulator.

Refuting outcome

Variant and isogenic control cardiomyocytes show indistinguishable gating and adaptation under the same challenge.

Show evidence (1 reference)

PMID:36170658 SUPPORT Other

"while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness"

States the cross-reactivity problem that makes KATP pharmacology hard to point at a single tissue, which is the obstacle this gap describes.

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Pathophysiology

10

ABCC9 C-Terminal Catalytic-Domain Variant

A heterozygous exon-38 ABCC9 variant in conserved C-terminal sequence adjacent to the second catalytic ATPase pocket of SUR2A. The two founding alleles are a missense p.(Ala1513Thr) and a frameshift p.(Leu1524fs); neither is a simple whole-protein null, and the frameshift truncates within the nucleotide-binding region rather than removing the subunit. Their location is the mechanistic point - these residues sit where the receptor performs nucleotide catalysis, not where it conducts potassium.

Downstream

Aberrant SUR2A ATP Hydrolytic Cycle The variants were shown to alter the conformational behaviour of the recombinant receptor's own hydrolytic cycle.

Show evidence (2 references)

PMID:15034580 SUPPORT Human Clinical

"These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A."

States the allele class and the domain, which is what defines this node.

PMID:39337275 SUPPORT Other

"One is a frameshift mutation (c.4570_4572delinsAAAT, p.(Leu1524fs)) and the second one is a missense mutation (c.4537G>A, p.(Ala1513Thr)), both altering KATP channel function in vitro and suggesting a mechanistic link to DCM pathogenesis"

Gives the coding and protein-level descriptions of both founding alleles as restated by a later review.

Aberrant SUR2A ATP Hydrolytic Cycle

SUR2A is an ABC protein and its nucleotide-binding domains hydrolyse ATP as part of normal channel operation; the hydrolytic cycle is the transduction step, not a housekeeping side reaction. In the mutant receptor the distribution of conformational states across that cycle is shifted, so the receptor no longer reports the prevailing Mg-nucleotide state faithfully to the pore. The defect is qualitative - regulation is displaced rather than simply reduced - which is why the modifier here is DYSREGULATED and not DECREASED.

SUR2A nucleotide-binding-domain ATP hydrolysis GO:0016887 ↕ DYSREGULATED

Downstream

Defective Catalysis-Mediated KATP Pore Gating Disturbed catalysis in the regulatory subunit propagates to the gating of the Kir6.2 pore it controls.

Show evidence (1 reference)

PMID:15034580 SUPPORT In Vitro

"Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding."

Establishes the hydrolytic-cycle abnormality as a measured property of the mutant proteins.

Defective Catalysis-Mediated KATP Pore Gating

The sarcolemmal KATP channel is an octamer of four SUR2A subunits around four Kir6.2 pores. With catalysis in SUR2A displaced, the pore's nucleotide sensitivity is set incorrectly: the channel is present and can conduct, but it is no longer under proper regulatory control by the cell's energetic state. That qualitative loss of regulatory control - rather than a quantitative drop in potassium current - is the reason this node carries LOSS_OF_FUNCTION rather than DECREASED.

nucleotide-gated cardiac KATP channel activity GO:0015272 ⇓ LOSS OF FUNCTION

Downstream

Compromised Metabolic Signal Decoding in the Cardiomyocyte

Show evidence (2 references)

PMID:31061927 SUPPORT Other

"The major ventricular cardiomyocyte KATP channel is composed of SUR2 and Kir6.2, encoded by ABCC9 and KCNJ11, respectively."

Establishes the subunit composition of the channel whose gating this node describes, and so which cardiac channel an ABCC9 variant acts on.

PMID:36170658 SUPPORT Other

"ABCC9 gives rise to distinct SUR2A and SUR2B subunits that differ in the carboxyl terminal 42 amino acids."

Explains why a C-terminal ABCC9 variant is isoform-relevant, since the cardiac SUR2A and vascular SUR2B forms differ precisely in that region.

Compromised Metabolic Signal Decoding in the Cardiomyocyte

In an intact ventricular cardiomyocyte the KATP channel behaves as a rheostat that couples the ATP/ADP ratio to membrane potential. When the receptor mis-reads that ratio, the coupling between energetic state and electrical behaviour is broken - the cell can no longer translate a metabolic signal into the appropriate change in potassium conductance and membrane potential.

ventricular cardiomyocyte CL:0002131

metabolically gated potassium efflux GO:0071805 ↕ DYSREGULATED coupling of energetic state to membrane potential GO:0042391 ↕ DYSREGULATED

Downstream

Failure of Metabolic-Electrical Adaptation Under Cardiac Stress The consequence of mis-decoding is only exposed when energetic demand rises, which is what makes this a stress-conditional lesion.

Show evidence (2 references)

PMID:20033705 SUPPORT Other

"KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands."

Defines the normal decoding function whose failure this node describes.

PMID:36170658 SUPPORT Other

"Ubiquitously expressed throughout the body, ATP-sensitive potassium (KATP) channels couple cellular metabolism to electrical activity in multiple tissues"

Independent statement of the metabolism-to-electrical-activity coupling this node claims is broken.

Failure of Metabolic-Electrical Adaptation Under Cardiac Stress

This is the primary myocyte insult of CMD1O, and it is conditional rather than constitutive: at rest the heart is largely unremarkable, and the deficit emerges when adrenergic, ischemic, exercise or pressure load raises energetic demand and the myocyte cannot shorten its action potential and trim its membrane-potential-dependent work accordingly. The direct human demonstration is missing; the step is supported by KATP-deficient animals, in which baseline phenotypes are mild and the failure is unmasked by imposed stress.

ventricular cardiomyocyte CL:0002131

stress-adaptive shortening of the cardiac action potential GO:0099622 ↓ DECREASED myocardial response to ischemic and energetic stress GO:0002931 ↓ DECREASED

Animal models

Kir6.2/KCNJ11-null mouse under experimental hypertension Mouse partially recapitulates Reproduces the failure of metabolic-electrical adaptation and its unmasking by imposed hemodynamic load.

Adult cardiomyocyte-specific SUR2 deletion mouse Mouse fails to recapitulate Adult cardiomyocyte-restricted removal of the same subunit produced protection from ischemic stress rather than failed stress adaptation, the opposite direction to the node.

Downstream

Cytosolic Calcium Overload In the Kir6.2-null mouse the uncoupling of metabolic distress from membrane response is what sets calcium overload in motion. The step is pathway-level rather than ABCC9-allele-specific.

Show evidence (2 references)

PMID:15910878 SUPPORT Other

"K(ATP) channels have been further implicated in the adaptive cardiac response to chronic (patho)physiologic hemodynamic load, with K(ATP) channel deficiency affecting structural remodeling, rendering the heart vulnerable to calcium-dependent maladaptation and predisposing to heart failure."

States the adaptive role under chronic load whose failure defines this node, and names the calcium-dependent maladaptation that follows it.

PMID:16782803 SUPPORT INDIRECT Model Organism

"The intact KCNJ11-encoded K(ATP) channel is thus a required safety element preventing hypertension-induced heart failure"

Frames the channel as a stress-conditional safety element, supporting this node through the pore subunit rather than the regulatory subunit.

Cytosolic Calcium Overload

Loss of the KATP-dependent brake on membrane-potential-dependent calcium entry permits pathological calcium accumulation in the stressed myocyte. That this is the operative intermediate, and not merely a correlate, is shown by rescue: in the Kir6.2-null mouse the failing phenotype was corrected by controlling myocardial calcium influx by an alternative route, bypassing the uncoupled metabolic-electrical step entirely.

ventricular cardiomyocyte CL:0002131

cardiomyocyte calcium homeostasis GO:0006874 ↕ DYSREGULATED

Animal models

Kir6.2/KCNJ11-null mouse under experimental hypertension Mouse recapitulates Calcium overload is demonstrated and, more usefully, shown to be the operative intermediate by rescue through an alternative route of calcium control.

Downstream

Calcineurin-Dependent Maladaptive Remodeling

Ventricular Electrical Instability Calcium overload in a myocyte whose repolarization is already unadapted is the arrhythmic arm of the branch.

Show evidence (2 references)

PMID:16782803 SUPPORT INDIRECT Model Organism

"Rescue of the failing K(ATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration."

The rescue experiment that establishes calcium influx as the operative intermediate rather than an epiphenomenon, in the pore-subunit knockout.

PMID:31061927 SUPPORT INDIRECT Model Organism

"In the mouse, genetic deletion of Kir6.2 leads to calcium overload and myocardial damage"

Independent restatement that removing the channel produces calcium overload and myocyte damage, again via the pore subunit.

Calcineurin-Dependent Maladaptive Remodeling

Sustained calcium loading activates the calcineurin-NFAT axis and drives a hypertrophic and profibrotic transcriptional programme, converting a reversible signalling failure into structural change. In the KATP knockout this arm is cyclosporine-sensitive, which is what identifies calcineurin as the mediator rather than a bystander.

calcineurin-NFAT signaling GO:0033173 ↑ INCREASED stress-induced cardiac muscle hypertrophy GO:0014898 ↑ INCREASED

Downstream

Left Ventricular Dilation and Systolic Dysfunction

Show evidence (1 reference)

PMID:16782803 SUPPORT INDIRECT Model Organism

"Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."

Identifies the calcineurin-dependent, cyclosporine-sensitive remodeling pathway that this node names, in the KATP pore knockout.

Ventricular Electrical Instability

The electrical arm of the branch. A ventricle whose repolarization no longer tracks energetic state and whose myocytes are calcium-loaded supports triggered and re-entrant activity; ventricular tachycardia and rhythm disturbance were prominent in both founding CMD1O probands and are part of what distinguishes the ABCC9 phenotype within the DCM series.

ventricular cardiac action potential GO:0086001 ↕ DYSREGULATED

Downstream

Ventricular tachycardia

Show evidence (1 reference)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

The probands were ascertained with rhythm disturbances as well as heart failure, which is the clinical basis for an electrical arm in this graph.

Left Ventricular Dilation and Systolic Dysfunction

The mechanical arm and the defining phenotype: progressive chamber enlargement with severely impaired contraction, arrived at from a metabolic-sensing lesion rather than from a contractile-protein defect. Every affected individual in the founding report presented in adulthood with severe disease already established at diagnosis.

Animal models

SUR2/Abcc9 loss-of-function mouse Mouse partially recapitulates Cardiac dysfunction in the SUR2 loss-of-function mouse reproduces the contractile half of the mechanical endpoint of the human chain, without the dilated geometry being reported here.

abcc9 loss-of-function zebrafish Zebrafish partially recapitulates Ventricular enlargement together with cardiac dysfunction is the closest animal counterpart of the human dilated, hypocontractile ventricle.

Downstream

Dilated cardiomyopathy

Left ventricular dilatation

Reduced left ventricular ejection fraction

Structural Cardiac Impairment and Heart Failure

Show evidence (1 reference)

PMID:15910878 SUPPORT Other

"These findings are underscored by the identification in humans that defective K(ATP) channels induced by mutations in ABCC9, the gene encoding the cardiac sulfonylurea receptor subunit, confer susceptibility to dilated cardiomyopathy."

States the human endpoint of the chain in the terms this entry uses - susceptibility conferred by defective channels, not a proven monogenic cause.

Structural Cardiac Impairment and Heart Failure

End-stage low-output and congestive physiology. The founding report describes fatal heart failure in affected family members within a few years of diagnosis, but the ages and intervals sit in the paper's paywalled body and, at two deaths in an ascertainment-biased series, would not constitute a survival estimate even if they were citable.

Downstream

Congestive heart failure

Show evidence (1 reference)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

The founding probands were ascertained with heart failure, which is the clinical endpoint this node names.

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Pathograph

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

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Phenotypes

5

Dilated cardiomyopathy Cardiovascular HP:0001644

Course: PROGRESSIVE Onset: ADULT

Show evidence (2 references)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

The ascertainment phenotype of the founding cohort was idiopathic dilated cardiomyopathy.

PMID:39337275 SUPPORT Other

"Initial discoveries highlighted two specific mutations in exon 38 based on a genetic screening of 323 DCM patients."

Restates the denominator and the disease context of the founding observation.

Left ventricular dilatation Cardiovascular HP:4000141

Show evidence (1 reference)

PMID:20033705 SUPPORT Other

"KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."

Places CMD1O among the mechanical heart diseases of the KATP channelopathy group, of which ventricular dilation is the structural expression.

Reduced left ventricular ejection fraction Cardiovascular HP:0012664

Show evidence (1 reference)

PMID:15910878 SUPPORT Other

"These findings are underscored by the identification in humans that defective K(ATP) channels induced by mutations in ABCC9, the gene encoding the cardiac sulfonylurea receptor subunit, confer susceptibility to dilated cardiomyopathy."

Supports the human dilated-cardiomyopathy phenotype of which severe systolic impairment is the functional measure. The individual ejection-fraction values quoted in the deep-research report are not in any cached abstract and are therefore not asserted here as sourced numbers.

Ventricular tachycardia Cardiovascular HP:0004756

Show evidence (2 references)

PMID:20033705 SUPPORT Other

"KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."

Explicitly attaches ventricular arrhythmia to the CMD1O concept.

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

Records rhythm disturbance as part of the phenotype in which the founding variants were found.

Congestive heart failure Cardiovascular HP:0001635

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

Heart failure was the presenting syndrome of the individuals in whom the founding ABCC9 variants were identified.

🧬

Genetic Associations

1

ABCC9 variants of limited clinical validity for dilated cardiomyopathy (Limited)

Gene: ABCC9 hgnc:60 relationship_type: DISPUTED

Show evidence (5 references)

CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z REFUTE Other

ClinGen's Dilated Cardiomyopathy GCEP classifies the ABCC9-DCM gene-disease relationship as Limited under an autosomal dominant model. Recorded as REFUTE against the implicit claim that ABCC9 is an established cause of dilated cardiomyopathy. Note the assertion is filed against the parent term MONDO:0005021, not against MONDO:0012062.

PMID:33947203 SUPPORT Other

"We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."

The published recommendation of the same expert panel, which is why this entry does not treat an ABCC9 variant as diagnostic.

PMID:15034580 SUPPORT Human Clinical

"These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A."

Establishes the allele class and domain location of the two founding variants recorded above.

+ 2 more references

Variants (5)

p.(Ala1513Thr)

Missense variant, c.4537G>A, in exon 38, in conserved C-terminal sequence adjacent to the second catalytic ATPase pocket of SUR2A. One of the two founding alleles from the 323-patient idiopathic dilated cardiomyopathy screen. Case-level particulars (the proband's sex and age at diagnosis, her affected father, and the size of the control panel) appear only in the paywalled body of the 2004 paper and are not snippet-verifiable from the cached record, so they are not asserted as cited evidence anywhere in this entry.

p.(Leu1524fs)

Frameshift variant, c.4570_4572delTTAinsAAAT, in exon 38, generating aberrant terminal residues and a premature stop within the SUR2A nucleotide-binding region. The second founding allele from the same screen. Because the truncation falls inside the regulatory nucleotide-binding machinery rather than removing the subunit, its consequence is curated as a catalytic and regulatory defect, not as a whole-protein null. As above, the case-level particulars are in the paywalled body of the 2004 paper only.

p.(Arg1506fs)

Frameshift variant c.4517_4527del, reported subsequently in Mexican patients with dilated cardiomyopathy. Listed as part of the accumulating allele spectrum; not independently functionally characterised here.

p.(Lys976Ile)

Missense variant reported in a Chinese dilated cardiomyopathy cohort. Listed as part of the accumulating allele spectrum.

p.(Arg1197Cys)

Missense variant reported in a Chinese dilated cardiomyopathy cohort. Listed as part of the accumulating allele spectrum.

💊

Medical Actions

6

Clinical Surveillance of First-Degree Relatives

Action: cardiac surveillance of at-risk relatives Ontology label: Disease Screening NCIT:C15419

Platform: Other

The recommendation that survives this gene's weak validity. Because ABCC9 is only Limited for dilated cardiomyopathy, a variant result cannot be used to release a relative from follow-up - but familial dilated cardiomyopathy is itself an indication for periodic clinical and imaging surveillance of first-degree relatives regardless of genotype, aimed at detecting disease early enough to treat. This entry elsewhere warns against acting on the genotype; without this record it would leave a reader with no positive recommendation for the family at all.

Show evidence (2 references)

PMID:20301486 SUPPORT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."

GeneReviews states the purpose of assessing at-risk asymptomatic relatives as informing cardiac surveillance for early detection and treatment, which is the recommendation curated here.

PMID:37653361 SUPPORT Other

"In first-degree relatives of selected patients with genetic or inherited cardiomyopathies for early detection and prompt management"

Records the class-1 recommendation covering first-degree relatives of patients with inherited cardiomyopathy for early detection and prompt management.

Cardiac Resynchronization Therapy

Action: cardiac resynchronization therapy Ontology label: Cardiac Resynchronization Therapy NCIT:C80436

Platform: Device

Device therapy for the subset who remain symptomatic on optimal medical therapy with a severely reduced ejection fraction and a wide left-bundle-branch QRS. It is downstream of the KATP lesion and entirely genotype-independent, but it belongs in the entry because the defibrillator is already curated and the two device decisions are made together in this population.

Mechanism Target:

Structural Cardiac Impairment and Heart Failure — Resynchronizing ventricular activation improves pump efficiency in the dyssynchronous failing ventricle; it does not touch the upstream channel defect.

Show evidence (1 reference)

PMID:37653361 SUPPORT Other

"Cardiac resynchronization therapy (CRT) is strongly recommended for symptomatic patients (NYHA class II-IV on best medical management) who have LVEF ≤ 35%, sinus rhythm, left bundle branch block (LBBB) with a QRS of ≥ 150 ms to reduce total mortality and hospitalizations, and improve symptoms..."

States the indication, the eligibility thresholds and the outcomes curated here.

Guideline-Directed Medical Therapy for HFrEF

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin receptor-neprilysin inhibitor NCIT:C190796 beta-blocker NCIT:C29576 mineralocorticoid receptor antagonist NCIT:C101255 SGLT2 inhibitor NCIT:C98083 loop diuretic NCIT:C49184

Platform: Small molecule

There is no genotype-specific therapy for CMD1O. Management is the standard four-pillar regimen for heart failure with reduced ejection fraction - an angiotensin receptor-neprilysin inhibitor (or an ACE inhibitor/ARB where ARNI is unsuitable), an evidence-based beta-blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor - with a loop diuretic added for congestion. Nothing in this regimen addresses the KATP lesion; it treats the downstream remodeling and neurohormonal arms.

Mechanism Target:

INHIBITS Calcineurin-Dependent Maladaptive Remodeling — Neurohormonal blockade and SGLT2 inhibition act on the remodeling arm of the chain, downstream of the channel defect, which is why they are expected to work in CMD1O exactly as in other dilated cardiomyopathies and equally why they are not disease-modifying for the lesion itself.

Show evidence (1 reference)

PMID:37653361 SUPPORT Other

"recommendations on treatments such as sodium glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNIs)"

Names the guideline-recommended drug classes that constitute this treatment. The recommendation is for heart failure generally, not for CMD1O.

Implantable Cardioverter-Defibrillator

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

Platform: Device

Secondary prevention after a malignant ventricular arrhythmia or cardiac arrest, and primary prevention by standard criteria after therapy is optimised. The arrhythmic phenotype of the founding CMD1O cases makes this salient, but there is no CMD1O-specific risk score and the criteria for prophylactic implantation are one of the areas where DCM guidelines explicitly diverge.

Mechanism Target:

INHIBITS Ventricular Electrical Instability — Terminates ventricular arrhythmia rather than preventing the electrical substrate that generates it.

Show evidence (1 reference)

PMID:39674807 SUPPORT Other

"Nonetheless, notable areas of variation included the formation of multidisciplinary management teams, the role of cascade genetic testing, pathways for arrhythmic risk stratification, and the criteria for prophylactic defibrillator implantation."

Documents that defibrillator implantation criteria are a point of guideline divergence, which is the caveat this treatment records.

Heart Transplantation

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

Platform: Surgery

For advanced heart failure refractory to medical and device therapy, by standard criteria; mechanical circulatory support may bridge to it. Both male family members in the founding report died of heart failure without reaching transplantation, in an era before contemporary HFrEF therapy.

Mechanism Target:

BYPASSES Structural Cardiac Impairment and Heart Failure — Replaces the failing organ; the only intervention that removes the ABCC9-variant myocardium.

Show evidence (1 reference)

PMID:39674807 SUPPORT Other

"Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of..."

Records guideline consensus on the management of advanced disease, of which transplantation is the endpoint.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Appropriate for at-risk families, but the counselling content is unusual here: the conversation has to include that the ABCC9-DCM relationship is classified as Limited. Cascade predictive testing is justified only for a familial variant independently classified as pathogenic or likely pathogenic with persuasive segregation; it should not be offered on an ABCC9 variant of uncertain significance as though disease were certain.

Show evidence (2 references)

PMID:33947203 SUPPORT Other

"We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."

The recommendation that shapes what a counselling conversation about an ABCC9 result can honestly claim.

CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z SUPPORT Other

The classification that must be disclosed in counselling.

🔬

Diagnosis

5

Cardiac Magnetic Resonance Imaging

Recommended in the initial evaluation for function and tissue characterization, and specifically for separating a primary cardiomyopathy from its phenocopies - which matters here, because ABCC9 carries only Limited gene-disease validity and the differential does most of the diagnostic work. Late gadolinium enhancement also informs arrhythmic risk, and so sits behind the defibrillator decision this entry already curates.

cardiac magnetic resonance imaging with tissue characterization NCIT:C137915

The deep-research report gives a quantitative late-gadolinium-enhancement threshold predicting sudden cardiac death. That figure is not present in any reference cached for this entry and is therefore not curated.

Show evidence (1 reference)

PMID:39674807 SUPPORT Other

"cardiac magnetic resonance (CMR) is universally recommended for its ability to assess cardiac function and tissue characterization during the initial evaluation, as well as for identifying specific cardiomyopathy phenotypes and distinguishing them from phenocopies."

Establishes cardiac magnetic resonance in the initial evaluation and, specifically, its role in distinguishing cardiomyopathy phenotypes from phenocopies.

B-type Natriuretic Peptide and Cardiac Troponin

Circulating markers used both to establish the diagnosis and to grade severity, prognosis and treatment response. They are not ABCC9-specific and carry no genotype information; they are curated because the entry otherwise describes a heart-failure phenotype with no laboratory assessment attached to it.

B-type natriuretic peptide and cardiac troponin measurement NCIT:C25294

Show evidence (1 reference)

PMID:39674807 SUPPORT Other

"All guidelines and recommendations endorse the use of B-type natriuretic peptide (BNP) and troponin assessments as primary diagnostic tools, not only for initial diagnosis but also for evaluating severity, prognosis, and response to treatment."

Supports both analytes as primary diagnostic tools and names the severity, prognosis and treatment-response uses curated here.

Echocardiography

First-line and usually diagnostic. Left-ventricular internal dimensions and ejection fraction establish the dilated, hypocontractile phenotype. Nothing about the imaging is ABCC9-specific, and the diagnosis of dilated cardiomyopathy remains a clinical one requiring exclusion of coronary disease and abnormal loading.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:39674807 SUPPORT Other

"Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of..."

Records guideline consensus that multimodality cardiovascular imaging is essential for the initial diagnosis of dilated cardiomyopathy.

Ambulatory Rhythm Monitoring

Because ventricular tachycardia is part of the CMD1O concept rather than an incidental complication, rhythm assessment carries more weight here than in a purely mechanical dilated cardiomyopathy. There is no CMD1O-specific monitoring protocol; this reflects the arrhythmic phenotype of the founding cases and the general arrhythmic-risk-stratification pathway for DCM, which is itself an area where guidelines diverge.

ambulatory electrocardiographic monitoring NCIT:C38064

Show evidence (1 reference)

PMID:15034580 SUPPORT Human Clinical

"Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."

Rhythm disturbance was part of the phenotype in which the founding variants were ascertained, which is why rhythm assessment belongs in this workup.

Cardiomyopathy Gene Panel Testing

A phenotype-focused, evidence-curated cardiomyopathy panel rather than ABCC9-only testing. ABCC9 appears on many commercial panels as a limited-evidence gene; a variant found there is not diagnostic, must not drive cascade predictive testing on its own, and should be interpreted against the ClinGen classification of the gene-disease relationship as Limited.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:33947203 SUPPORT Other

"Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence."

Documents that commercial panels carry minimal-evidence genes, which is the interpretive hazard this diagnostic entry warns about.

PMID:33947203 SUPPORT Other

"We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."

The recommendation that governs how an ABCC9 result on such a panel should be handled.

📊

Prevalence

2

Worldwide

Unknown Not yet documented

There is no CMD1O-specific prevalence, incidence or carrier-frequency estimate, and none can be derived while the gene-disease relationship is classified as Limited. The only denominator in the literature is the founding screen — two ABCC9 variants among 323 people with idiopathic dilated cardiomyopathy — which is a yield within a selected case series and must not be converted into a population rate. Dilated cardiomyopathy as a whole has been estimated at approximately 1 in 250 adults; ABCC9 accounts for no established share of that.

Show evidence (1 reference)

PMID:39394525 SUPPORT Other

"The prevalence of DCM has been estimated at approximately 1 in 250 adults"

Supplies the all-cause dilated cardiomyopathy prevalence that frames this record. It is deliberately not a CMD1O figure, which is the point the record makes.

Worldwide

Unknown Unknown

Sex distribution is unknown for CMD1O; the two index cases were one woman and one man. Recorded here only because dilated cardiomyopathy overall carries a roughly 2:1 male excess that persists in genotype-positive patients, so a future CMD1O series should be read against that background rather than against an assumption of equal ascertainment.

Show evidence (1 reference)

PMID:39895490 SUPPORT Human Clinical

"The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28-0.32), corresponding to a male:female ratio (M:F) of 2.38:1."

Quantifies the all-cause dilated cardiomyopathy sex ratio that this record uses as background. Not a CMD1O measurement.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1O:

ABCC9-related intellectual disability and myopathy syndrome

Overlapping Features The other ABCC9 loss-of-function disease and the one most likely to be conflated with CMD1O, because both are described in the literature as KATP loss of function in the same gene. They are not the same disease. AIMS is autosomal RECESSIVE and requires BIALLELIC loss of function; its defining features are intellectual disability, myopathy with fatigability, and cerebral white matter abnormalities, with cardiac systolic dysfunction appearing only in older affected individuals as one feature among many. CMD1O is asserted as dominant, is cardiac-restricted, and is attributed to heterozygous catalytic-domain alleles. The decisive discriminator is that heterozygous carriers of AIMS alleles show no conserved clinical pathology. A curated dismech entry for AIMS exists separately and was deliberately not edited by this curation.

Show evidence (3 references)

PMID:31575858 SUPPORT Human Clinical

"We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS)."

Names the separate recessive disease entity that must not be merged with CMD1O.

PMID:38217872 SUPPORT Human Clinical

"Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness."

The AIMS phenotype, which is neurological and myopathic rather than a primary dilated cardiomyopathy.

PMID:38217872 SUPPORT Human Clinical

"Heterozygous parents do not show any conserved clinical pathology"

The discriminating observation - one AIMS allele does not produce the AIMS phenotype, so a dominant ABCC9 cardiac disease is a separate claim.

Cantu syndrome

Overlapping Features The gain-of-function pole of ABCC9 disease, and the mechanistic opposite of both CMD1O and AIMS. Cantu syndrome is autosomal dominant like CMD1O, so mode of inheritance does not separate them; the direction of the channel defect and the multisystem phenotype - hypertrichosis, vasodilation, hypotension, cardiomegaly - do. A report that says only "ABCC9 variant" without a direction cannot be assigned to any of the three.

Show evidence (1 reference)

PMID:31575858 SUPPORT Human Clinical

"The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function."

States the direction of the Cantu channel defect and that it produces a different phenotype from ABCC9 loss of function.

Sarcomeric and cytoskeletal dilated cardiomyopathy

Overlapping Features The high-evidence genetic causes of dilated cardiomyopathy - TTN, LMNA, FLNC, DSP, RBM20, PLN, BAG3, SCN5A, MYH7 and the other definitive and strong genes - are the differential that matters clinically, because they are what a cardiomyopathy panel is actually for and because an ABCC9 variant found alongside one of them does not explain the case. LMNA and FLNC in particular carry arrhythmic risk that changes management, so an arrhythmic dilated cardiomyopathy should not be attributed to ABCC9 until those are excluded.

Show evidence (1 reference)

PMID:33947203 SUPPORT Other

"Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence."

Names the high-evidence DCM genes that constitute this differential and that should be interrogated before an ABCC9 variant is invoked.

🐁

Animal Models

4

Kir6.2/KCNJ11-null mouse under experimental hypertension

Pathway-level rather than allele-level. This model removes the pore subunit of the same channel complex, not the ABCC9 regulatory subunit, and it removes it entirely rather than reproducing a C-terminal catalytic-domain variant. Its value is that it isolates the stress-conditional logic of the lesion: baseline findings are comparatively mild, and hypertension unmasks calcium overload, calcineurin-dependent remodeling, heart failure and death.

Species

Mouse

Genotype

Kcnj11 knockout (Kir6.2-null)

Publication

PMID:16782803

Pathograph links

Failure of Metabolic-Electrical Adaptation Under Cardiac Stress partially recapitulates fidelity: moderate Reproduces the failure of metabolic-electrical adaptation and its unmasking by imposed hemodynamic load.

Limitations: The deleted gene is KCNJ11, not ABCC9, so this is the pore subunit rather than the regulatory subunit in which the human variants sit; and it is a complete knockout, which cannot model a variant whose proposed defect is displaced catalysis in a subunit that is still present.

Show evidence (1 reference)

PMID:16782803 SUPPORT Model Organism

"The intact KCNJ11-encoded K(ATP) channel is thus a required safety element preventing hypertension-induced heart failure"

Establishes the channel as a stress-conditional protective element, which is the node this link addresses.

Cytosolic Calcium Overload recapitulates fidelity: moderate Calcium overload is demonstrated and, more usefully, shown to be the operative intermediate by rescue through an alternative route of calcium control.

Limitations: Again a KCNJ11 rather than ABCC9 lesion; the inference that an ABCC9 catalytic-domain variant produces the same calcium phenotype has not been tested directly.

Readouts

Myocardial calcium influx after alternative pharmacological control

Direction: RESTORED

Interpretation: Bypassing the uncoupled metabolic-electrical step rescued the failing phenotype, which is what identifies calcium influx as causal rather than correlative.

Show evidence (1 reference)

PMID:16782803 SUPPORT Model Organism

"Rescue of the failing K(ATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration."

Reports the rescue measurement behind this readout.

Show evidence (1 reference)

PMID:16782803 SUPPORT Model Organism

"Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."

Supports treating this model as informative for the calcium-overload node.

SUR2/Abcc9 loss-of-function mouse

The closest available mouse model by gene, generated in the course of defining the recessive ABCC9 disorder rather than CMD1O. SUR2 loss produces fatigability and cardiac dysfunction. It is a complete loss-of-function model of the whole subunit, so it speaks to the pathway and not to the dominant catalytic-domain allele class.

Species

Mouse

Genotype

Abcc9 (SUR2) loss of function

Publication

PMID:31575858

Pathograph links

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate Cardiac dysfunction in the SUR2 loss-of-function mouse reproduces the contractile half of the mechanical endpoint of the human chain, without the dilated geometry being reported here.

Limitations: A complete loss-of-function model made for the recessive AIMS phenotype, not a heterozygous knock-in of a C-terminal catalytic-domain allele; and global SUR2 loss additionally removes vascular smooth-muscle KATP channels, with hypertension and coronary vasospasm, so the cardiac readout is not cell-autonomously attributable to the cardiomyocyte.

Show evidence (1 reference)

PMID:31575858 SUPPORT Model Organism

"SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."

Supports treating SUR2 loss-of-function mice as informative for the cardiac endpoint of this entry.

abcc9 loss-of-function zebrafish

The one animal model that reproduces the geometry CMD1O is named for. abcc9 loss-of-function zebrafish show reduced activity, cardiac dysfunction and ventricular enlargement. As with the mouse, it is a complete loss-of-function model built for the recessive disorder, not a heterozygous catalytic-domain allele.

Species

Zebrafish

Genotype

abcc9 loss of function

Publication

PMID:31575858

Pathograph links

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate Ventricular enlargement together with cardiac dysfunction is the closest animal counterpart of the human dilated, hypocontractile ventricle.

Limitations: A fish two-chambered heart is not a four-chambered mammalian one, the allele is a complete loss of function rather than the human catalytic-domain variant class, and zebrafish KATP channels respond differently to some pharmacological openers, which limits how far the model can be pushed.

Readouts

Ventricular chamber size in abcc9 loss-of-function zebrafish

Direction: INCREASED

Interpretation: Ventricular enlargement in the fish is the closest animal counterpart of the human dilated geometry.

Show evidence (1 reference)

PMID:31575858 SUPPORT Model Organism

"SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."

Reports the ventricular enlargement and cardiac dysfunction behind this readout.

Show evidence (1 reference)

PMID:31575858 SUPPORT Model Organism

"SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."

Supports treating abcc9 loss-of-function zebrafish as informative for the cardiac endpoint of this entry.

Adult cardiomyocyte-specific SUR2 deletion mouse

The negative control the entry needs, and the single most important caveat on its mechanism. Deleting SUR2 selectively in the ADULT myocardium did not cause cardiomyopathy - it enhanced cardiomyocyte glucose uptake and protected against ischemia-reperfusion injury. Timing and tissue restriction therefore change the sign of the result, which argues against any simple rule that reduced cardiac SUR2 function produces dilated cardiomyopathy.

Species

Mouse

Genotype

Adult myocardium-restricted Abcc9 (SUR2) deletion

Publication

PMID:31061927

Pathograph links

Failure of Metabolic-Electrical Adaptation Under Cardiac Stress fails to recapitulate fidelity: moderate Adult cardiomyocyte-restricted removal of the same subunit produced protection from ischemic stress rather than failed stress adaptation, the opposite direction to the node.

Limitations: This is a conditional complete deletion in the adult heart, not a germline heterozygous catalytic-domain variant, and its protective effect is attributed to a metabolic shift toward glucose uptake rather than to restored channel gating. It therefore constrains the causal claim without refuting the human association, and the discrepancy may reflect developmental timing, allele class, or the type of stress imposed.

Readouts

Cardiomyocyte glucose uptake after adult SUR2 deletion

Direction: INCREASED

Interpretation: The metabolic consequence of adult SUR2 deletion is a shift toward glucose utilisation, a compensation rather than the predicted failure.

Show evidence (1 reference)

PMID:31061927 SUPPORT Model Organism

"SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter."

Reports the glucose-uptake measurement behind this readout.

Show evidence (1 reference)

PMID:31061927 REFUTE Model Organism

"This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury."

Contradicts the expectation that loss of cardiac SUR2 function impairs the myocardial stress response, which is what this node asserts for the human variants.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1O
creation_date: "2026-09-04T02:26:58Z"
category: Mendelian
synonyms:
- CMD1O
- DCM1O
- cardiomyopathy, dilated, 1O
- cardiomyopathy, dilated, type 1O
- dilated cardiomyopathy type 1O
- dilated cardiomyopathy with ventricular tachycardia
- cardiomyopathy, dilated, with ventricular tachycardia
- ABCC9 familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in ABCC9
- ABCC9-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1O (CMD1O) is the ABCC9-attributed node of the familial
  isolated dilated cardiomyopathy series, and it is the one member of that series
  whose proposed lesion is not sarcomeric or cytoskeletal. ABCC9 encodes
  sulfonylurea receptor 2; its cardiac splice form SUR2A is the regulatory
  subunit that, with the Kir6.2 pore encoded by KCNJ11, builds the sarcolemmal
  ATP-sensitive potassium (KATP) channel of the ventricular cardiomyocyte. That
  channel is not a contractile element at all — it is a metabolic sensor, a
  nucleotide-gated rheostat that reads the cytosolic ATP/ADP ratio and adjusts
  action-potential duration and membrane-potential-dependent work to match
  available energy. The disease is therefore modelled here as a channelopathy
  route into dilated cardiomyopathy: the failure is in metabolic-stress
  adaptation, not in force generation.


  The two founding alleles both sit in exon 38, in conserved C-terminal sequence
  flanking the second catalytic ATPase pocket of SUR2A — a missense
  c.4537G>A p.(Ala1513Thr) and a frameshift c.4570_4572delTTAinsAAAT
  p.(Leu1524fs) that appends four aberrant residues and terminates early. The
  reported defect is correspondingly specific: recombinant mutant SUR2A
  redistributes the conformational states of its intrinsic ATP hydrolytic cycle,
  so the pore is no longer correctly gated by Mg-nucleotide occupancy. That is a
  catalytic/regulatory failure rather than an absence of potassium permeation,
  and this entry curates it at that level rather than collapsing it to generic
  loss of function.


  THE GENE-DISEASE RELATIONSHIP IS NOT ESTABLISHED. The ClinGen Dilated
  Cardiomyopathy Gene Curation Expert Panel classified ABCC9-dilated
  cardiomyopathy as LIMITED on 2024-11-15 under SOP10, and the same panel's
  published curation of 51 DCM genes recommends that only high-evidence genes
  drive clinical practice. The human evidence is two index cases from a
  323-patient screen, one affected but ungenotyped father, and a ClinVar spectrum
  dominated by variants of uncertain significance. The pathophysiology below is
  curated as a proposed mechanism, and the dispute is carried on the genetic
  block, in a dedicated discussion, and on the causal edges.


  CMD1O is not either of the other two ABCC9 diseases and must not be merged with
  them. AIMS (ABCC9-related intellectual disability and myopathy syndrome,
  curated separately) is autosomal RECESSIVE, caused by BIALLELIC loss of
  function, and presents with intellectual disability, myopathy and cerebral
  white matter disease — its heterozygous carriers show no conserved clinical
  pathology, which is precisely what CMD1O claims heterozygotes do have. Cantu
  syndrome is autosomal dominant but arises from GAIN-of-function ABCC9 variants
  and is mechanistically the opposite pole. CMD1O is the third position: dominant,
  cardiac-restricted, and attributed to a regulatory rather than a null defect.
disease_term:
  preferred_term: dilated cardiomyopathy 1O
  term:
    id: MONDO:0012062
    label: dilated cardiomyopathy 1O
parents:
- Dilated Cardiomyopathy
- Channelopathy
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  channelopathy_category:
    classification_value: cardiac channelopathy
    notes: >-
      CMD1O is a KATP channelopathy of the ventricular cardiomyocyte. Note that
      the value is used here for a channel defect that presents as structural and
      contractile disease rather than as a primary rhythm syndrome in a
      structurally normal heart: ventricular tachycardia was prominent in both
      index cases, but the defining phenotype is chamber dilation with severely
      reduced systolic function. This is also why the entry conforms to
      cardiomyopathy_maladaptive_remodeling and NOT to
      cardiac_ion_channel_repolarization, whose scope is explicitly inherited
      arrhythmia syndromes in structurally normal hearts.
    evidence:
    - reference: PMID:20033705
      reference_title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."
      explanation: >-
        Names CMD1O explicitly as a KATP channelopathy with combined mechanical
        and electrical heart disease, which is the classification asserted here.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    There is no CMD1O-specific prevalence, incidence or carrier-frequency
    estimate, and none can be derived while the gene-disease relationship is
    classified as Limited. The only denominator in the literature is the founding
    screen — two ABCC9 variants among 323 people with idiopathic dilated
    cardiomyopathy — which is a yield within a selected case series and must not
    be converted into a population rate. Dilated cardiomyopathy as a whole has
    been estimated at approximately 1 in 250 adults; ABCC9 accounts for no
    established share of that.
  evidence:
  - reference: PMID:39394525
    reference_title: "Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The prevalence of DCM has been estimated at approximately 1 in 250 adults"
    explanation: >-
      Supplies the all-cause dilated cardiomyopathy prevalence that frames this
      record. It is deliberately not a CMD1O figure, which is the point the
      record makes.
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Sex distribution is unknown for CMD1O; the two index cases were one woman and
    one man. Recorded here only because dilated cardiomyopathy overall carries a
    roughly 2:1 male excess that persists in genotype-positive patients, so a
    future CMD1O series should be read against that background rather than
    against an assumption of equal ascertainment.
  evidence:
  - reference: PMID:39895490
    reference_title: "Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28-0.32), corresponding to a male:female ratio (M:F) of 2.38:1."
    explanation: >-
      Quantifies the all-cause dilated cardiomyopathy sex ratio that this record
      uses as background. Not a CMD1O measurement.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The asserted model is autosomal dominant: both founding probands carried a
    heterozygous ABCC9 variant. The 2004 report additionally describes an affected
    parent in one family from whom DNA was not available, so the transmission was
    never genotype-confirmed; that family detail sits in the paper's paywalled
    body and is recorded here as context rather than as cited evidence.
    Penetrance and expressivity are unknown from two families, and ClinGen's
    autosomal dominant classification of the gene-disease relationship is
    Limited rather than an endorsement of the mode. The contrast with the
    recessive ABCC9 disorder is
    load-bearing rather than incidental — in AIMS, heterozygous parents of
    biallelic probands show no conserved clinical pathology, so a single ABCC9
    loss-of-function allele is not on its own sufficient for the AIMS phenotype.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      The founding human genetic observation on which the dominant model rests:
      heterozygous variants ascertained in affected individuals.
  - reference: PMID:38217872
    reference_title: "Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous parents do not show any conserved clinical pathology"
    explanation: >-
      Supports the separation of dominant CMD1O from recessive AIMS by an
      inference step - carriers of one AIMS allele do not manifest the AIMS
      phenotype, so any dominant ABCC9 cardiac disease has to be a different
      claim about a different allele class.
pathophysiology:
- name: ABCC9 C-Terminal Catalytic-Domain Variant
  description: >-
    A heterozygous exon-38 ABCC9 variant in conserved C-terminal sequence adjacent
    to the second catalytic ATPase pocket of SUR2A. The two founding alleles are a
    missense p.(Ala1513Thr) and a frameshift p.(Leu1524fs); neither is a simple
    whole-protein null, and the frameshift truncates within the nucleotide-binding
    region rather than removing the subunit. Their location is the mechanistic
    point - these residues sit where the receptor performs nucleotide catalysis,
    not where it conducts potassium.
  biological_scale: MOLECULAR
  downstream:
  - target: Aberrant SUR2A ATP Hydrolytic Cycle
    causal_link_type: DIRECT
    description: >-
      The variants were shown to alter the conformational behaviour of the
      recombinant receptor's own hydrolytic cycle.
    evidence:
    - reference: PMID:15034580
      reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding."
      explanation: >-
        Directly links the mutant protein to a disturbed ATP hydrolytic cycle,
        which is the step this edge asserts.
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A."
    explanation: >-
      States the allele class and the domain, which is what defines this node.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One is a frameshift mutation (c.4570_4572delinsAAAT, p.(Leu1524fs)) and the second one is a missense mutation (c.4537G>A, p.(Ala1513Thr)), both altering KATP channel function in vitro and suggesting a mechanistic link to DCM pathogenesis"
    explanation: >-
      Gives the coding and protein-level descriptions of both founding alleles as
      restated by a later review.
- name: Aberrant SUR2A ATP Hydrolytic Cycle
  description: >-
    SUR2A is an ABC protein and its nucleotide-binding domains hydrolyse ATP as
    part of normal channel operation; the hydrolytic cycle is the transduction
    step, not a housekeeping side reaction. In the mutant receptor the
    distribution of conformational states across that cycle is shifted, so the
    receptor no longer reports the prevailing Mg-nucleotide state faithfully to
    the pore. The defect is qualitative - regulation is displaced rather than
    simply reduced - which is why the modifier here is DYSREGULATED and not
    DECREASED.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: SUR2A nucleotide-binding-domain ATP hydrolysis
    modifier: DYSREGULATED
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
  downstream:
  - target: Defective Catalysis-Mediated KATP Pore Gating
    causal_link_type: DIRECT
    description: >-
      Disturbed catalysis in the regulatory subunit propagates to the gating of
      the Kir6.2 pore it controls.
    evidence:
    - reference: PMID:15034580
      reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy."
      explanation: >-
        The authors' own statement of the catalysis-to-pore-regulation step this
        edge draws.
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding."
    explanation: >-
      Establishes the hydrolytic-cycle abnormality as a measured property of the
      mutant proteins.
- name: Defective Catalysis-Mediated KATP Pore Gating
  description: >-
    The sarcolemmal KATP channel is an octamer of four SUR2A subunits around four
    Kir6.2 pores. With catalysis in SUR2A displaced, the pore's nucleotide
    sensitivity is set incorrectly: the channel is present and can conduct, but it
    is no longer under proper regulatory control by the cell's energetic state.
    That qualitative loss of regulatory control - rather than a quantitative drop
    in potassium current - is the reason this node carries LOSS_OF_FUNCTION rather
    than DECREASED.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: nucleotide-gated cardiac KATP channel activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0015272
      label: ATP-activated inward rectifier potassium channel activity
  downstream:
  - target: Compromised Metabolic Signal Decoding in the Cardiomyocyte
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15034580
      reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding."
      explanation: >-
        The same sentence states both the channel phenotype and the resulting
        failure to decode a metabolic signal, which is the edge asserted here.
  evidence:
  - reference: PMID:31061927
    reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The major ventricular cardiomyocyte KATP channel is composed of SUR2 and Kir6.2, encoded by ABCC9 and KCNJ11, respectively."
    explanation: >-
      Establishes the subunit composition of the channel whose gating this node
      describes, and so which cardiac channel an ABCC9 variant acts on.
  - reference: PMID:36170658
    reference_title: "Personalized Therapeutics for K(ATP)-Dependent Pathologies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCC9 gives rise to distinct SUR2A and SUR2B subunits that differ in the carboxyl terminal 42 amino acids."
    explanation: >-
      Explains why a C-terminal ABCC9 variant is isoform-relevant, since the
      cardiac SUR2A and vascular SUR2B forms differ precisely in that region.
- name: Compromised Metabolic Signal Decoding in the Cardiomyocyte
  description: >-
    In an intact ventricular cardiomyocyte the KATP channel behaves as a rheostat
    that couples the ATP/ADP ratio to membrane potential. When the receptor
    mis-reads that ratio, the coupling between energetic state and electrical
    behaviour is broken - the cell can no longer translate a metabolic signal into
    the appropriate change in potassium conductance and membrane potential.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: metabolically gated potassium efflux
    modifier: DYSREGULATED
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
  - preferred_term: coupling of energetic state to membrane potential
    modifier: DYSREGULATED
    term:
      id: GO:0042391
      label: regulation of membrane potential
  downstream:
  - target: Failure of Metabolic-Electrical Adaptation Under Cardiac Stress
    causal_link_type: DIRECT
    description: >-
      The consequence of mis-decoding is only exposed when energetic demand rises,
      which is what makes this a stress-conditional lesion.
    evidence:
    - reference: PMID:15034580
      reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K(ATP)) channels that adjust membrane potential-dependent functions to match cellular energetic demand."
      explanation: >-
        States the premise this edge depends on - that the decoded metabolic
        signal is what confers stress tolerance, so mis-decoding shows up as
        failed adaptation.
  evidence:
  - reference: PMID:20033705
    reference_title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands."
    explanation: >-
      Defines the normal decoding function whose failure this node describes.
  - reference: PMID:36170658
    reference_title: "Personalized Therapeutics for K(ATP)-Dependent Pathologies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ubiquitously expressed throughout the body, ATP-sensitive potassium (KATP) channels couple cellular metabolism to electrical activity in multiple tissues"
    explanation: >-
      Independent statement of the metabolism-to-electrical-activity coupling this
      node claims is broken.
- name: Failure of Metabolic-Electrical Adaptation Under Cardiac Stress
  description: >-
    This is the primary myocyte insult of CMD1O, and it is conditional rather than
    constitutive: at rest the heart is largely unremarkable, and the deficit
    emerges when adrenergic, ischemic, exercise or pressure load raises energetic
    demand and the myocyte cannot shorten its action potential and trim its
    membrane-potential-dependent work accordingly. The direct human demonstration
    is missing; the step is supported by KATP-deficient animals, in which baseline
    phenotypes are mild and the failure is unmasked by imposed stress.
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: stress-adaptive shortening of the cardiac action potential
    modifier: DECREASED
    term:
      id: GO:0099622
      label: cardiac muscle cell membrane repolarization
  - preferred_term: myocardial response to ischemic and energetic stress
    modifier: DECREASED
    term:
      id: GO:0002931
      label: response to ischemia
  downstream:
  - target: Cytosolic Calcium Overload
    causal_link_type: DIRECT
    description: >-
      In the Kir6.2-null mouse the uncoupling of metabolic distress from membrane
      response is what sets calcium overload in motion. The step is
      pathway-level rather than ABCC9-allele-specific.
    evidence:
    - reference: PMID:16782803
      reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."
      explanation: >-
        Demonstrates the decoding-failure-to-calcium-overload step, but in a
        Kir6.2 pore knockout rather than in an ABCC9 regulatory-subunit variant,
        so it reaches CMD1O by an inference step across the channel complex.
  evidence:
  - reference: PMID:15910878
    reference_title: "Cardiac KATP channels in health and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "K(ATP) channels have been further implicated in the adaptive cardiac response to chronic (patho)physiologic hemodynamic load, with K(ATP) channel deficiency affecting structural remodeling, rendering the heart vulnerable to calcium-dependent maladaptation and predisposing to heart failure."
    explanation: >-
      States the adaptive role under chronic load whose failure defines this node,
      and names the calcium-dependent maladaptation that follows it.
  - reference: PMID:16782803
    reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The intact KCNJ11-encoded K(ATP) channel is thus a required safety element preventing hypertension-induced heart failure"
    explanation: >-
      Frames the channel as a stress-conditional safety element, supporting this
      node through the pore subunit rather than the regulatory subunit.
- name: Cytosolic Calcium Overload
  description: >-
    Loss of the KATP-dependent brake on membrane-potential-dependent calcium entry
    permits pathological calcium accumulation in the stressed myocyte. That this
    is the operative intermediate, and not merely a correlate, is shown by rescue:
    in the Kir6.2-null mouse the failing phenotype was corrected by controlling
    myocardial calcium influx by an alternative route, bypassing the uncoupled
    metabolic-electrical step entirely.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: cardiomyocyte calcium homeostasis
    modifier: DYSREGULATED
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  downstream:
  - target: Calcineurin-Dependent Maladaptive Remodeling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16782803
      reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."
      explanation: >-
        Names calcium overload as the driver of remodeling and identifies the
        calcineurin pathway that carries it, in a KATP pore knockout.
  - target: Ventricular Electrical Instability
    causal_link_type: DIRECT
    description: >-
      Calcium overload in a myocyte whose repolarization is already
      unadapted is the arrhythmic arm of the branch.
    evidence:
    - reference: PMID:15910878
      reference_title: "Cardiac KATP channels in health and disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "K(ATP) channels have been further implicated in the adaptive cardiac response to chronic (patho)physiologic hemodynamic load, with K(ATP) channel deficiency affecting structural remodeling, rendering the heart vulnerable to calcium-dependent maladaptation and predisposing to heart failure."
      explanation: >-
        Supports calcium-dependent maladaptation as the shared consequence of
        channel deficiency; the specifically arrhythmic reading of it is an
        inference step from this review's framing.
  evidence:
  - reference: PMID:16782803
    reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Rescue of the failing K(ATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration."
    explanation: >-
      The rescue experiment that establishes calcium influx as the operative
      intermediate rather than an epiphenomenon, in the pore-subunit knockout.
  - reference: PMID:31061927
    reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In the mouse, genetic deletion of Kir6.2 leads to calcium overload and myocardial damage"
    explanation: >-
      Independent restatement that removing the channel produces calcium overload
      and myocyte damage, again via the pore subunit.
- name: Calcineurin-Dependent Maladaptive Remodeling
  description: >-
    Sustained calcium loading activates the calcineurin-NFAT axis and drives a
    hypertrophic and profibrotic transcriptional programme, converting a
    reversible signalling failure into structural change. In the KATP knockout
    this arm is cyclosporine-sensitive, which is what identifies calcineurin as
    the mediator rather than a bystander.
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_processes:
  - preferred_term: calcineurin-NFAT signaling
    modifier: INCREASED
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
  - preferred_term: stress-induced cardiac muscle hypertrophy
    modifier: INCREASED
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15910878
      reference_title: "Cardiac KATP channels in health and disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "K(ATP) channels have been further implicated in the adaptive cardiac response to chronic (patho)physiologic hemodynamic load, with K(ATP) channel deficiency affecting structural remodeling, rendering the heart vulnerable to calcium-dependent maladaptation and predisposing to heart failure."
      explanation: >-
        Connects channel deficiency through structural remodeling to heart
        failure, which is the remodeling-to-contractile-failure step drawn here.
  evidence:
  - reference: PMID:16782803
    reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."
    explanation: >-
      Identifies the calcineurin-dependent, cyclosporine-sensitive remodeling
      pathway that this node names, in the KATP pore knockout.
- name: Ventricular Electrical Instability
  description: >-
    The electrical arm of the branch. A ventricle whose repolarization no longer
    tracks energetic state and whose myocytes are calcium-loaded supports
    triggered and re-entrant activity; ventricular tachycardia and rhythm
    disturbance were prominent in both founding CMD1O probands and are part of
    what distinguishes the ABCC9 phenotype within the DCM series.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: ventricular cardiac action potential
    modifier: DYSREGULATED
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
  downstream:
  - target: Ventricular tachycardia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20033705
      reference_title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."
      explanation: >-
        States that the CMD1O phenotype includes ventricular arrhythmia alongside
        the mechanical disease, which is the edge drawn here.
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      The probands were ascertained with rhythm disturbances as well as heart
      failure, which is the clinical basis for an electrical arm in this graph.
- name: Left Ventricular Dilation and Systolic Dysfunction
  description: >-
    The mechanical arm and the defining phenotype: progressive chamber enlargement
    with severely impaired contraction, arrived at from a metabolic-sensing lesion
    rather than from a contractile-protein defect. Every affected individual in
    the founding report presented in adulthood with severe disease already
    established at diagnosis.
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Left ventricular dilatation
    causal_link_type: DIRECT
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
  - target: Structural Cardiac Impairment and Heart Failure
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:15910878
    reference_title: "Cardiac KATP channels in health and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings are underscored by the identification in humans that defective K(ATP) channels induced by mutations in ABCC9, the gene encoding the cardiac sulfonylurea receptor subunit, confer susceptibility to dilated cardiomyopathy."
    explanation: >-
      States the human endpoint of the chain in the terms this entry uses -
      susceptibility conferred by defective channels, not a proven monogenic
      cause.
- name: Structural Cardiac Impairment and Heart Failure
  description: >-
    End-stage low-output and congestive physiology. The founding report describes
    fatal heart failure in affected family members within a few years of
    diagnosis, but the ages and intervals sit in the paper's paywalled body and,
    at two deaths in an ascertainment-biased series, would not constitute a
    survival estimate even if they were citable.
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      The founding probands were ascertained with heart failure, which is the
      clinical endpoint this node names.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    The defining phenotype. Present in both index cases and in the clinically
    affected but ungenotyped parent of one of them. Onset was insidious and adult,
    with severe disease already established when first recognised. The individual
    ages at diagnosis are reported only in the paper's paywalled body and are not
    asserted here.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      The ascertainment phenotype of the founding cohort was idiopathic dilated
      cardiomyopathy.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Initial discoveries highlighted two specific mutations in exon 38 based on a genetic screening of 323 DCM patients."
    explanation: >-
      Restates the denominator and the disease context of the founding
      observation.
- category: Cardiovascular
  name: Left ventricular dilatation
  description: >-
    Chamber enlargement is the structural correlate. Reported left-ventricular
    end-diastolic dimensions in the founding families were markedly increased.
    Frequency is recorded as observed in the founding cases, not as a population
    estimate.
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:20033705
    reference_title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."
    explanation: >-
      Places CMD1O among the mechanical heart diseases of the KATP channelopathy
      group, of which ventricular dilation is the structural expression.
- category: Cardiovascular
  name: Reduced left ventricular ejection fraction
  description: >-
    Systolic function was impaired in every affected individual described, and the
    founding report characterises the disease as severe. The binding is
    deliberately the ungraded parent term rather than the severe grade
    (HP:0012666), because assigning a grade would rest on ejection-fraction values
    that appear only in the paywalled body of the 2004 paper and cannot be
    supported by a verified snippet.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:15910878
    reference_title: "Cardiac KATP channels in health and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings are underscored by the identification in humans that defective K(ATP) channels induced by mutations in ABCC9, the gene encoding the cardiac sulfonylurea receptor subunit, confer susceptibility to dilated cardiomyopathy."
    explanation: >-
      Supports the human dilated-cardiomyopathy phenotype of which severe systolic
      impairment is the functional measure. The individual ejection-fraction
      values quoted in the deep-research report are not in any cached abstract and
      are therefore not asserted here as sourced numbers.
- category: Cardiovascular
  name: Ventricular tachycardia
  description: >-
    Rhythm disturbance was part of the ascertainment phenotype of both founding
    probands, and the arrhythmic component is written into the concept - one of
    MONDO's own synonyms for this disease is "dilated cardiomyopathy with
    ventricular tachycardia". It is what most distinguishes CMD1O clinically from
    the sarcomeric members of the numbered DCM series.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:20033705
    reference_title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation."
    explanation: >-
      Explicitly attaches ventricular arrhythmia to the CMD1O concept.
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      Records rhythm disturbance as part of the phenotype in which the founding
      variants were found.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Progressive heart failure was the terminal event in the two affected men
    described in the founding report. Recorded as observed in those cases; no
    frequency is asserted.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      Heart failure was the presenting syndrome of the individuals in whom the
      founding ABCC9 variants were identified.
genetic:
- name: ABCC9 variants of limited clinical validity for dilated cardiomyopathy
  gene_term:
    preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  association: Limited
  relationship_type: DISPUTED
  notes: >-
    Curated as DISPUTED rather than CAUSATIVE. The ClinGen Dilated Cardiomyopathy
    Gene Curation Expert Panel classified the ABCC9-dilated cardiomyopathy
    relationship as LIMITED on 2024-11-15 under SOP10, filed against the parent
    concept MONDO:0005021 rather than against MONDO:0012062. The human evidence
    has the shape that produces a Limited call: two probands from one 323-patient
    screen; segregation supported only by an affected father from whom no DNA was
    available; no independent replication cohort with comparable functional work;
    and a ClinVar spectrum in which variants of uncertain significance dominate.
    Later reports have added further ABCC9 alleles in Mexican and Chinese DCM
    cohorts, which is genuine accumulation but has not yet moved the
    classification. MONDO nonetheless models CMD1O as a gene-anchored disease
    concept, which is why this entry exists - DISPUTED records the evidence state,
    it does not retire the concept.
  variants:
  - name: p.(Ala1513Thr)
    description: >-
      Missense variant, c.4537G>A, in exon 38, in conserved C-terminal sequence
      adjacent to the second catalytic ATPase pocket of SUR2A. One of the two
      founding alleles from the 323-patient idiopathic dilated cardiomyopathy
      screen. Case-level particulars (the proband's sex and age at diagnosis, her
      affected father, and the size of the control panel) appear only in the
      paywalled body of the 2004 paper and are not snippet-verifiable from the
      cached record, so they are not asserted as cited evidence anywhere in this
      entry.
  - name: p.(Leu1524fs)
    description: >-
      Frameshift variant, c.4570_4572delTTAinsAAAT, in exon 38, generating
      aberrant terminal residues and a premature stop within the SUR2A
      nucleotide-binding region. The second founding allele from the same screen.
      Because the truncation falls inside the regulatory nucleotide-binding
      machinery rather than removing the subunit, its consequence is curated as a
      catalytic and regulatory defect, not as a whole-protein null. As above, the
      case-level particulars are in the paywalled body of the 2004 paper only.
  - name: p.(Arg1506fs)
    description: >-
      Frameshift variant c.4517_4527del, reported subsequently in Mexican patients
      with dilated cardiomyopathy. Listed as part of the accumulating allele
      spectrum; not independently functionally characterised here.
  - name: p.(Lys976Ile)
    description: >-
      Missense variant reported in a Chinese dilated cardiomyopathy cohort. Listed
      as part of the accumulating allele spectrum.
  - name: p.(Arg1197Cys)
    description: >-
      Missense variant reported in a Chinese dilated cardiomyopathy cohort. Listed
      as part of the accumulating allele spectrum.
  evidence:
  - reference: CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z
    reference_title: "ABCC9 / dilated cardiomyopathy (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "ABCC9 | HGNC:60 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: >-
      ClinGen's Dilated Cardiomyopathy GCEP classifies the ABCC9-DCM gene-disease
      relationship as Limited under an autosomal dominant model. Recorded as
      REFUTE against the implicit claim that ABCC9 is an established cause of
      dilated cardiomyopathy. Note the assertion is filed against the parent term
      MONDO:0005021, not against MONDO:0012062.
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."
    explanation: >-
      The published recommendation of the same expert panel, which is why this
      entry does not treat an ABCC9 variant as diagnostic.
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A."
    explanation: >-
      Establishes the allele class and domain location of the two founding
      variants recorded above.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Further research identified additional variants: the c.4517_4527del, p.(Arg1506fs) in Mexican DCM patients, and p.(Lys976Ile) and p.(Arg1197Cys) in a Chinese cohort"
    explanation: >-
      Source for the three later alleles listed in this block.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "In DCM, ABCC9 and MYH6 have a high number of variants, predominantly VUS."
    explanation: >-
      Recorded as REFUTE against the claim that ABCC9 variation is clinically
      interpretable in dilated cardiomyopathy - the ClinVar spectrum for this gene
      is dominated by variants of uncertain significance.
diagnosis:
- name: Cardiac Magnetic Resonance Imaging
  description: >-
    Recommended in the initial evaluation for function and tissue characterization, and
    specifically for separating a primary cardiomyopathy from its phenocopies - which
    matters here, because ABCC9 carries only Limited gene-disease validity and the
    differential does most of the diagnostic work. Late gadolinium enhancement also
    informs arrhythmic risk, and so sits behind the defibrillator decision this entry
    already curates.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with tissue characterization
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:39674807
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cardiac magnetic resonance (CMR) is universally recommended for its ability to assess cardiac function and tissue characterization during the initial evaluation, as well as for identifying specific cardiomyopathy phenotypes and distinguishing them from phenocopies."
    explanation: >-
      Establishes cardiac magnetic resonance in the initial evaluation and, specifically,
      its role in distinguishing cardiomyopathy phenotypes from phenocopies.
  notes: >-
    The deep-research report gives a quantitative late-gadolinium-enhancement threshold
    predicting sudden cardiac death. That figure is not present in any reference cached
    for this entry and is therefore not curated.
- name: B-type Natriuretic Peptide and Cardiac Troponin
  description: >-
    Circulating markers used both to establish the diagnosis and to grade severity,
    prognosis and treatment response. They are not ABCC9-specific and carry no genotype
    information; they are curated because the entry otherwise describes a heart-failure
    phenotype with no laboratory assessment attached to it.
  diagnosis_term:
    preferred_term: B-type natriuretic peptide and cardiac troponin measurement
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:39674807
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All guidelines and recommendations endorse the use of B-type natriuretic peptide (BNP) and troponin assessments as primary diagnostic tools, not only for initial diagnosis but also for evaluating severity, prognosis, and response to treatment."
    explanation: >-
      Supports both analytes as primary diagnostic tools and names the severity,
      prognosis and treatment-response uses curated here.
- name: Echocardiography
  description: >-
    First-line and usually diagnostic. Left-ventricular internal dimensions and
    ejection fraction establish the dilated, hypocontractile phenotype. Nothing
    about the imaging is ABCC9-specific, and the diagnosis of dilated
    cardiomyopathy remains a clinical one requiring exclusion of coronary disease
    and abnormal loading.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:39674807
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of advanced disease."
    explanation: >-
      Records guideline consensus that multimodality cardiovascular imaging is
      essential for the initial diagnosis of dilated cardiomyopathy.
- name: Ambulatory Rhythm Monitoring
  description: >-
    Because ventricular tachycardia is part of the CMD1O concept rather than an
    incidental complication, rhythm assessment carries more weight here than in a
    purely mechanical dilated cardiomyopathy. There is no CMD1O-specific
    monitoring protocol; this reflects the arrhythmic phenotype of the founding
    cases and the general arrhythmic-risk-stratification pathway for DCM, which is
    itself an area where guidelines diverge.
  diagnosis_term:
    preferred_term: ambulatory electrocardiographic monitoring
    term:
      id: NCIT:C38064
      label: Holter Monitoring
  evidence:
  - reference: PMID:15034580
    reference_title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel."
    explanation: >-
      Rhythm disturbance was part of the phenotype in which the founding variants
      were ascertained, which is why rhythm assessment belongs in this workup.
- name: Cardiomyopathy Gene Panel Testing
  description: >-
    A phenotype-focused, evidence-curated cardiomyopathy panel rather than
    ABCC9-only testing. ABCC9 appears on many commercial panels as a
    limited-evidence gene; a variant found there is not diagnostic, must not
    drive cascade predictive testing on its own, and should be interpreted against
    the ClinGen classification of the gene-disease relationship as Limited.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence."
    explanation: >-
      Documents that commercial panels carry minimal-evidence genes, which is the
      interpretive hazard this diagnostic entry warns about.
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."
    explanation: >-
      The recommendation that governs how an ABCC9 result on such a panel should
      be handled.
animal_models:
- name: Kir6.2/KCNJ11-null mouse under experimental hypertension
  species: Mouse
  genotype: Kcnj11 knockout (Kir6.2-null)
  publication: PMID:16782803
  description: >-
    Pathway-level rather than allele-level. This model removes the pore subunit of
    the same channel complex, not the ABCC9 regulatory subunit, and it removes it
    entirely rather than reproducing a C-terminal catalytic-domain variant. Its
    value is that it isolates the stress-conditional logic of the lesion: baseline
    findings are comparatively mild, and hypertension unmasks calcium overload,
    calcineurin-dependent remodeling, heart failure and death.
  modeled_mechanisms:
  - target: Failure of Metabolic-Electrical Adaptation Under Cardiac Stress
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the failure of metabolic-electrical adaptation and its unmasking
      by imposed hemodynamic load.
    limitations: >-
      The deleted gene is KCNJ11, not ABCC9, so this is the pore subunit rather
      than the regulatory subunit in which the human variants sit; and it is a
      complete knockout, which cannot model a variant whose proposed defect is
      displaced catalysis in a subunit that is still present.
    evidence:
    - reference: PMID:16782803
      reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The intact KCNJ11-encoded K(ATP) channel is thus a required safety element preventing hypertension-induced heart failure"
      explanation: >-
        Establishes the channel as a stress-conditional protective element, which
        is the node this link addresses.
  - target: Cytosolic Calcium Overload
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Calcium overload is demonstrated and, more usefully, shown to be the
      operative intermediate by rescue through an alternative route of calcium
      control.
    limitations: >-
      Again a KCNJ11 rather than ABCC9 lesion; the inference that an ABCC9
      catalytic-domain variant produces the same calcium phenotype has not been
      tested directly.
    readouts:
    - name: Myocardial calcium influx after alternative pharmacological control
      target: Cytosolic Calcium Overload
      direction: RESTORED
      interpretation: >-
        Bypassing the uncoupled metabolic-electrical step rescued the failing
        phenotype, which is what identifies calcium influx as causal rather than
        correlative.
      evidence:
      - reference: PMID:16782803
        reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Rescue of the failing K(ATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration."
        explanation: >-
          Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:16782803
      reference_title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway."
      explanation: >-
        Supports treating this model as informative for the calcium-overload node.
- name: SUR2/Abcc9 loss-of-function mouse
  species: Mouse
  genotype: Abcc9 (SUR2) loss of function
  publication: PMID:31575858
  description: >-
    The closest available mouse model by gene, generated in the course of defining
    the recessive ABCC9 disorder rather than CMD1O. SUR2 loss produces fatigability
    and cardiac dysfunction. It is a complete loss-of-function model of the whole
    subunit, so it speaks to the pathway and not to the dominant catalytic-domain
    allele class.
  modeled_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cardiac dysfunction in the SUR2 loss-of-function mouse reproduces the
      contractile half of the mechanical endpoint of the human chain, without the
      dilated geometry being reported here.
    limitations: >-
      A complete loss-of-function model made for the recessive AIMS phenotype, not
      a heterozygous knock-in of a C-terminal catalytic-domain allele; and global
      SUR2 loss additionally removes vascular smooth-muscle KATP channels, with
      hypertension and coronary vasospasm, so the cardiac readout is not
      cell-autonomously attributable to the cardiomyocyte.
    evidence:
    - reference: PMID:31575858
      reference_title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."
      explanation: >-
        Supports treating SUR2 loss-of-function mice as informative for the cardiac
        endpoint of this entry.
- name: abcc9 loss-of-function zebrafish
  species: Zebrafish
  genotype: abcc9 loss of function
  publication: PMID:31575858
  description: >-
    The one animal model that reproduces the geometry CMD1O is named for. abcc9
    loss-of-function zebrafish show reduced activity, cardiac dysfunction and
    ventricular enlargement. As with the mouse, it is a complete loss-of-function
    model built for the recessive disorder, not a heterozygous catalytic-domain
    allele.
  modeled_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Ventricular enlargement together with cardiac dysfunction is the closest
      animal counterpart of the human dilated, hypocontractile ventricle.
    limitations: >-
      A fish two-chambered heart is not a four-chambered mammalian one, the allele
      is a complete loss of function rather than the human catalytic-domain
      variant class, and zebrafish KATP channels respond differently to some
      pharmacological openers, which limits how far the model can be pushed.
    readouts:
    - name: Ventricular chamber size in abcc9 loss-of-function zebrafish
      target: Left Ventricular Dilation and Systolic Dysfunction
      direction: INCREASED
      interpretation: >-
        Ventricular enlargement in the fish is the closest animal counterpart of
        the human dilated geometry.
      evidence:
      - reference: PMID:31575858
        reference_title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."
        explanation: >-
          Reports the ventricular enlargement and cardiac dysfunction behind this
          readout.
    evidence:
    - reference: PMID:31575858
      reference_title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish."
      explanation: >-
        Supports treating abcc9 loss-of-function zebrafish as informative for the
        cardiac endpoint of this entry.
- name: Adult cardiomyocyte-specific SUR2 deletion mouse
  species: Mouse
  genotype: Adult myocardium-restricted Abcc9 (SUR2) deletion
  publication: PMID:31061927
  description: >-
    The negative control the entry needs, and the single most important caveat on
    its mechanism. Deleting SUR2 selectively in the ADULT myocardium did not cause
    cardiomyopathy - it enhanced cardiomyocyte glucose uptake and protected against
    ischemia-reperfusion injury. Timing and tissue restriction therefore change the
    sign of the result, which argues against any simple rule that reduced cardiac
    SUR2 function produces dilated cardiomyopathy.
  modeled_mechanisms:
  - target: Failure of Metabolic-Electrical Adaptation Under Cardiac Stress
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    description: >-
      Adult cardiomyocyte-restricted removal of the same subunit produced
      protection from ischemic stress rather than failed stress adaptation, the
      opposite direction to the node.
    limitations: >-
      This is a conditional complete deletion in the adult heart, not a germline
      heterozygous catalytic-domain variant, and its protective effect is
      attributed to a metabolic shift toward glucose uptake rather than to
      restored channel gating. It therefore constrains the causal claim without
      refuting the human association, and the discrepancy may reflect
      developmental timing, allele class, or the type of stress imposed.
    evidence:
    - reference: PMID:31061927
      reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury."
      explanation: >-
        Contradicts the expectation that loss of cardiac SUR2 function impairs the
        myocardial stress response, which is what this node asserts for the human
        variants.
    readouts:
    - name: Cardiomyocyte glucose uptake after adult SUR2 deletion
      target: Failure of Metabolic-Electrical Adaptation Under Cardiac Stress
      direction: INCREASED
      interpretation: >-
        The metabolic consequence of adult SUR2 deletion is a shift toward glucose
        utilisation, a compensation rather than the predicted failure.
      evidence:
      - reference: PMID:31061927
        reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter."
        explanation: >-
          Reports the glucose-uptake measurement behind this readout.
treatments:
- name: Clinical Surveillance of First-Degree Relatives
  description: >-
    The recommendation that survives this gene's weak validity. Because ABCC9 is only
    Limited for dilated cardiomyopathy, a variant result cannot be used to release a
    relative from follow-up - but familial dilated cardiomyopathy is itself an indication
    for periodic clinical and imaging surveillance of first-degree relatives regardless of
    genotype, aimed at detecting disease early enough to treat. This entry elsewhere warns
    against acting on the genotype; without this record it would leave a reader with no
    positive recommendation for the family at all.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cardiac surveillance of at-risk relatives
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."
    explanation: >-
      GeneReviews states the purpose of assessing at-risk asymptomatic relatives as
      informing cardiac surveillance for early detection and treatment, which is the
      recommendation curated here.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In first-degree relatives of selected patients with genetic or inherited cardiomyopathies for early detection and prompt management"
    explanation: >-
      Records the class-1 recommendation covering first-degree relatives of patients with
      inherited cardiomyopathy for early detection and prompt management.
  notes: >-
    Curated as surveillance rather than as cascade genetic testing. The distinction is
    load-bearing for this gene: the testing caveat is covered separately under genetic
    counselling, and a Limited-validity gene does not support predictive testing, whereas
    clinical follow-up of the family stands on the familial phenotype alone.
- name: Cardiac Resynchronization Therapy
  description: >-
    Device therapy for the subset who remain symptomatic on optimal medical therapy with a
    severely reduced ejection fraction and a wide left-bundle-branch QRS. It is downstream
    of the KATP lesion and entirely genotype-independent, but it belongs in the entry
    because the defibrillator is already curated and the two device decisions are made
    together in this population.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
  target_mechanisms:
  - target: Structural Cardiac Impairment and Heart Failure
    description: >-
      Resynchronizing ventricular activation improves pump efficiency in the dyssynchronous
      failing ventricle; it does not touch the upstream channel defect.
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac resynchronization therapy (CRT) is strongly recommended for symptomatic patients (NYHA class II-IV on best medical management) who have LVEF ≤ 35%, sinus rhythm, left bundle branch block (LBBB) with a QRS of ≥ 150 ms to reduce total mortality and hospitalizations, and improve symptoms and quality of life (CoR: 1)."
    explanation: >-
      States the indication, the eligibility thresholds and the outcomes curated here.
- name: Guideline-Directed Medical Therapy for HFrEF
  description: >-
    There is no genotype-specific therapy for CMD1O. Management is the standard
    four-pillar regimen for heart failure with reduced ejection fraction - an
    angiotensin receptor-neprilysin inhibitor (or an ACE inhibitor/ARB where ARNI
    is unsuitable), an evidence-based beta-blocker, a mineralocorticoid receptor
    antagonist, and an SGLT2 inhibitor - with a loop diuretic added for congestion.
    Nothing in this regimen addresses the KATP lesion; it treats the downstream
    remodeling and neurohormonal arms.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin receptor-neprilysin inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
    - preferred_term: loop diuretic
      term:
        id: NCIT:C49184
        label: Loop Diuretic
  target_mechanisms:
  - target: Calcineurin-Dependent Maladaptive Remodeling
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade and SGLT2 inhibition act on the remodeling arm of the
      chain, downstream of the channel defect, which is why they are expected to
      work in CMD1O exactly as in other dilated cardiomyopathies and equally why
      they are not disease-modifying for the lesion itself.
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recommendations on treatments such as sodium glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNIs)"
    explanation: >-
      Names the guideline-recommended drug classes that constitute this treatment.
      The recommendation is for heart failure generally, not for CMD1O.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Secondary prevention after a malignant ventricular arrhythmia or cardiac
    arrest, and primary prevention by standard criteria after therapy is
    optimised. The arrhythmic phenotype of the founding CMD1O cases makes this
    salient, but there is no CMD1O-specific risk score and the criteria for
    prophylactic implantation are one of the areas where DCM guidelines
    explicitly diverge.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: implantable cardioverter-defibrillator
        term:
          id: NCIT:C93238
          label: Implantable Cardioverter-Defibrillator
  target_mechanisms:
  - target: Ventricular Electrical Instability
    treatment_effect: INHIBITS
    description: >-
      Terminates ventricular arrhythmia rather than preventing the electrical
      substrate that generates it.
  evidence:
  - reference: PMID:39674807
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nonetheless, notable areas of variation included the formation of multidisciplinary management teams, the role of cascade genetic testing, pathways for arrhythmic risk stratification, and the criteria for prophylactic defibrillator implantation."
    explanation: >-
      Documents that defibrillator implantation criteria are a point of guideline
      divergence, which is the caveat this treatment records.
- name: Heart Transplantation
  description: >-
    For advanced heart failure refractory to medical and device therapy, by
    standard criteria; mechanical circulatory support may bridge to it. Both male
    family members in the founding report died of heart failure without reaching
    transplantation, in an era before contemporary HFrEF therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Structural Cardiac Impairment and Heart Failure
    treatment_effect: BYPASSES
    description: >-
      Replaces the failing organ; the only intervention that removes the
      ABCC9-variant myocardium.
  evidence:
  - reference: PMID:39674807
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of advanced disease."
    explanation: >-
      Records guideline consensus on the management of advanced disease, of which
      transplantation is the endpoint.
- name: Genetic Counseling
  description: >-
    Appropriate for at-risk families, but the counselling content is unusual here:
    the conversation has to include that the ABCC9-DCM relationship is classified
    as Limited. Cascade predictive testing is justified only for a familial variant
    independently classified as pathogenic or likely pathogenic with persuasive
    segregation; it should not be offered on an ABCC9 variant of uncertain
    significance as though disease were certain.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."
    explanation: >-
      The recommendation that shapes what a counselling conversation about an
      ABCC9 result can honestly claim.
  - reference: CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z
    reference_title: "ABCC9 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCC9 | HGNC:60 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: >-
      The classification that must be disclosed in counselling.
mechanistic_hypotheses:
- hypothesis_group_id: katp_metabolic_gating_failure
  hypothesis_label: Failure of KATP metabolic-stress gating as the CMD1O lesion
  status: EMERGING
  description: >-
    The proposed model: a C-terminal ABCC9 variant displaces SUR2A's catalytic
    cycle, the Kir6.2 pore is consequently mis-gated, the cardiomyocyte cannot
    match electrical and contractile work to energetic demand under stress,
    calcium overload follows, and calcineurin-dependent remodeling converts that
    into a dilated, arrhythmogenic ventricle. The molecular arm is demonstrated in
    recombinant systems; the myocardial arm is supported by KATP-deficient animals
    but has never been shown for an ABCC9 catalytic-domain allele in a heart,
    human or otherwise. It is recorded as EMERGING rather than CANONICAL because
    the gene-disease relationship it explains is itself classified as Limited.
discussions:
- discussion_id: abcc9_dcm_gene_disease_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is a heterozygous ABCC9 variant sufficient to cause dilated cardiomyopathy in
    humans, and if so which allele classes do it?
  attaches_to:
  - "pathophysiology#ABCC9 C-Terminal Catalytic-Domain Variant"
  - "genetic#ABCC9 variants of limited clinical validity for dilated cardiomyopathy"
  rationale: >-
    ClinGen's Dilated Cardiomyopathy GCEP classifies ABCC9-DCM as Limited. The
    weaknesses are specific rather than general: two probands from a single
    screen; segregation resting on an affected father from whom no DNA was
    available; no replication cohort combining independent human genetics with
    comparable functional characterisation; and a ClinVar spectrum dominated by
    variants of uncertain significance. The functional work is strong for what it
    covers - the recombinant catalytic and gating defect is real and quantified -
    but it does not establish that a heterozygous allele is sufficient to produce
    the disease in a human heart. Until this is resolved no clinical inference
    should be drawn from an ABCC9 variant, and this entry curates the mechanism as
    proposed rather than established.
  proposed_experiments:
  - experiment_id: exp_cmd1o_case_control_burden
    name: Case-control rare-variant burden test for ABCC9 in dilated cardiomyopathy
    description: >-
      Test whether rare ABCC9 variants, and specifically C-terminal
      nucleotide-binding-domain variants, are enriched in large sequenced dilated
      cardiomyopathy cohorts relative to ancestry-matched population controls.
      This is the analysis that would move the ClinGen classification in either
      direction and it has not been reported.
    would_support:
    - "pathophysiology#ABCC9 C-Terminal Catalytic-Domain Variant"
    supporting_outcome:
    - >-
      Significant excess of rare C-terminal ABCC9 variants in DCM cases over
      ancestry-matched controls after correction for multiple testing.
    refuting_outcome:
    - >-
      No enrichment, with the observed variant frequency in cases indistinguishable
      from population background.
  - experiment_id: exp_cmd1o_knockin_heterozygote
    name: Heterozygous knock-in of a human ABCC9 catalytic-domain allele
    description: >-
      Generate a heterozygous knock-in of p.(Ala1513Thr) or p.(Leu1524fs), or the
      murine equivalent, and test for stress-conditional cardiac disease. This
      would distinguish a dominant effect of the actual disease alleles from the
      complete-absence phenotype of the existing null models, which is the
      distinction the current animal evidence cannot make.
    would_support:
    - "pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress"
    supporting_outcome:
    - >-
      Heterozygous knock-in animals develop ventricular dilation and reduced
      systolic function under adrenergic or pressure load while remaining
      near-normal at baseline.
    refuting_outcome:
    - >-
      Heterozygous knock-in animals are indistinguishable from wild type under the
      same imposed stress.
  evidence:
  - reference: CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z
    reference_title: "ABCC9 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCC9 | HGNC:60 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: >-
      The expert-panel classification that defines this gap.
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only."
    explanation: >-
      Situates ABCC9 in the large limited-evidence tail of the curated DCM gene
      set, which is why this gap is not unique to this gene.
- discussion_id: abcc9_adult_deletion_direction_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does deleting cardiac SUR2 in the adult mouse myocardium PROTECT the
    heart, when the human disease model says loss of SUR2A regulatory function
    causes dilated cardiomyopathy?
  attaches_to:
  - "pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress"
  rationale: >-
    This is the sharpest tension in the entry and it is a direction mismatch, not
    a strength-of-evidence quibble. Adult cardiomyocyte-restricted SUR2 deletion
    increased glucose uptake and protected against ischemia-reperfusion injury,
    the opposite sign to what the CMD1O mechanism predicts. Several things could
    explain it and they have different consequences. Developmental timing may
    matter, since the same gene deleted earlier produces cardiomyopathy. Allele
    class may matter: a conditional complete deletion is not a heterozygous
    catalytic-domain variant, and a receptor that is absent is not the same as a
    receptor that mis-reports nucleotide state - a mis-gated channel could plausibly
    be worse than no channel. The stressor may matter, since acute
    ischemia-reperfusion is not chronic hemodynamic load, and the KATP-null
    literature is explicit that phenotypes are unmasked by the specific stress
    imposed. Until this is resolved, the entry does not assert that reducing
    cardiac SUR2 function is sufficient for dilated cardiomyopathy.
  proposed_experiments:
  - experiment_id: exp_cmd1o_timing_and_allele_comparison
    name: Matched comparison of adult conditional deletion, germline null, and catalytic-domain knock-in
    description: >-
      Impose the same chronic pressure-overload protocol on adult
      cardiomyocyte-specific SUR2 deletion, germline SUR2 loss, and a heterozygous
      catalytic-domain knock-in, with identical imaging and calcium readouts, to
      separate the timing, allele-class and stressor explanations for the sign
      reversal.
    would_refute:
    - "pathophysiology#Failure of Metabolic-Electrical Adaptation Under Cardiac Stress"
    supporting_outcome:
    - >-
      The catalytic-domain knock-in fails under chronic load while the adult
      conditional deletion does not, isolating allele class as the explanation.
    refuting_outcome:
    - >-
      All three genotypes are protected under chronic load, which would place the
      human association rather than the model in question.
  evidence:
  - reference: PMID:31061927
    reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury."
    explanation: >-
      The result that creates the mismatch.
  - reference: PMID:31061927
    reference_title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter."
    explanation: >-
      Identifies the metabolic compensation the authors propose as the reason for
      protection, which is one of the candidate explanations for the mismatch.
- discussion_id: abcc9_no_targeted_therapy_or_trials
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any CMD1O-directed therapy, and can KATP pharmacology be turned on
    this disease at all?
  attaches_to:
  - "treatments#Guideline-Directed Medical Therapy for HFrEF"
  - "pathophysiology#Defective Catalysis-Mediated KATP Pore Gating"
  rationale: >-
    A ClinicalTrials.gov search performed for this entry on 2026-09-04 returned no
    interventional trial for dilated cardiomyopathy 1O, CMD1O, or SUR2A-related
    cardiomyopathy. The single ABCC9-named registered study (NCT04120766) is a
    nicorandil trial in hippocampal sclerosis and dementia, not a cardiac study, so
    no `clinical_trials` block is curated here. The pharmacological obstacle is
    real rather than a matter of neglect: KATP openers and blockers cross-react
    across Kir6 and SUR subfamilies, so a drug aimed at cardiac SUR2A can produce
    the pancreatic or vascular version of the opposite pathology. The existing
    preclinical glibenclamide work addresses gain-of-function Cantu syndrome, which
    is the wrong direction for CMD1O, and the adult-deletion mouse result means
    even the intended direction of correction is not settled.
  proposed_experiments:
  - experiment_id: exp_cmd1o_ipsc_cardiomyocyte_gating_rescue
    name: Patient-allele iPSC-cardiomyocyte gating and metabolic-stress rescue screen
    description: >-
      Build isogenic iPSC-derived cardiomyocytes carrying p.(Ala1513Thr) or
      p.(Leu1524fs), measure KATP gating and action-potential adaptation under
      metabolic challenge, and test whether subunit-selective channel modulators
      restore the adaptation. This would establish both whether the human alleles
      break stress adaptation in a human cardiomyocyte and whether the defect is
      pharmacologically addressable.
    would_support:
    - "pathophysiology#Defective Catalysis-Mediated KATP Pore Gating"
    supporting_outcome:
    - >-
      Variant cardiomyocytes fail to adapt action-potential duration under
      metabolic challenge and adaptation is restored by a SUR2-selective
      modulator.
    refuting_outcome:
    - >-
      Variant and isogenic control cardiomyocytes show indistinguishable gating and
      adaptation under the same challenge.
  evidence:
  - reference: PMID:36170658
    reference_title: "Personalized Therapeutics for K(ATP)-Dependent Pathologies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness"
    explanation: >-
      States the cross-reactivity problem that makes KATP pharmacology hard to
      point at a single tissue, which is the obstacle this gap describes.
differential_diagnoses:
- name: ABCC9-related intellectual disability and myopathy syndrome
  description: >-
    The other ABCC9 loss-of-function disease and the one most likely to be
    conflated with CMD1O, because both are described in the literature as KATP
    loss of function in the same gene. They are not the same disease. AIMS is
    autosomal RECESSIVE and requires BIALLELIC loss of function; its defining
    features are intellectual disability, myopathy with fatigability, and cerebral
    white matter abnormalities, with cardiac systolic dysfunction appearing only in
    older affected individuals as one feature among many. CMD1O is asserted as
    dominant, is cardiac-restricted, and is attributed to heterozygous
    catalytic-domain alleles. The decisive discriminator is that heterozygous
    carriers of AIMS alleles show no conserved clinical pathology. A curated
    dismech entry for AIMS exists separately and was deliberately not edited by
    this curation.
  evidence:
  - reference: PMID:31575858
    reference_title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS)."
    explanation: >-
      Names the separate recessive disease entity that must not be merged with
      CMD1O.
  - reference: PMID:38217872
    reference_title: "Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness."
    explanation: >-
      The AIMS phenotype, which is neurological and myopathic rather than a
      primary dilated cardiomyopathy.
  - reference: PMID:38217872
    reference_title: "Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous parents do not show any conserved clinical pathology"
    explanation: >-
      The discriminating observation - one AIMS allele does not produce the AIMS
      phenotype, so a dominant ABCC9 cardiac disease is a separate claim.
- name: Cantu syndrome
  description: >-
    The gain-of-function pole of ABCC9 disease, and the mechanistic opposite of
    both CMD1O and AIMS. Cantu syndrome is autosomal dominant like CMD1O, so mode
    of inheritance does not separate them; the direction of the channel defect and
    the multisystem phenotype - hypertrichosis, vasodilation, hypotension,
    cardiomegaly - do. A report that says only "ABCC9 variant" without a direction
    cannot be assigned to any of the three.
  evidence:
  - reference: PMID:31575858
    reference_title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function."
    explanation: >-
      States the direction of the Cantu channel defect and that it produces a
      different phenotype from ABCC9 loss of function.
- name: Sarcomeric and cytoskeletal dilated cardiomyopathy
  description: >-
    The high-evidence genetic causes of dilated cardiomyopathy - TTN, LMNA, FLNC,
    DSP, RBM20, PLN, BAG3, SCN5A, MYH7 and the other definitive and strong genes -
    are the differential that matters clinically, because they are what a
    cardiomyopathy panel is actually for and because an ABCC9 variant found
    alongside one of them does not explain the case. LMNA and FLNC in particular
    carry arrhythmic risk that changes management, so an arrhythmic dilated
    cardiomyopathy should not be attributed to ABCC9 until those are excluded.
  evidence:
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence."
    explanation: >-
      Names the high-evidence DCM genes that constitute this differential and that
      should be interrogated before an ABCC9 variant is invoked.
notes: >-
  SCOPE AND EPISTEMIC STANCE. MONDO models CMD1O as a gene-anchored member of the
  familial isolated dilated cardiomyopathy series and this entry follows that
  concept, but it does not follow it into asserting that ABCC9 is an established
  cause of human dilated cardiomyopathy. ClinGen's Dilated Cardiomyopathy GCEP
  classifies that relationship as Limited, and the dispute is carried in the
  description, the genetic block (`relationship_type: DISPUTED`, with a
  REFUTE-typed ClinGen evidence item), a dedicated KNOWLEDGE_GAP discussion, and
  the diagnosis and treatment blocks.

  GENEREVIEWS SCOPE. The applicable GeneReviews resource is the disease-level "Dilated
  Cardiomyopathy Overview" (PMID:20301486), tagged in `references` and cited on the
  relative-surveillance treatment. Its indexed PubMed record is content_type
  abstract_only and carries only the chapter's statement of purpose, not the Clinical
  Characteristics, Management or Genetic Counseling sections, so section-by-section
  mining is not possible from the cache. The one substantive sentence the abstract does
  carry - that assessing at-risk asymptomatic relatives serves to inform cardiac
  surveillance for early detection and treatment - is quoted; nothing beyond it is.


  WHY THE PATHOGRAPH IS ROUTED THROUGH METABOLIC SENSING. Every other numbered
  member of the DCM series curated in dismech reaches ventricular dilation through
  a sarcomeric, cytoskeletal, desmosomal, splicing, or calcium-handling protein.
  ABCC9 does not encode a structural or contractile protein at all - it encodes
  the nucleotide-sensing regulatory subunit of a channel. The chain is therefore
  built from the catalytic defect outward: displaced ATP hydrolytic cycling in
  SUR2A, mis-gating of the Kir6.2 pore, failure of the cardiomyocyte to decode its
  own energetic state, failure of stress adaptation, calcium overload, and only
  then convergence on the conserved maladaptive-remodeling pathway. The two
  founding alleles are handled at that resolution - as C-terminal
  catalytic-domain variants with a demonstrated conformational-cycling defect -
  rather than as generic loss of function, because the source measurement is a
  redistribution of hydrolytic-cycle conformations and not an absence of
  potassium current.


  MODULE CONFORMANCE. Three nodes conform to
  `cardiomyopathy_maladaptive_remodeling`. The entry does NOT conform to
  `cardiac_ion_channel_repolarization` despite being a channelopathy: that
  module's scope is inherited arrhythmia syndromes in structurally normal hearts,
  and CMD1O is defined by a structurally abnormal one.


  CORRECTIONS MADE TO THE DEEP-RESEARCH REPORT. The falcon report
  (`research/Dilated_Cardiomyopathy_1O-deep-research-falcon.md`) was used as a
  lead and three of its claims did not survive checking. First, it attributes the
  "ClinGen Limited" classification of ABCC9-DCM to the Micolonghi 2024 review
  (PMID:39337275); the word "Limited" does not appear anywhere in that paper's
  cached full text, which instead says "Mutations in ABCC9 are directly associated
  with DCM". The Limited classification is real but comes from ClinGen itself
  (CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z) and
  is cited from there. Second, the report cites zero PMIDs and only DOIs; every
  reference used here was resolved to a PMID through the PMC ID converter or
  PubMed so that nothing sits on the `DOI:` prefix that the gating validator
  skips. Third, its frontmatter carries `mondo_id: ''` (dismech#10335); the
  Named Entity Confusion preflight was therefore run by hand against
  MONDO:0012062 and passed, with ABCC9 mentioned 37 times and no competing gene.
  No ontology CURIE proposed by the report needed correcting - the only term it
  suggested with an identifier was UBERON:0000948 for "heart", which resolves
  correctly and is not used in this entry. Every HP, GO, CL and NCIT term below
  was independently re-derived against OLS rather than copied from the report.


  UNSOURCED CONTENT DELIBERATELY NOT CARRIED OVER. The report relays specific
  left-ventricular ejection fractions, end-diastolic dimensions, ages at diagnosis
  and death, and a control-panel size, all from the body of the 2004 Nature
  Genetics paper. That body is paywalled and the cached record carries the
  abstract and reference list only, so none of those numbers can be supported by
  an exact-substring snippet. They are therefore not written into the entry, in
  either evidence or prose; the phenotype is described qualitatively instead
  (adult onset, severe disease established at diagnosis). One consequence worth
  naming: the ejection-fraction phenotype is bound to HP:0012664 *Reduced* left
  ventricular ejection fraction rather than to the severe grade HP:0012666,
  because the grade would depend entirely on numbers this entry cannot cite. The
  same discipline applies to the report's claim of nine ClinVar pathogenic or
  likely-pathogenic entries against 712 variants of uncertain significance for
  ABCC9, which is replaced by the weaker but quotable statement that the ABCC9
  dilated-cardiomyopathy variant spectrum is predominantly VUS.


  NO CLINICAL TRIALS BLOCK. ClinicalTrials.gov was searched directly on
  2026-09-04 for "dilated cardiomyopathy 1O", "CMD1O", "ABCC9", "SUR2A
  cardiomyopathy" and "sulfonylurea receptor 2 cardiomyopathy". The only
  ABCC9-named study is NCT04120766, a nicorandil trial in hippocampal sclerosis
  and dementia. No CMD1O trial exists, so the block is omitted and the absence is
  recorded as a KNOWLEDGE_GAP discussion rather than left implicit.


  NO ENVIRONMENTAL BLOCK. No environmental exposure has been demonstrated for
  CMD1O. Hemodynamic, adrenergic and ischemic stress are central to the mechanism
  but they are physiological load states rather than exposures, and they are
  modelled inside the pathophysiology chain (the stress-conditional
  metabolic-electrical adaptation node) rather than as `environmental` entries
  with ECTO terms that would not fit them.


  NO ORPHA OR DATASETS BLOCK. No cached ORPHA record maps to MONDO:0012062. No
  CMD1O-specific omics accession was identified, and searching ABCC9 alone would
  surface datasets about Cantu syndrome, AIMS, pancreatic KATP biology or
  hippocampal sclerosis - the Named Entity Confusion hazard the dataset SOP warns
  about - so no `datasets:` block is curated.


  GROUPING MEMBERSHIP NOT UPDATED. `kb/groupings/Familial_Dilated_Cardiomyopathy.yaml`
  should gain CMD1O as a member, but several sibling curation PRs are in flight
  against that file's `members:` list and would conflict on it. It is deliberately
  left for a batched maintainer pass.
references:
- reference: PMID:15034580
  title: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."
  findings: []
- reference: PMID:20033705
  title: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."
  findings: []
- reference: PMID:15910878
  title: "Cardiac KATP channels in health and disease."
  findings: []
- reference: PMID:16782803
  title: "KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension."
  findings: []
- reference: PMID:31061927
  title: "Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective."
  findings: []
- reference: PMID:31575858
  title: "ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9."
  findings: []
- reference: PMID:38217872
  title: "Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome."
  findings: []
- reference: PMID:33947203
  title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
  findings: []
- reference: PMID:39337275
  title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
  findings: []
- reference: PMID:36170658
  title: "Personalized Therapeutics for K(ATP)-Dependent Pathologies."
  findings: []
- reference: PMID:39674807
  title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations."
  findings: []
- reference: PMID:37653361
  title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
  findings: []
- reference: PMID:39394525
  title: "Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine."
  findings: []
- reference: PMID:39895490
  title: "Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy."
  findings: []
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
  findings: []
- reference: CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z
  title: "ABCC9 / dilated cardiomyopathy (Limited)"
  findings: []

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References & Deep Research