| domain | finding | evidence type | strength/limitations |
|---|---|---|---|
| Gene-disease association | PSEN1 Asp333Gly (reported as D333G; exon 10, 1539A>G) segregated with aggressive dilated cardiomyopathy/heart failure in a single reported family; later reviews still cite this same family as the key PSEN1-DCM evidence. | Direct human genetic evidence | Strength: segregation in an affected pedigree with severe phenotype. Limitations: essentially one family, no independent replication, incomplete modern variant-level reassessment, evidence base vulnerable to ascertainment bias (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000004) |
| Discovery cohort / controls | Original study screened 315 DCM probands and reported the PSEN1 variant absent in 413 unaffected controls (206 White, 207 African American). | Direct human case-control/discovery evidence | Strength: discovery performed in a sizeable DCM cohort for the era; variant not seen in tested controls. Limitations: still only one PSEN1 family identified; control set predates modern population databases and broad sequencing reference resources (pqac-00000002, pqac-00000004) |
| Natural history / penetrance | Reported affected family members were aged 35-80 years; third-generation carriers younger than 35 reportedly had no evidence of DCM, implying age-dependent expression despite the paper's statement of full penetrance among clinically affected/evaluable relatives. | Direct human clinical evidence | Strength: supports adult onset and progressive course. Limitations: small pedigree, limited follow-up detail, penetrance estimate unstable because of few carriers and age censoring (pqac-00000001, pqac-00000004) |
| Cellular phenotype | Cultured skin fibroblasts from PSEN1 mutation carriers showed elevated baseline intracellular Ca2+ and increased histamine-stimulated Ca2+ responses/area under the curve versus controls. | Direct human ex vivo functional evidence | Strength: disease-linked functional abnormality observed in carrier cells. Limitations: fibroblasts are a surrogate tissue, not cardiomyocytes; quantitative mechanistic link to ventricular dilation remains indirect (pqac-00000001, pqac-00000010, pqac-00000011) |
| Amyloid pathway testing | D333G expression/transfection studies in HEK293 cells reportedly did not alter the Aβ42/Aβ40 ratio. | In vitro mechanistic evidence | Strength: argues against a simple amyloidogenic mechanism for CMD1U. Limitations: non-cardiac heterologous system; negative result does not establish the actual cardiac disease mechanism (pqac-00000003, pqac-00000009) |
| Broader PSEN1 cardiac biology | Reviews summarize broader evidence that PSEN1/presenilin participates in γ-secretase signaling, with plausible links to Notch, β-catenin, cardiac development, and calcium homeostasis. | Inferred mechanistic/general biology evidence | Strength: biologically plausible framework connecting PSEN1 to heart development and function. Limitations: mostly extrapolated from non-CMD1U systems; not direct proof that D333G causes DCM through these pathways (pqac-00000009, pqac-00000010, pqac-00000011) |
| Mouse/developmental evidence | Murine knockout/developmental studies cited in reviews indicate presenilin is important for cardiac development, with defects such as ventricular septal defect and double-outlet right ventricle in knockout contexts. | Model-organism evidence | Strength: supports cardiac relevance of gene loss/dysfunction. Limitations: developmental knockout phenotypes are not equivalent to adult familial DCM from a heterozygous missense variant; mechanism may differ substantially (pqac-00000009, pqac-00000011) |
| Clinical validity in modern DCM genetics | Recent DCM reviews emphasize that only a core subset of genes has definitive/strong evidence; PSEN1 is discussed, if at all, as a minor/limited-evidence gene rather than a core validated DCM gene. | Expert review / evidence-synthesis | Strength: aligns current interpretation with evidence-based gene curation principles. Limitations: no retrieved formal PSEN1-specific ClinGen curation text in context; conclusion based on review framing and lack of replication (pqac-00000003, pqac-00000005) |
| Diagnostic/management applicability | No CMD1U-specific diagnostic or treatment guideline exists; management therefore follows contemporary DCM/cardiomyopathy guidance: phenotype-first evaluation, ECG/Holter, echocardiography, CMR, BNP/troponin, selective biopsy, genetic counseling, and cascade screening when a pathogenic/likely pathogenic familial variant is established. | General DCM guideline evidence | Strength: actionable for real-world care despite rarity. Limitations: guidance is for DCM broadly, not validated specifically for PSEN1-associated CMD1U; uncertainty remains if PSEN1 should be routinely included on restricted evidence-based panels (pqac-00000005, pqac-00000006, pqac-00000007) |
| Therapeutics / trials | No disease-specific interventional clinical trials for PSEN1-associated CMD1U were retrieved. | Direct trial landscape evidence | Strength: prevents overstatement of precision-therapy availability. Limitations: absence of retrieved trials does not exclude unpublished, local, or future studies; no approved PSEN1-targeted cardiac therapy identified (pqac-00000000) |


*Table: This table grades the current evidence base for PSEN1-associated dilated cardiomyopathy (CMD1U), separating direct human findings from inferred mechanisms and general DCM management guidance. It is useful because the condition appears to rest on a very limited primary literature base despite ongoing mention in databases and reviews.*