| domain | best-supported finding | evidence type | key quantitative detail or variant | source/year |
|---|---|---|---|---|
| Identity / causal gene | Dilated Cardiomyopathy 1AA is best interpreted as rare ACTN2-related familial/intrinsic dilated cardiomyopathy within a broader ACTN2 cardiomyopathy spectrum; modern resources strongly support ACTN2 as a DCM-associated target, but a distinct current MONDO record for the legacy subtype label is not clearly exposed | Curated disease-target association + review + primary human genetics | ACTN2 association score present for dilated cardiomyopathy/familial DCM; first DCM ACTN2 report noted in 2003 | Open Targets / literature synthesis 2024-2025 (pqac-00000000, pqac-00000009) |
| Inheritance | ACTN2 cardiomyopathy can be autosomal dominant or recessive depending on variant class; dominant disease is supported for heterozygous indel/missense variants, while recessive severe disease is supported for homozygous truncation | Human clinical genetics + family segregation + functional validation | Heterozygous exon 8-10 deletion family; homozygous p.Gln860Ter (Q860X) restrictive/end-stage phenotype; recessive causality established | Lindholm et al. 2021 (pqac-00000009, pqac-00000010, pqac-00000011) |
| Phenotypic spectrum | ACTN2 variants cause a mixed cardiomyopathy spectrum including DCM, arrhythmic phenotypes, LV noncompaction, restrictive cardiomyopathy, heart failure, and sudden death in some families | Human clinical + review | Family 2 had ventricular tachyarrhythmias, atrial fibrillation, LV noncompaction, symptomatic HF, and 2 early sudden cardiac deaths; Q860X patient required transplant at 23 years | Lindholm et al. 2021; review synthesis 2024 (pqac-00000010, pqac-00000003) |
| Core mechanism | Disease mechanisms converge on Z-disc/sarcomere dysfunction with impaired contractility, structural disarray, abnormal Ca2+ handling, and disrupted protein interactions; mechanism differs by zygosity | iPSC-CM, EM, RNA-seq, AP-MS, CRISPR | Heterozygous indel protein incorporates into sarcomeres with aberrant Z-disc ultrastructure; C-terminal truncation disrupts ACTN1 and GJA1 interactions | Lindholm et al. 2021 (pqac-00000004, pqac-00000006, pqac-00000009, pqac-00000011) |
| Recent 2023 mouse study | A CRISPR knock-in Actn2 p.Met228Thr mouse provided recent in vivo evidence that ACTN2 dysfunction can drive cardiomyopathy-related biology via protein instability, mitochondrial dysfunction, and cell-cycle abnormalities | Mouse model + proteomics | Heterozygotes had no overt phenotype except molecular changes in mature males; homozygotes were embryonic lethal at/after E15.5 analysis | Broadway-Stringer et al. 2023 (pqac-00000007, pqac-00000020) |
| 2023 human deletion case | A pediatric case with 1q43 deletion involving ACTN2 and RYR2 linked ACTN2 loss to severe early-onset DCM with LV noncompaction and reduced EF | Human case report | chr1:236,686,454-237,833,988 (hg38) deletion; enlarged LV with LVIDd 48 mm, Z-score 3.81; follow-up LVEF 41%; transplant recommended | Zhou et al. 2023 (pqac-00000001, pqac-00000002) |
| Molecular profiling | ACTN2 disease models show transcriptional and proteomic abnormalities consistent with fibrosis, hypertrophy, metabolic remodeling, and altered interaction networks | RNA-seq + GSEA + proteomics | Elevated MYL2; enriched extracellular matrix remodeling/collagen biosynthesis in Q860X tissue; induced respiratory electron transport and gluconeogenesis in hiPSC-CMs | Lindholm et al. 2021 (pqac-00000010, pqac-00000011, pqac-00000021, pqac-00000025) |
| Developmental / model evidence | Loss of ACTN2 perturbs cardiomyocyte maturation and cardiac development; zebrafish and mammalian models support reduced chamber/cell size and structural defects | Zebrafish LOF + mouse + human case synthesis | Zebrafish ACTN2 depletion reduced end-diastolic diameter, cardiomyocyte size/number, and ventricular chamber size; ACTN3 could not rescue LOF phenotype | Wadmore 2021; Lindholm 2021; Zhou 2023 (pqac-00000023, pqac-00000024, pqac-00000002) |
| Diagnosis / prognosis | For DCM generally, diagnosis relies on multimodal imaging and genetics; prognosis is informed by genotype and CMR fibrosis burden more than EF alone in some contexts | Guideline review + population study + meta-analysis | DCM true prevalence estimated about 1:250 and 1:220 by UK Biobank CMR; in NIDCM, LGE HR 1.81 for all-cause mortality and 2.69 for arrhythmic events; Q860X patient progressed to transplant | Newman 2024; Eichhorn 2024; Lindholm 2021 (pqac-00000018, pqac-00000019, pqac-00000010) |
| Current treatment status | No ACTN2-specific approved therapy or ACTN2-directed clinical trial was found; management follows standard DCM/HFrEF care, arrhythmia surveillance, family screening, devices, and advanced HF therapies when indicated | Guideline review + trial landscape + case report | Standard “quadruple” HFrEF drug classes apply broadly; pediatric deletion case received digoxin, captopril, metoprolol, levocarnitine/creatine phosphate, but remained severe; no ACTN2-specific interventional trial identified | Badger 2023 / MacDonald 2023 summaries, trial search, Zhou 2023 (pqac-00000001) |
| Major evidence gaps | Evidence remains sparse, mostly case-based, with limited penetrance data, no subtype-specific epidemiology, and no validated preventive or genotype-specific treatment pathway for ACTN2-DCM | Evidence-gap synthesis | Do not overstate prevalence for DCM1AA specifically; available epidemiology/penetrance figures are for broader DCM gene sets or general DCM, not ACTN2 subtype alone | Shah 2022; Newman 2024; review synthesis 2024 (pqac-00000017, pqac-00000018, pqac-00000003) |


*Table: This table summarizes the strongest currently available evidence for Dilated Cardiomyopathy 1AA as ACTN2-related cardiomyopathy, separating subtype-specific findings from broader DCM context. It is useful for quickly identifying what is well supported, what remains generic to DCM, and where major evidence gaps remain.*