Dilated Cardiomyopathy 1V

1. Disease Information

Overview. Dilated Cardiomyopathy 1V (CMD1V/DCM1V) is a numbered OMIM locus for autosomal dominant familial dilated cardiomyopathy (DCM) attributed to heterozygous missense variation in PSEN2, the presenilin-2 gene far better known as a cause of early-onset familial Alzheimer disease (AD3, OMIM 606889). The locus was defined by a single 2006 candidate-gene screen of 315 DCM probands that found the PSEN2 variant Ser130Leu (S130L) segregating with DCM and heart failure in two families (Li et al., Am J Hum Genet 2006; PMID:17186461, DOI: 10.1086/509900). It is the companion locus to CMD1U (OMIM 613694, PSEN1 Asp333Gly), defined by the same screen.

Critical framing — the gene–disease relationship is not established. The ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies PSEN2–DCM1V as Limited (SOP v10; re-evaluated 2024-10-04, approved by the DCM Working Group 2025-05-30, report dated 2026-03-04; ClinGen curation CCID:005915, assertion CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f). The panel's summary states: "Two missense variants have been reported in 4 probands in two studies (Li et al. PMID: 17186461, Gianni et al. PMID: 20194882)… both of the reported missense variants have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. No new human genetic evidence has emerged since the last curation… The overall genetic evidence points decreased over time." Limited is one tier above PSEN1's Disputed at the sibling CMD1U locus. Every claim below should be read through that lens.

Identifiers.

Synonyms: CMD1V; DCM1V; cardiomyopathy, dilated, 1V; PSEN2-related dilated cardiomyopathy.

Data provenance: All clinical information derives from aggregated disease-level resources (OMIM, ClinGen) and two family/cohort studies — not EHR or population-level patient data.

2. Etiology

Putative causal factor. Heterozygous PSEN2 missense variant c.389C>T, p.Ser130Leu (reported by OMIM as a "756C-T transition in exon 5"; Alzforum annotates it to exon 6 of isoform 1; rs63750197; GRCh38 chr1:226885570 C>T). Li et al. 2006: "A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure" (PMID:17186461). A second study identified PSEN2 p.Arg62His (R62H) in 2 of 20 sequenced idiopathic DCM patients (Gianni et al., Circulation 2010; PMID:20194882, DOI: 10.1161/CIRCULATIONAHA.109.879510).

Why causality is contested (risk-factor reading). - Population frequency: S130L appears in gnomAD v2.1.1 at allele frequency ≈ 6.6×10⁻⁴ (187 alleles) — far above expectation for a fully penetrant dominant DCM allele — and ClinGen states both variants are "found at a frequency higher than would be expected for a monogenic, pathogenic effect." Alzforum's ACMG assessment of S130L (for AD) is Benign with a "may be a risk factor" caveat (BS1, BS2 met; in the Alzheimer's Disease Sequencing Project it appeared in 28 cases vs 26 controls). - R62H was likewise detected in AD cohorts at AF ≈ 0.016 and "none of PSEN1-92delC, E318G or PSEN2 R62H was segregated with AD affection status in identified AD families" (PMID:20194882).

Genetic risk factors: carriage of PSEN2 S130L (two pedigrees) or R62H (two sporadic iDCM probands). No susceptibility loci, modifier genes, or protective variants are documented for this locus.

Environmental risk/protective factors and G×E: None established. A speculative gene–environment axis exists at the expression level: presenilin-2 mRNA is upregulated >2-fold by combined hypoxia and glucose deprivation in rat H9c2 cardiac cells ("Glucose deprivation itself caused significant up-regulation of the presenilin-2 (to 160%) and with low oxygen increased presenilin-2 level to over 200% of the control" — Mohuczy et al., Regul Pept 2002; PMID:12468103), and PS2 expression is increased in failing canine left ventricle and normalized by cardiac contractility modulation therapy (Gupta et al., Clin Transl Sci 2009; PMID:20443895). ClinGen cites exactly these two expression studies as the experimental support for the relationship.

3. Phenotypes

All phenotype data derive from the two Li 2006 pedigrees (small-n caveat applies to every frequency statement).

Key quotes: "The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis" (PMID:17186461). Per OMIM 613697: onset of cardiovascular disease occurred between 48 and 55 years in one family; in the second family three sibs were diagnosed with DCM between 36 and 45 years; one mutation-positive family member had normal cardiovascular screening.

Quality-of-life impact: No CMD1V-specific QoL data exist. Generic DCM/heart-failure QoL burden (fatigue, exercise intolerance, hospitalization) applies to affected members.

Laboratory abnormality (research-grade): "Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers" (PMID:17186461) — elevated resting intracellular Ca²⁺ in carrier fibroblasts (Alzforum functional annotation). Not a clinical diagnostic finding.

4. Genetic/Molecular Information

• Gene: PSEN2 (HGNC:9509; OMIM 600759; chromosome 1q42 per OMIM, 1q42.13), 448-aa polytopic membrane protein; catalytic-capable subunit of the γ-secretase complex; homolog of PSEN1.
• Variants reported for CMD1V:
• p.Ser130Leu (c.389C>T; rs63750197; GRCh38 chr1:226885570 C>T; OMIM allele 600759.0008). Missense; germline; heterozygous. Segregated with DCM in 2 families with partial penetrance. Functional data: no effect on APP processing (no change in Aβ42 or Aβ42/40 in vitro) but altered calcium signaling in carrier fibroblasts; in-silico "possibly damaging/damaging," CADD >20; computer modeling suggests loss of a PKC phosphorylation site at S130 (Alzforum). Also reported in early- and late-onset AD, posterior cortical atrophy, Parkinson disease dementia — with healthy-control observations driving a Benign/risk-factor ACMG call for AD. gnomAD v2.1.1 AF 6.6×10⁻⁴.
• p.Arg62His (Gianni 2010): "PSEN2 R62H enhances PS2 degradation, reduces PS2 stability and compromises Notch function" (PMID:20194882, citing prior work); located in a divergent N-terminal "hot spot"; AD-cohort AF 0.016; did not segregate with AD.
• Mechanistic class: Uncertain. Neither variant has an established loss- vs gain-of-function assignment in myocardium; the fibroblast phenotype suggests altered Ca²⁺ handling rather than γ-secretase catalytic failure.
• ClinVar/ACMG status: Conflicting interpretations historically; current expert synthesis (Alzforum, ADSP data) is Benign-with-risk-factor-caveat for AD; no ClinVar pathogenic consensus for cardiomyopathy. A PSEN2 variant should not be reported as a molecular diagnosis of DCM given the Limited classification.
• Modifier genes, epigenetics, chromosomal abnormalities: None documented for this locus.

5. Environmental Information

No environmental, lifestyle, or infectious factors are implicated in CMD1V specifically. The generic DCM phenocopy environment (alcohol, anthracyclines, myocarditis, peripartum state) is relevant only to differential diagnosis (§10). The hypoxia/low-glucose induction of PS2 expression (PMID:12468103) is an in-vitro observation, not an exposure claim.

6. Mechanism / Pathophysiology

Status: hypothetical throughout. No cardiomyocyte carrying S130L has ever been studied; the causal chain below is an inference scaffold, and the single in-vivo cardiac calcium phenotype (Psen2-null mouse) runs in the opposite direction to the disease claim.

Proposed causal chain (calcium-handling hypothesis): 1. Heterozygous PSEN2 missense variant (S130L) leads to altered presenilin-2 protein function (inferred; demonstrated only as altered Ca²⁺ signaling in carrier skin fibroblasts — PMID:17186461). 2. Presenilin-2 normally localizes to cardiomyocyte Z-lines and physically interacts with the ryanodine receptor RyR2 and its modulator sorcin — "PS2, sorcin, and RyR2 interact with each other… PS2 colocalizes with RyR2 and sorcin at the Z-lines" (Takeda et al., FASEB J 2005; PMID:16204356) — so variant PS2 is proposed to result in dysregulated sarcoplasmic-reticulum Ca²⁺ release and excitation–contraction coupling (inferred; shown only for wild-type/knockout PS2, not for S130L). 3. Chronic cardiomyocyte Ca²⁺ dyshomeostasis leads to impaired contractile performance (inferred from general heart-failure biology). 4. Sustained contractile impairment results in left ventricular remodeling and dilatation, reduced ejection fraction, and clinically manifest heart failure (the observed family phenotype).

Branch — proteostasis/oligomer hypothesis (Gianni 2010): presenilin variants lead to altered protein quality control; misfolded-protein oligomers accumulate in iDCM myocardium (pre-amyloid oligomer staining in 5/6 iDCM hearts; tangle- and plaque-like fibrillar deposits by EM even in early-stage biopsies); applied oligomers cause "a sudden increase in peak systolic Ca2+ transient together with an enhanced velocity of Ca2+ release" in mouse cardiomyocytes, converging on the same Ca²⁺-dyshomeostasis step (PMID:20194882). This branch is generic to iDCM, not specific to PSEN2 carriers. The related PS1–SERCA2a co-immunoprecipitation belongs primarily to the sibling CMD1U story.

Directly contradicting evidence: Psen2-knockout mice show increased contractility and Ca²⁺ transients with "no evidence of cardiac hypertrophy and fibrosis" (PMID:16204356) — i.e., loss of PS2 alone does not produce DCM in mouse, and pushes calcium physiology the "wrong" way for a simple haploinsufficiency model.

Ontology suggestions (verified against repo term caches unless flagged): GO:0006874 intracellular calcium ion homeostasis; GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling; GO:0016529 sarcoplasmic reticulum; GO:0007219 Notch signaling pathway (for R62H); GO:0006457 protein folding (oligomer branch); GO:0030018 Z disc (unverified — validate before binding). Cell type: CL:0000746 cardiac muscle cell; CL:0000057 fibroblast (carrier assay tissue).

Omics: No CMD1V-specific transcriptomic/proteomic/single-cell datasets exist. Expression-level support only: PMID:12468103 (rat H9c2 macroarray + qRT-PCR), PMID:20443895 (failing dog LV: S100A1/sorcin/HRC decreased, PS2 increased, CCM therapy normalized S100A1/sorcin/PS2).

7. Anatomical Structures Affected

• Organ: heart (UBERON:0000948); primary chamber: heart left ventricle (UBERON:0002084); tissue: myocardium (UBERON:0002349; left ventricle myocardium UBERON:0006566). Secondary involvement: systemic congestion of heart failure. System: cardiovascular.
• Cells: cardiac muscle cell (CL:0000746). Research assays additionally used dermal fibroblasts (CL:0000057) from carriers.
• Subcellular: sarcoplasmic reticulum (GO:0016529) and its membrane (GO:0033017); Z-line/Z disc region (PS2–RyR2–sorcin colocalization); endoplasmic reticulum (presenilin residence).
• Lateralization: Not applicable (global LV disease).

8. Temporal Development

• Onset: adult, insidious. Family 1: cardiovascular disease onset 48–55 y; family 2: DCM diagnosed in three sibs at 36–45 y (OMIM 613697).
• Progression: chronic and progressive in affected members, but explicitly "milder disease, and a more favorable prognosis" than PSEN1-associated CMD1U, which required transplantation or ended in death (PMID:17186461).
• Course pattern: presumed progressive; no remission described; lifelong once manifest.
• Critical periods: none defined; family surveillance from early adulthood is the practical window (see §13).

9. Inheritance and Population

• Inheritance: autosomal dominant (ClinGen MOI: AD) with partial penetrance (HP:0000006; HP:0003829). No anticipation, germline mosaicism, founder effect, or consanguinity documented.
• Epidemiology: No prevalence or incidence exists and none can be estimated. The entire case literature is 2 missense variants in 4 probands (ClinGen count): 2/315 probands in Li 2006 (0.6%; the paper's companion phrasing: presenilin mutations in "0.9% of tested DCM families (3/325)" counts the PSEN1 family too), plus 2/20 iDCM patients with R62H in Gianni 2010. These are variant-detection yields in selected cohorts, not disease prevalences.
• Demographics: Both founding families from a US familial-DCM cohort (Hershberger group, Oregon). Gianni's 4 presenilin-variant iDCM patients were all Caucasian women, prompting an untested estrogen/sex-modifier speculation (PMID:20194882). Population carrier frequency of S130L ≈ 0.066% (gnomAD v2.1.1) — itself the strongest argument against high-penetrance causality.

10. Diagnostics

• Clinical work-up (standard DCM, not locus-specific): echocardiography (LV dilatation + reduced LVEF), ECG, natriuretic peptides (BNP/NT-proBNP; LOINC-codable), cardiac MRI with late gadolinium enhancement, exclusion of ischemic/valvular/toxic causes.
• Genetic testing: In the founding era, targeted PSEN1/PSEN2 sequencing. Today, PSEN2 is not a recommended DCM panel gene: ClinGen's Limited classification means a PSEN2 variant in a DCM patient is weak evidence and should not be returned as a molecular diagnosis. WES/WGS will incidentally cover PSEN2; interpretation must apply the population-frequency evidence above (expect Benign/VUS-risk-factor calls for S130L). GTR lists tests under condition C3150958.
• Differential diagnosis: all other genetic DCM loci (TTN, LMNA, MYH7, TNNT2, DSP, FLNC, BAG3, RBM20, SCN5A, PLN, TAB2 …), plus phenocopies (ischemic, alcoholic, chemotherapy-induced, myocarditic, peripartum, tachycardia-induced) and infiltrative disease — notably cardiac amyloidosis, which is mechanistically adjacent to the oligomer hypothesis but is a distinct diagnosis (light-chain, transthyretin, desmin-related; PMID:20194882 background).
• Screening: cascade clinical screening (echo/ECG) of first-degree relatives per familial-DCM guidelines; predictive genetic testing for PSEN2 alone is not supportable at Limited validity.

11. Outcome/Prognosis

• No survival curves or registry data exist for CMD1V. The only comparative statement: PSEN2 disease showed "partial penetrance, milder disease, and a more favorable prognosis", versus PSEN1-CMD1U's complete penetrance and "progressive disease that resulted in the necessity of cardiac transplantation or in death" (PMID:17186461).
• Complications, once DCM is established, are those of DCM generally: congestive heart failure (HP:0001635), arrhythmia, thromboembolism, sudden cardiac death (HP:0001645) — none specifically quantified in the two pedigrees.
• Prognostic factors/biomarkers: none locus-specific; standard heart-failure prognostics (LVEF, NYHA class, NT-proBNP) apply.

12. Treatment

There is no PSEN2-specific therapy; management is standard guideline-directed care for DCM/heart failure with reduced EF.

Pharmacogenomics, gene/cell/RNA therapy, targeted therapy: none exist or are in trials for this locus (no CMD1V-specific NCT records).

13. Prevention

• Primary prevention: none possible (no proven modifiable cause).
• Secondary prevention: periodic clinical surveillance (echo/ECG) of first-degree relatives in the two known families and in any family where a segregating PSEN2 variant is suspected — driven by the familial-DCM phenotype, not by the genotype.
• Genetic counseling: must communicate (a) autosomal dominant transmission within the reported pedigrees, (b) partial penetrance, (c) the Limited ClinGen classification, and (d) that the cardiac classification is independent of PSEN2's established Alzheimer-disease role — an S130L result does not carry an AD diagnosis either (ACMG Benign/risk-factor for AD).
• Tertiary prevention: standard heart-failure disease management.

14. Other Species / Natural Disease

No naturally occurring PSEN2-mutant cardiomyopathy is known in any non-human species (no OMIA phenotype). Comparative data are all engineered or disease-context expression studies: dog (failing LV PS2 upregulation, Canis lupus familiaris, NCBITaxon:9615; PMID:20443895), mouse (NCBITaxon:10090), rat cell line (NCBITaxon:10116; PMID:12468103). Psen2 is evolutionarily conserved; mouse Psen2 is the ortholog used in all knockout work. No zoonotic/transmission relevance.

15. Model Organisms

Missing model: no S130L (or R62H) knock-in animal, iPSC-derived cardiomyocyte line, or engineered-tissue model exists — precisely the experiment that would move this locus off Limited.

Summary Assessment for KB Curation

CMD1V is a queried, historically established OMIM locus resting on a weak and shrinking evidence base: two variants, four probands, two studies (2006, 2010), zero new human genetic evidence since, population frequencies incompatible with high-penetrance causality, and a knockout mouse pointing the wrong way. Curate the locus (it exists, is indexed, and is asked about), anchor it to MONDO:0013373, carry the ClinGen Limited assertion as first-class evidence, hold the calcium-handling mechanism inside an explicitly hypothetical grouping rather than as asserted pathophysiology, and state plainly that a PSEN2 variant is not a reportable molecular diagnosis of DCM.

Primary citations: PMID:17186461 (Li 2006, founding study); PMID:20194882 (Gianni 2010, second human study + oligomer mechanism); PMID:16204356 (Takeda 2005, Psen2-KO mouse / RyR2–sorcin); PMID:12468103 (Mohuczy 2002, cardiac PS2 expression); PMID:20443895 (Gupta 2009, failing-dog PS2 expression); CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z (ClinGen Limited, 2026).

Sources: - OMIM #613697 — Cardiomyopathy, Dilated, 1V; CMD1V - OMIM *600759 — Presenilin 2; PSEN2 - ClinGen Gene-Validity report: PSEN2 / dilated cardiomyopathy 1V (Limited) - Alzforum mutation page: PSEN2 S130L - Li et al. 2006, Am J Hum Genet — Mutations of presenilin genes in dilated cardiomyopathy and heart failure (PMID:17186461) - Gianni et al. 2010, Circulation — Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy (PMID:20194882) - Presenilin 1 is essential for cardiac morphogenesis (PubMed 15254914) - Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction (J Cell Physiol) - NIH Genetic Testing Registry — Dilated cardiomyopathy 1V (C3150958) - MalaCards — Cardiomyopathy, Dilated, 1v - Ensembl — rs63750197

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0013373 (3 mentions) - the report calls it "MONDO"; MONDO calls it dilated cardiomyopathy 1V

Terms whose name is worth a second look

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

• GO:0016529 (2 mentions) - the report calls it "Subcellular: sarcoplasmic reticulum"; GO calls it sarcoplasmic reticulum**
• UBERON:0000948 (1 mention) - the report calls it "Organ: heart"; UBERON calls it heart**, and lists "branchial heart" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: CCID, ORPHA.