| Domain | Best-supported finding | Evidence type | Confidence/caveat |
|---|---|---|---|
| Identifiers | Dilated cardiomyopathy 1O (CMD1O); **MONDO:0012062**; **OMIM 608569**. | Aggregated disease databases | Stable historical identifiers; no dedicated ICD-10/ICD-11 code. (pqac-00000000, pqac-00000003) |
| Gene/protein | **ABCC9** (MIM 601439) encodes SUR2; cardiac SUR2A partners with Kir6.2/KCNJ11 in ATP-sensitive K⁺ channels. | Database, biochemical | Gene–protein relationship is established; gene–CMD1O causality is less certain. (pqac-00000003, pqac-00000016) |
| Original variants/cases | A 323-patient DCM screen found heterozygous **c.4537G>A (p.Ala1513Thr)** in a woman diagnosed at 40 and **c.4570_4572delTTAinsAAAT (p.Leu1524fs)** in a man diagnosed at 55; neither occurred in 500 controls. | Human case-level genetics | Only two index cases; limited segregation and no robust independent replication. (pqac-00000001, pqac-00000002) |
| Clinical validity | Modern review classifies the autosomal-dominant **ABCC9–DCM** relationship as **ClinGen Limited**. | Expert curation/database review | ABCC9 findings should not independently establish diagnosis or direct predictive testing without rigorous variant-level evidence. (pqac-00000014) |
| Core phenotype | Severe LV dilation and systolic dysfunction with ventricular tachycardia; reported LVEFs were 15% and 23%, and both index cases developed fatal or severe heart failure. | Human case reports | Adult-onset observations only; penetrance, phenotype frequencies, and full spectrum are unknown. (pqac-00000001, pqac-00000003) |
| Proposed mechanism | Variants flank the SUR2A ATPase pocket, disturb nucleotide-dependent conformational cycling, and impair KATP metabolic-signal decoding and pore gating. | In vitro electrophysiology/biochemistry | Functional effect demonstrated; causal path from channel dysfunction to human DCM remains incompletely proven. (pqac-00000001, pqac-00000015) |
| Models | SUR2 loss causes cardiac dysfunction in mice and ventricular enlargement/dysfunction in zebrafish; KATP-deficient mice develop stress-induced calcium/calcineurin-dependent remodeling. | Mouse and zebrafish | Supportive but not exact CMD1O-variant models; related KCNJ11 knockout evidence is indirect. (pqac-00000018, pqac-00000020, pqac-00000022) |
| Contradictory/context evidence | Adult cardiomyocyte-specific SUR2 deletion increased glucose uptake and protected mice from ischemia–reperfusion injury. | Conditional mouse model | Shows tissue-, age-, and stress-dependent effects; global deletion is confounded by vascular dysfunction and vasospasm. (pqac-00000017) |
| Diagnosis | Establish the DCM phenotype using history/pedigree, ECG, biomarkers, echocardiography and CMR; exclude coronary/loading and acquired causes, then use a curated cardiomyopathy panel with counseling and segregation analysis. | Clinical guidelines | An ABCC9 VUS is non-diagnostic; cascade testing is appropriate only for a convincingly pathogenic familial variant. (pqac-00000007, pqac-00000008, pqac-00000014) |
| Treatment | Treat manifest HFrEF with ARNI/ACEi/ARB, evidence-based β-blocker, MRA and SGLT2 inhibitor; add diuretics for congestion and consider ICD/CRT, LVAD or transplantation by standard criteria. | Guideline extrapolation | General DCM/HFrEF care, not genotype-specific CMD1O evidence. (pqac-00000023, pqac-00000025, pqac-00000027) |
| Targeted therapy/trials | No ABCC9-specific approved therapy or CMD1O clinical trial was identified; KATP modulators remain mechanistic/preclinical concepts. | Trial search and pharmacology review | Absence of retrieved trials is not proof that none exists globally; channel modulation may have opposing tissue-specific effects. (pqac-00000017, pqac-00000021) |


*Table: A compact, database-oriented summary of CMD1O identity, foundational human evidence, current gene-validity concerns, mechanism, models, diagnosis, and treatment.*