Dilated Cardiomyopathy 1V

Mendelian MONDO:0013373 Pathograph 12 Show in embeddings browser Familial Dilated Cardiomyopathy

A numbered OMIM dilated-cardiomyopathy locus assigned to PSEN2, the second presenilin and, like its sibling PSEN1, far better known as an early-onset Alzheimer disease gene. This entry is the companion of dismech's Dilated Cardiomyopathy 1U: the two loci were defined by the same 2006 screen of the same 315 probands, and they are curated on the same evidence base for the same reason - the locus exists and is queried, not because the gene-disease relationship is settled. The single most important thing in the entry is the expert-panel verdict, and it differs from 1U's. In March 2026 the ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel reported the PSEN2 - dilated cardiomyopathy 1V relationship as **Limited** under SOP10. Limited is a positive but weak tier: some human genetic evidence is scorable, and it is not enough. That is one tier better than PSEN1's **Disputed** at the sibling locus, and the difference is real rather than cosmetic - for PSEN1 the panel found no scorable human genetic evidence at all, whereas for PSEN2 it counted two missense variants in four probands across two studies. The panel nevertheless records that the genetic evidence points decreased over time, that both reported variants turn out to be too common in population reference data for a monogenic effect, and that no new human genetic evidence has emerged since the previous curation. The clinical phenotype also differs, and in the direction that matters for a family. Where the PSEN1 family showed complete penetrance and progressive disease ending in transplantation or death, the PSEN2 variant Ser130Leu - found in two families in the same screen - showed partial penetrance, milder disease and a more favourable prognosis. Any statement about penetrance here rests on two small pedigrees and is not a lifetime estimate. The mechanism is held loosely, as at the sibling locus, but the cardiac anchor is a different molecule. For PSEN1 the proposed route runs through the sarcoplasmic-reticulum calcium pump SERCA2a. For PSEN2 the specific cardiac interaction reported is with the ryanodine receptor RyR2 and its modulator sorcin, demonstrated by co-immunoprecipitation and colocalisation at the Z-lines in mouse heart. Presenilin-2 is expressed in myocardium, and its expression rises with hypoxia and glucose deprivation in cardiac cells and in failing canine myocardium - which is the expression work ClinGen names as supporting the relationship. What is missing is the step that would matter: no cardiomyocyte carrying Ser130Leu has ever been studied, and the one in vivo cardiac calcium phenotype - from a Psen2 knockout mouse - runs in the wrong direction, showing increased contractility and no dilatation. The causal chain below is therefore held inside a single ALTERNATIVE mechanistic hypothesis rather than asserted as the disease mechanism. Practically: a PSEN2 variant found in a patient with dilated cardiomyopathy is weak evidence and should not be reported as a molecular diagnosis on its own. The Limited classification is specific to the cardiac phenotype and says nothing about PSEN2's established role in early-onset familial Alzheimer disease.

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Inheritance
5
Pathophys.
2
Phenotypes
1
Hypotheses
2
Gaps
12
Pathograph
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Genes
2
Variants
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous transmission in the two reported families, and the mode of inheritance ClinGen curated the relationship under. The founding paper describes partial penetrance for the PSEN2 variant, in contrast to complete penetrance for the PSEN1 variant at the sibling locus. No penetrance_percentage is recorded: a penetrance statement drawn from two small pedigrees, with younger carriers still unaffected, is not a population estimate, and recording a number would give it a precision the source does not have.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:17186461 SUPPORT Human Clinical
"The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis."
The reported penetrance of the CMD1V allele, quoted for the penetrance clause. Partial penetrance is the feature that distinguishes this locus's inheritance from the sibling locus's.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel"
Records the mode of inheritance the expert panel curated the relationship under, alongside the classification.
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Mechanistic Hypotheses

1
Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
psen2_calcium_handling_dcm ALTERNATIVE
Evidence balance 3 support 1 refute
The only mechanistic model proposed for CMD1V: a PSEN2 variant perturbs presenilin-2 in the cardiomyocyte, which disturbs sarcoplasmic-reticulum calcium handling - plausibly through the presenilin-2 association with RyR2 and sorcin - and the resulting excitation-contraction defect drives dilatation and pump failure. It is recorded as ALTERNATIVE, not CANONICAL, because the disease it explains carries only Limited gene-disease validity and because every support falls short of the claim. Carrier calcium signalling was measured in skin fibroblasts. The RyR2 and sorcin interaction was demonstrated in mouse heart and in a heterologous cell line, not in a carrier. No cardiomyocyte carrying Ser130Leu has ever been studied. Worse for the model than any of that: the one in vivo cardiac phenotype attributable to losing presenilin-2 points the wrong way. Psen2 knockout mice show increased contractility and larger calcium transients, with no hypertrophy or fibrosis - not the failing, dilating ventricle this entry is named for. That does not refute the hypothesis, since the CMD1V allele is a missense variant whose functional consequence is unknown and need not resemble deletion, but it does mean the mechanism cannot simply be read off the knockout. The model is nevertheless worth keeping, because it is amyloid-independent and stated as such in the sources, which distinguishes it from the neuronal presenilin literature and makes it falsifiable: an isogenic Ser130Leu human iPSC-cardiomyocyte line with calcium-transient and RyR2-flux readouts would settle it in either direction.
Pathograph links
PSEN2 Ser130Leu Missense Variant in Cardiomyocytes -> Dysregulated Cardiomyocyte Calcium Handling INDIRECT UNKNOWN INTERMEDIATES The proposed first step. Its support is calcium signalling measured in cultured skin fibroblasts from carriers, not in cardiomyocytes, so the intermediates between the variant and a myocardial calcium defect are unknown.
Dysregulated Cardiomyocyte Calcium Handling -> Ventricular Remodeling and Chamber Dilatation INDIRECT UNKNOWN INTERMEDIATES Impaired excitation-contraction coupling as a chronic cardiomyocyte insult driving adverse remodeling. This edge is the general cardiomyopathy chain rather than a CMD1V-specific finding; nothing in the PSEN2 literature measures it.
Show evidence (4 references)
PMID:37176125 SUPPORT Other
"DCM may not be related to impaired APP cleavage by gamma secretase, suggesting that PSEN1 (and PSEN2) could impact heart failure through an amyloid-independent mechanism"
A review's statement of the amyloid-independent framing this hypothesis adopts, naming PSEN2 explicitly, and the reason the neuronal amyloid literature is excluded from the entry.
PMID:16204356 SUPPORT Model Organism
"Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2."
The authors' conclusion, which is the strongest available statement that presenilin-2 has a real role in cardiomyocyte calcium handling - the premise this hypothesis needs.
PMID:16204356 REFUTE Model Organism
"Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls."
The result that cuts against this hypothesis and is quoted so the entry does not overstate it: removing presenilin-2 from a mouse heart makes it contract better, not worse, which is the opposite of the direction a dilated cardiomyopathy mechanism requires.
+ 1 more reference
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Discussions and Knowledge Gaps

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Is PSEN2 a dilated cardiomyopathy gene, or is CMD1V an OMIM locus resting on two families and a variant that turns out to be too common?
CONTROVERSY OPEN psen2_dcm_gene_validity
Attached to
genetic#PSEN2 disease#Dilated Cardiomyopathy 1V
Twenty years after the founding report the human evidence is two families from the original screen plus two sporadic patients carrying a different allele, and the expert panel counts four probands in total. ClinGen has looked at it three times - 2019, 2024, 2026 - and each time called it Limited, on the ground that both reported disease-causing variants are too common in population reference data for a monogenic effect, and that nothing new has appeared. The counter-argument is stronger here than at the sibling PSEN1 locus, and that asymmetry is the interesting part. The panel credits the founding study with limited segregation and functional evidence for this allele - where for PSEN1 it found no scorable human genetic evidence at all - and there is a defined cardiac interaction partner for presenilin-2 in RyR2 and sorcin. Limited is a positive tier: it means some evidence exists and more is needed, not that the relationship is contested. This is recorded as an open controversy rather than resolved in either direction because the deciding work - a modern population-frequency and case-control reassessment of PSEN2 in a large dilated-cardiomyopathy cohort, or a cardiomyocyte model of Ser130Leu - has not been done. It matters practically: it determines whether PSEN2 belongs on a dilated-cardiomyopathy panel.
Proposed experiments
Modern population-frequency and case-control reassessment of PSEN2 in dilated cardiomyopathy
psen2_dcm_case_control_burden
Genotype PSEN2 across a large sequenced dilated-cardiomyopathy cohort and compare variant burden against a matched population reference, testing directly the observation the Limited classification rests on.
Would support
pathophysiology#PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
Would refute
pathophysiology#PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
Supporting outcome
  • Excess of rare, conserved PSEN2 missense variants in cases over ancestry-matched population controls, with Ser130Leu rare enough to be compatible with a monogenic effect.
Refuting outcome
  • No case-control burden difference, and reported disease-causing alleles present in population reference data at frequencies incompatible with a rare dominant cardiomyopathy.
Show evidence (2 references)
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z REFUTE Other
"No new human genetic evidence has emerged since the last curation."
The specific deficiency the classification rests on: the evidence base has not grown between curations.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"While Li et al. demonstrated limited segregation and functional evidence for the missense variant identified in their study"
The counter-argument in the panel's own words: unlike the sibling locus, this one has some scorable positive evidence, which is what puts it a tier higher.
The only in vivo cardiac phenotype for presenilin-2 loss is increased contractility with no dilatation. Does the proposed calcium mechanism actually point towards dilated cardiomyopathy?
HUMAN MODEL MISMATCH OPEN psen2_knockout_direction_mismatch
Attached to
pathophysiology#Dysregulated Cardiomyocyte Calcium Handling mechanistic_hypotheses#psen2_calcium_handling_dcm
Every piece of evidence for the calcium mechanism at this locus comes from the wrong cell, the wrong genotype, or the wrong direction. Carrier calcium signalling was measured in cultured skin fibroblasts, which are not contractile. The RyR2 and sorcin interaction was demonstrated in mouse heart and in a heterologous overexpression system, not in a carrier. And the one functional cardiac phenotype - from Psen2 knockout mice - shows increased contractility, larger calcium transients and no hypertrophy, fibrosis or dilatation. That last point is the substance of this mismatch and is worth stating precisely. It is not a refutation: CMD1V is a heterozygous missense allele, and a missense variant need not behave like a deletion - it could be a gain of function, a dominant negative, or act on a presenilin-2 function the knockout does not isolate. But it does mean the mechanism cannot be read off the knockout, and any account that treats "presenilin-2 dysfunction impairs cardiomyocyte calcium handling and the heart dilates" as established is asserting a direction that the only in vivo experiment contradicts. This is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap because the evidence is not absent - the model exists, is well characterised and is internally sound. What is missing is any demonstration that it composes into the human disease mechanism in the relevant genotype and direction.
Proposed experiments
Isogenic PSEN2 Ser130Leu human iPSC-cardiomyocyte calcium phenotyping
psen2_s130l_ipsc_cardiomyocyte_calcium
Introduce Ser130Leu into a human iPSC line by genome editing, differentiate to cardiomyocytes alongside the isogenic wild-type parent, and measure calcium transients, sarcoplasmic-reticulum calcium load, RyR2-mediated leak and contractility.
Would support
pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
Would refute
pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
Supporting outcome
  • Altered calcium transient kinetics and impaired contractility in the Ser130Leu cardiomyocytes relative to the isogenic control, in the direction of reduced rather than enhanced systolic performance.
Refuting outcome
  • Calcium transients, sarcoplasmic-reticulum load and contractility indistinguishable from the isogenic wild-type control.
Show evidence (2 references)
PMID:16204356 REFUTE Model Organism
"Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls."
The directional mismatch this discussion is about, in the source's own words.
PMID:17186461 SUPPORT INDIRECT In Vitro
"Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers."
Names the tissue in which the carrier calcium phenotype was actually observed, which is the other half of the mismatch: a surrogate cell rather than a cardiomyocyte.
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Pathophysiology

5
PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
Mechanism confidence: Hypothetical
A heterozygous germline PSEN2 missense variant, Ser130Leu, reported in two dilated cardiomyopathy families in the founding screen and segregating with disease in them. Presenilin-2 is expressed in myocardium as well as brain, so a cardiomyocyte-autonomous lesion is anatomically possible. What the variant does to presenilin-2 in a cardiomyocyte has never been measured. There is no structural or biochemical characterisation of Ser130Leu in cardiac tissue, no Ser130Leu cardiomyocyte model, and no directional statement available about gamma-secretase activity in the heart of a carrier. The node is therefore typed as the proposed initiating lesion and given no modifier and no functional_impact_category: neither loss nor gain of function has been shown for this allele in this tissue, and FunctionalImpactEnum has no value that would be honest here. A second PSEN2 allele has been reported in myocardial disease and is placed at the same point in the chain rather than given its own node: the missense variant Arg62His, found in two of twenty sporadic idiopathic dilated-cardiomyopathy patients whose presenilin genes were sequenced. It is a different allele in different, non-familial patients, and it is recorded because the expert panel counts it as one of the two variants behind the Limited classification.
Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
PSEN2 hgnc:9509 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSEN2 (hgnc:9509). hgnc:9509 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context PSEN2 hgnc:9509 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PSEN2 (hgnc:9509). hgnc:9509 is a gene from the HUGO Gene Nomenclature Committee. allele_type: MISSENSE variant_origin: GERMLINE zygosity: HETEROZYGOUS
Heterozygous germline PSEN2 p.Ser130Leu, reported in two dilated-cardiomyopathy families. No functional_impact_category is assigned because the functional consequence of this allele has not been determined in cardiac tissue or in a cardiomyocyte model.
Downstream
Dysregulated Cardiomyocyte Calcium Handling The proposed first step. Its support is calcium signalling measured in cultured skin fibroblasts from carriers, not in cardiomyocytes, so the intermediates between the variant and a myocardial calcium defect are unknown. Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
Show evidence (4 references)
PMID:17186461 SUPPORT Human Clinical
"Both mutations segregated with DCM and heart failure."
The segregation observation in the index families that produced the CMD1U and CMD1V locus assignments.
PMID:17186461 SUPPORT INDIRECT Human Clinical
"The presenilins are also expressed in the heart and are critical to cardiac development."
The anatomical premise that makes a cardiomyocyte-autonomous presenilin lesion possible at all. INDIRECT because expression in a tissue does not establish that this variant acts there.
PMID:20194882 SUPPORT INDIRECT Human Clinical
"The coding region and promoters of PSEN1 and PSEN2 were sequenced in 20 patients with iDCM."
The design of the second study the expert panel counts, in which the PSEN2 Arg62His allele was found. INDIRECT for this node because those were sporadic idiopathic cases, not CMD1V families, and the allele is not Ser130Leu.
+ 1 more reference
Dysregulated Cardiomyocyte Calcium Handling
Mechanism confidence: Hypothetical
The proposed effector step: disturbed intracellular calcium regulation in the cardiomyocyte. Three observations point at it, and none was made in a cardiomyocyte carrying the CMD1V allele. First, cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers in the founding families showed altered calcium signalling. Fibroblasts are an accessible surrogate, not a contractile cell, and the paper reports the abnormality without asserting a myocardial equivalent. Second, and this is where the PSEN2 story diverges from its PSEN1 sibling, presenilin-2 physically associates with the cardiac ryanodine receptor RyR2 and with sorcin, its modulator - shown by co-immunoprecipitation in mouse heart and by colocalisation at the Z-lines. Where the PSEN1 cardiac work implicates the sarcoplasmic-reticulum calcium pump SERCA2a, the PSEN2 work implicates the release channel. Both are calcium handling; they are not the same lesion. Third, the presenilin sequencing study in sporadic disease concluded that presenilin missense mutations may alter the interaction of these proteins with the excitation-contraction coupling machinery. The node carries no direction. The interaction results are physical associations rather than rates, the only in vivo cardiac measurement comes from a knockout mouse and points towards increased rather than decreased calcium release, and the human sources say "altered". The biological process below is therefore tagged DYSREGULATED: choosing INCREASED or DECREASED would be an invention.
Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↕ DYSREGULATED
RyR2 ryanodine-sensitive calcium-release channel activity GO:0005219 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves RyR2 ryanodine-sensitive calcium-release channel activity, annotated with ryanodine-sensitive calcium-release channel activity (GO:0005219). GO:0005219 is a molecular function from the Gene Ontology.
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Presenilin-2 knockout mouse (cardiac phenotype) Mouse partially recapitulates Establishes that presenilin-2 is a real participant in cardiomyocyte calcium handling in the intact heart, through a defined interaction with RyR2 and sorcin - the mechanistic premise this entry's hypothesis rests on.
Downstream
Ventricular Remodeling and Chamber Dilatation Impaired excitation-contraction coupling as a chronic cardiomyocyte insult driving adverse remodeling. This edge is the general cardiomyopathy chain rather than a CMD1V-specific finding; nothing in the PSEN2 literature measures it. Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
Show evidence (4 references)
PMID:17186461 SUPPORT INDIRECT In Vitro
"Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers."
The only functional measurement made in cells from CMD1V carriers. Graded IN_VITRO because the measurement was made in cultured cells, and INDIRECT because skin fibroblasts are a surrogate tissue: it supports a calcium phenotype in carrier cells, not in myocardium.
PMID:16204356 SUPPORT Model Organism
"Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts."
The physical association that makes calcium handling, rather than amyloid, the proposed route for this locus - and specifically the release channel rather than the SERCA2a pump implicated at the sibling locus. Quoted with the source's own typography.
PMID:16204356 SUPPORT Model Organism
"Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines."
Places the interaction at the calcium-release apparatus of the cardiomyocyte rather than leaving it as a biochemical result in a lysate.
+ 1 more reference
Ventricular Remodeling and Chamber Dilatation
Adverse structural remodeling of the left ventricle - chamber dilatation with wall thinning - as the shared final common path of the cardiomyopathies. Nothing in the CMD1V literature characterises remodeling in a PSEN2 carrier heart specifically: there is no histology, no fibrosis quantification and no imaging series. The node is curated because the reported clinical phenotype is dilated cardiomyopathy and this is the step that word names, and it conforms to the shared module rather than claiming disease-specific detail.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Presenilin-2 knockout mouse (cardiac phenotype) Mouse fails to recapitulate The model does not reproduce the structural phenotype the human entity is named for: mice lacking presenilin-2 develop no dilatation, no hypertrophy and no fibrosis, and their hearts contract better than controls. This is the central model-fidelity problem for the locus, recorded structurally rather than left in prose.
Downstream
Systolic Dysfunction and Heart Failure Chamber dilatation with impaired contraction is by definition the dilated cardiomyopathy phenotype and the substrate for pump failure.
Dilated Cardiomyopathy The clinical phenotype is the imaging expression of this tissue-level state: a dilated left ventricle with impaired systolic function is what this node names, observed on echocardiography. Definitional rather than a separately evidenced causal step.
Show evidence (1 reference)
DOI:10.1093/ehjqcco/qcae109 SUPPORT INDIRECT 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..."
Cited to anchor the node in the recognised disease class rather than to make a mechanistic claim: a systematic review of dilated-cardiomyopathy guidelines reports cross-guideline consensus on the disease definition and on the imaging that establishes it, which is what this node names. INDIRECT because it is about dilated cardiomyopathy generally, not remodeling in a PSEN2 carrier - of which nothing has been reported.
Systolic Dysfunction and Heart Failure
Falling ejection fraction and clinical heart failure. This is the clinical endpoint of the entity and the only part of the chain observed directly in CMD1V patients. Note the qualifier the sources support is weaker here than at the sibling locus: the reported course in the PSEN2 families was milder, with a more favourable prognosis, and no transplantation or death is reported for this locus.
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Congestive Heart Failure The symptomatic clinical syndrome of the pump failure this node describes. Definitional rather than a separately evidenced causal step.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease."
The founding study's conclusion, naming heart failure as the reported endpoint. Note it says "associated with", which is a weaker claim than the locus name implies.
Stress-Responsive Myocardial Presenilin-2 Expression
Mechanism confidence: Hypothetical
Presenilin-2 is present in myocardium and its level moves with cardiac stress: it is detectable in cultured cardiac cells and in adult rat heart, rises with glucose deprivation and hypoxia in cardiac cells, and is increased in the failing myocardium of dogs with heart failure, where a contractility-modulation therapy that improves ventricular function normalises it again. This node is kept outside the disease's causal chain deliberately, and no downstream edge is drawn from it. It is the expression work the ClinGen panel names as supporting the gene-disease relationship, so it belongs in the entry; but every observation in it is correlative and none involves a PSEN2 variant. The direction of causality is exactly what is unresolved - presenilin-2 rising in a failing heart is at least as consistent with a response to failure as with a cause of it, and the canine result, in which the increase reverses when ventricular function improves, reads more naturally as the former.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Show evidence (5 references)
PMID:12468103 SUPPORT In Vitro
"Presenilin-2 (PS2) was detected in the cultured heart cells."
Establishes the presence of presenilin-2 in cardiac cells, which is the premise of this node. Graded IN_VITRO because the measurement was made in a cultured cardiac cell line.
PMID:12468103 SUPPORT In Vitro
"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."
The stress-responsiveness this node names, with the measured magnitudes. This is one of the two expression studies the ClinGen panel cites as supporting the relationship.
PMID:20443895 SUPPORT Model Organism
"Compared with NL, the expression of S100A1, sorcin, and HRC was decreased, whereas the expression of PS2 was increased in untreated HF dogs."
Presenilin-2 expression is altered in failing myocardium in vivo - the second expression study the panel cites. Graded MODEL_ORGANISM because it is a canine heart-failure model.
+ 2 more references
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 1V Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Dilated Cardiomyopathy Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
No frequency band is assigned, and no clinical_course qualifier either. The denominator is two pedigrees in a single paper, so a FrequencyEnum value would present a family observation as a disease-level frequency; and unlike the sibling locus, where the course is described as progressive, the only course statement available for CMD1V is that the disease was milder with a more favourable prognosis, which does not support PROGRESSIVE.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families."
Identifies the families in which the dilated-cardiomyopathy phenotype defining this locus was observed.
Congestive Heart Failure Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
No frequency band assigned, for the same reason as the dilated-cardiomyopathy phenotype: the only denominator available is two pedigrees.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease."
The founding study's own conclusion sentence, naming heart failure alongside dilated cardiomyopathy as the reported phenotype for both presenilin loci.
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Genetic Associations

1
PSEN2 (PSEN2 encodes presenilin-2, a catalytic subunit of the gamma-secretase intramembrane protease and a paralogue of PSEN1. Its relationship with dilated cardiomyopathy was proposed in 2006 on the strength of two families carrying Ser130Leu, found in a screen of 315 dilated-cardiomyopathy index patients, together with altered calcium signalling in carrier skin fibroblasts. A second missense allele, Arg62His, was later reported in two of twenty sporadic idiopathic cases. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel first evaluated PSEN2 for dilated cardiomyopathy in December 2019, re-evaluated it under SOP10 in October 2024, and the classification did not change: **Limited**, re-reported March 2026. The panel counts two missense variants in four probands across two studies as the whole human genetic evidence base, records that the genetic evidence points decreased over time, and notes that both reported variants have since been found too frequently in population reference data for a monogenic pathogenic effect. The relationship is typed UNKNOWN rather than CAUSATIVE or DISPUTED, and the choice is deliberate in both directions. CAUSATIVE would assert what the panel declines to assert - Limited explicitly means the evidence does not establish the relationship. DISPUTED would import the sibling locus's verdict: the enum's own description binds DISPUTED to ClinGen "Disputed" or "Refuted", and PSEN2 is neither. Limited sits between the two, and UNKNOWN - "the relationship between the gene and the disease is unclear or not yet classified" - is the closest honest value the enum offers. The precise classification is recorded in the external_assertions block and in the evidence below, which is where a reader should look rather than relying on this coarse slot. The verdict is specific to the cardiac phenotype. PSEN2's relationship with early-onset familial Alzheimer disease is not in question and is a separate matter from this entry.)
Gene: PSEN2 hgnc:9509 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSEN2 (hgnc:9509). hgnc:9509 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: GERMLINE
Show evidence (5 references)
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel"
The current expert-panel classification row, curated against this exact MONDO term. This is the single most important item in the entry for anyone interpreting a PSEN2 variant in a cardiomyopathy patient.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z REFUTE Other
"There is limited evidence to support this gene-disease relationship."
The panel's conclusion about the strength of the relationship, and the reason relationship_type is not CAUSATIVE.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"PSEN2 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2006 (Li et al. PMID: 17186461)."
Confirms the panel curated the same founding paper this entry is built on, so the Limited verdict and the entry's evidence base are about the same claim.
+ 2 more references
Variants (2)
PSEN2 p.Ser130Leu
The founding CMD1V allele. A heterozygous missense substitution replacing serine with leucine, reported in two dilated-cardiomyopathy families with partial penetrance and milder disease than the PSEN1 allele found in the same screen. The original paper describes it at the nucleotide level in a historical transcript convention; that description is not restated here because it cannot be converted to modern HGVS without transcript confirmation.
PSEN2 p.Arg62His
The second PSEN2 missense allele the expert panel counts, reported in two of twenty sporadic idiopathic dilated-cardiomyopathy patients rather than in a CMD1V family. It is recorded here because it forms part of the evidence base behind the Limited classification, not because it is a CMD1V allele. In the same report it did not segregate with disease status in the Alzheimer families in which it was also examined.
🗃️

External Assertions

1
ClinGen PSEN2-dilated cardiomyopathy 1V gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
The ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal dominant PSEN2 - dilated cardiomyopathy 1V relationship as Limited. The curation is against MONDO:0013373 itself, so it is about this entity rather than about dilated cardiomyopathy in general. First evaluated December 2019, re-evaluated under SOP v10 in October 2024 with no change, approved by the working group in May 2025, report dated 2026-03-04. Its evidence summary is specific about the shape of the evidence: two missense variants in four probands across two studies, both variants too common in population reference data, no new human genetic evidence since the previous curation, and experimental support resting on two expression studies. This is one tier above the Disputed classification the same panel gives PSEN1 for dilated cardiomyopathy 1U on the same report date - a difference worth preserving, since for PSEN1 the panel found no scorable human genetic evidence at all.
Show evidence (4 references)
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z REFUTE Other
"The overall genetic evidence points decreased over time."
The direction of travel of the evidence between curations, which is the panel's own summary of why the classification did not improve.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z REFUTE Other
"In summary, there is a lack of new supporting evidence in the period since the previous curation."
Records that the relationship has not strengthened in the twenty years since it was proposed, which is the substance of the Limited verdict.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"More evidence is needed to support the relationship of PSEN2 with AD DCM."
Quoted so the Limited classification is not read as a rejection. The panel asks for more evidence rather than ruling the relationship out, which is why this entry curates the locus.
+ 1 more reference
💊

Medical Actions

2
Guideline-Directed Heart Failure Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. angiotensin receptor-neprilysin inhibitor NCIT:C190796 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses angiotensin receptor-neprilysin inhibitor (NCIT:C190796). NCIT:C190796 is a therapeutic agent from the NCI Thesaurus. SGLT2 inhibitor NCIT:C98083 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses SGLT2 inhibitor (NCIT:C98083). NCIT:C98083 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Management of CMD1V is management of dilated cardiomyopathy: there is no PSEN2-directed therapy, no trial in this population, and no reason to expect genotype-specific treatment while the genotype-phenotype relationship carries only Limited validity. Treatment follows the contemporary heart-failure pathway, which acts on the remodeling and pump-failure end of the chain rather than on any presenilin lesion. The agents listed below are the standard classes of guideline-directed medical therapy for heart failure with reduced ejection fraction, recorded so the treatment is queryable by drug identity. They are not a CMD1V-specific regimen and no source names them for this locus. Beta-blockers belong in the same list but are not recorded as a therapeutic_agent, because the NCI Thesaurus build configured here has no drug-class term for them that could be verified.
Mechanism Target:
Systolic Dysfunction and Heart Failure — Acts on the clinical endpoint, not on the proposed molecular mechanism. Nothing in the standard regimen targets presenilin-2 or the calcium node above it.
Show evidence (1 reference)
PMID:35379503 SUPPORT INDIRECT Other
"The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests."
The guideline this treatment defers to. INDIRECT because it is written for heart failure as a whole and says nothing about PSEN2 - which is the point: no PSEN2-specific regimen exists, so the general pathway is the treatment.
Cardiac Surveillance of At-Risk Relatives
Action: serial cardiac surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is serial cardiac surveillance, annotated with Cardiac Disease Screening (NCIT:C168126). NCIT:C168126 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Disease Screening NCIT:C168126
Platform: Other
Serial cardiac assessment of first-degree relatives of an affected proband. For a partially penetrant, late-onset cardiomyopathy this is the intervention with the clearest rationale, because it detects dilatation before symptoms - and partial penetrance is exactly the setting in which a clinical rather than genotypic trigger matters, since an unaffected carrier may remain unaffected. Whether surveillance should be triggered by a PSEN2 variant specifically is a weaker question than at the sibling PSEN1 locus but still not settled: Limited validity does not support genotype-directed surveillance on a PSEN2 result alone. Clinical surveillance of relatives of an affected proband stands on the family history regardless of genotype.
Mechanism Target:
Ventricular Remodeling and Chamber Dilatation — Detects remodeling early rather than modifying it; the benefit comes from starting heart-failure therapy before decompensation.
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."
The rationale for surveillance of at-risk relatives, stated by GeneReviews as one of the purposes of its dilated-cardiomyopathy overview: early detection before symptoms so treatment can start sooner.
PMID:17186461 SUPPORT INDIRECT Human Clinical
"The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis."
The partial penetrance that makes clinical rather than genotype-driven surveillance the sensible framing here. INDIRECT because the sentence describes the reported families, not a surveillance study.
🔬

Diagnosis

3
Echocardiographic Diagnosis of Dilated Cardiomyopathy
The phenotype is established on imaging - a dilated left ventricle with impaired systolic function and no ischaemic, valvular or load-related explanation - before any genetic question arises. Nothing about CMD1V changes this step, and there is no PSEN2-specific diagnostic feature: no cardiac imaging, biopsy or biomarker finding distinguishes a PSEN2 carrier from any other dilated cardiomyopathy.
Show evidence (1 reference)
PMID:20301486 SUPPORT Other
"Provide the evaluation strategy of a proband with nonsyndromic DCM"
The GeneReviews overview's statement that it defines proband evaluation for this disease class.
Natriuretic Peptide, Troponin and Multimodality Cardiac Imaging
The laboratory and imaging workup that establishes the phenotype. A 2025 systematic review of dilated-cardiomyopathy guidelines found cross-guideline consensus on B-type natriuretic peptides and high-sensitivity troponin in laboratory testing and on multimodality cardiovascular imaging for initial diagnosis. None of this is PSEN2-specific, which is itself worth recording: it means the diagnosis of this entity rests entirely on sequencing plus pedigree.
Show evidence (1 reference)
DOI:10.1093/ehjqcco/qcae109 SUPPORT INDIRECT 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..."
The elements of the diagnostic workup that guidelines agree on. INDIRECT because the review is about dilated cardiomyopathy generally; nothing in it is specific to this locus.
Multigene Cardiomyopathy Panel Testing
Genetic testing is by panel or exome. For PSEN2 the point is interpretation rather than efficiency: with the gene-disease relationship classified Limited, a PSEN2 variant found in a dilated-cardiomyopathy proband is weak evidence and should not carry the weight of a molecular diagnosis on its own. The panel's specific observation - that both reported variants are too common in population reference data for a monogenic effect - applies directly to interpreting a new one. Limited is nevertheless a positive tier rather than a contested one, so this is a weaker caution than the sibling PSEN1 locus warrants. A PSEN2 finding in a proband with a compatible family history is worth pursuing; it is not on its own an answer.
Show evidence (2 references)
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel"
The classification that governs how much weight a PSEN2 result should carry in this setting.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z REFUTE Other
"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"
The population-frequency observation that should inform interpretation of any new PSEN2 variant found in this setting.
📈

Progression

2
Nonpenetrant carrier state
Unlike the sibling PSEN1 locus, where the founding paper describes complete penetrance, the PSEN2 variant is explicitly reported with partial penetrance: carriers in the two reported families were not uniformly affected. No penetrance_percentage is recorded on the inheritance block, because a penetrance statement drawn from two small pedigrees with age censoring is a family observation rather than a population estimate.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis."
The reported penetrance of the CMD1V variant, and the sentence that separates this locus clinically from CMD1U.
Symptomatic dilated cardiomyopathy
Where the disease did manifest it was reported as milder than at the PSEN1 locus, with a more favourable prognosis - the founding paper contrasts it directly with the progressive PSEN1 course that ended in transplantation or death. No case series, follow-up study or outcome data exist for this locus beyond that sentence, so nothing more specific about the trajectory can be stated.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis."
The only statement of clinical course available for this locus, quoted for the severity and prognosis clauses rather than the penetrance one.
📊

Prevalence

1
Dilated cardiomyopathy index patients screened for presenilin variants
Cases In Literature Not yet documented
No population prevalence exists for this locus and none can be estimated. The only frequency figures in the literature are yields within screened cohorts: two PSEN2 families out of 315 dilated-cardiomyopathy index patients in the founding study, and, on the expert panel's count across both reporting studies, two missense variants in four probands in total. Those are variant-detection rates in selected cohorts, not disease prevalences, and the Limited classification means they should not be read as one.
Show evidence (3 references)
PMID:17186461 SUPPORT Human Clinical
"A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2."
The size and design of the screen that produced the CMD1V families, which is the denominator behind the two-family yield.
PMID:17186461 SUPPORT Human Clinical
"A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families."
The numerator: two PSEN2 families. The PSEN1 family in the same sentence is the separate locus CMD1U and is not counted here.
CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z SUPPORT Other
"Two missense variants have been reported in 4 probands in two studies (Li et al. PMID: 17186461, Gianni et al. PMID: 20194882)."
The expert panel's own count of the reported cases across the whole literature, which is the largest number anyone has assembled for this locus.
🔀

Differential Diagnoses

2

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

Dilated Cardiomyopathy 1U
Overlapping Features The PSEN1 locus, and the sibling of this one in the most literal sense: both were defined by the same 2006 screen of the same 315 probands. PSEN1 Asp333Gly was found in one family with complete penetrance, aggressive disease and an outcome of transplantation or death. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies PSEN1 for dilated cardiomyopathy 1U as Disputed - one tier below this entry's Limited, on the same review date - because it found no scorable human genetic evidence at all. dismech curates CMD1U as a separate entry.
Distinguishing Features
  • Different gene (PSEN1, hgnc:9508) and a more severe reported phenotype with complete penetrance and a progressive course. The two cannot be told apart clinically; only sequencing separates them.
Show evidence (1 reference)
PMID:17186461 SUPPORT Human Clinical
"The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death."
The clinical contrast between the two presenilin loci as reported in the paper that defined both, quoted from the PSEN1 side.
Idiopathic Dilated Cardiomyopathy
Overlapping Features Dilated cardiomyopathy with no identified cause, which is what a CMD1V patient has if the PSEN2 attribution is not accepted. This is not an academic alternative: with the relationship at Limited and both reported variants too common in population data, it is the diagnosis implied for many PSEN2 carriers with the phenotype. Note also that the second PSEN2 allele the expert panel counts was itself found in idiopathic rather than familial cases, so the boundary between the two categories is where part of this locus's evidence base sits.
Distinguishing Features
  • Absence of a family history or of a segregating variant. Given how weak the genetic evidence is, the practical boundary between this and CMD1V is the pedigree at least as much as the genotype.
Show evidence (1 reference)
PMID:20194882 SUPPORT Human Clinical
"The coding region and promoters of PSEN1 and PSEN2 were sequenced in 20 patients with iDCM."
Establishes that part of the presenilin cardiac evidence base was assembled in idiopathic, not familial, cases - and in a cohort of twenty.
🐁

Animal Models

1
Presenilin-2 knockout mouse (cardiac phenotype)
Mice lacking presenilin-2, characterised specifically for cardiac phenotype rather than for Alzheimer biology. The animals develop normally with no hypertrophy or fibrosis, but invasive haemodynamics show increased contractility, and isolated papillary muscle shows larger calcium transients and higher peak tension. The study goes on to show that presenilin-2 interacts with sorcin and the cardiac ryanodine receptor RyR2 and colocalises with them at the Z-lines. This is the only in vivo work directed at the presenilin-2 cardiac question, and it is curated here as the molecular anchor for the calcium node while being explicit that its phenotype runs opposite to dilated cardiomyopathy.
Species
Mouse
Genotype
Psen2 germline knockout (PS2KO)
Genes
PSEN2 hgnc:9509 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PSEN2 (hgnc:9509). hgnc:9509 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:16204356
Pathograph links
Dysregulated Cardiomyocyte Calcium Handling partially recapitulates fidelity: low observes: molecular Establishes that presenilin-2 is a real participant in cardiomyocyte calcium handling in the intact heart, through a defined interaction with RyR2 and sorcin - the mechanistic premise this entry's hypothesis rests on.
Limitations: The allele is a germline deletion, while CMD1V is a heterozygous missense variant whose functional consequence has never been determined; a knockout therefore cannot be assumed to model it. More importantly the direction is wrong: knockout hearts contract better, with larger calcium transients and no hypertrophy, fibrosis or dilatation, which is the opposite of the phenotype this entity is named for. The model was not built on, or tested against, the Ser130Leu allele, and no claim about the human disease mechanism rests on it.
Divergences from the human mechanism
proxy quantity qualifying
The model's quantity is calcium transient amplitude and contractility in a presenilin-2-null heart. The node's quantity is disturbed calcium handling caused by a missense allele, which need not act by loss of function.
species mismatch qualifying
Murine cardiomyocyte calcium handling and heart rate differ substantially from human, and no human carrier cardiomyocyte has been studied for comparison.
Readouts
Peak amplitude of calcium transients in isolated papillary muscle
Direction: INCREASED
Interpretation: The calcium measurement that ties presenilin-2 to cardiomyocyte calcium handling in vivo - and the one whose direction is opposite to what a dilated cardiomyopathy mechanism would predict.
Show evidence (1 reference)
PMID:16204356 SUPPORT Model Organism
"A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls."
The calcium and tension measurements behind this readout, with their direction.
Cardiac hypertrophy and fibrosis
Direction: UNCHANGED
Interpretation: A negative structural result, recorded because it is what makes this model a poor analogue of the human entity: losing presenilin-2 does not remodel the mouse heart.
Show evidence (1 reference)
PMID:16204356 SUPPORT Model Organism
"PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis."
The absence of structural remodeling in the knockout heart.
Ventricular Remodeling and Chamber Dilatation fails to recapitulate fidelity: low The model does not reproduce the structural phenotype the human entity is named for: mice lacking presenilin-2 develop no dilatation, no hypertrophy and no fibrosis, and their hearts contract better than controls. This is the central model-fidelity problem for the locus, recorded structurally rather than left in prose.
Limitations: A germline knockout is not a Ser130Leu knock-in, so this negative does not rule the mechanism out - a heterozygous missense allele could act by gain of function, dominant negativity, or a presenilin-2 function the deletion does not isolate. It does establish that simple loss of presenilin-2 is insufficient to produce dilated cardiomyopathy in the mouse.
Show evidence (1 reference)
PMID:16204356 SUPPORT Model Organism
"PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis."
The measured absence of the remodeling phenotype in the knockout, which is what this negative link records.
Show evidence (2 references)
PMID:16204356 SUPPORT Model Organism
"Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2."
The authors' conclusion, which is the claim that makes this model informative for this entry: presenilin-2 has a genuine role in cardiomyocyte calcium handling.
PMID:16204356 SUPPORT INDIRECT Model Organism
"PS2 is ubiquitously expressed in various tissues including hearts."
The expression premise for studying this animal's heart at all. INDIRECT because expression is not a disease mechanism.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1V
creation_date: "2026-09-05T13:30:00Z"
category: Mendelian
disease_term:
  preferred_term: dilated cardiomyopathy 1V
  term:
    id: MONDO:0013373
    label: dilated cardiomyopathy 1V
synonyms:
- CMD1V
- DCM1V
- cardiomyopathy, dilated, 1V
- cardiomyopathy, dilated, type 1V
- dilated cardiomyopathy type 1V
- PSEN2 familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in PSEN2
description: >-
  A numbered OMIM dilated-cardiomyopathy locus assigned to PSEN2, the second presenilin and,
  like its sibling PSEN1, far better known as an early-onset Alzheimer disease gene. This entry
  is the companion of dismech's Dilated Cardiomyopathy 1U: the two loci were defined by the same
  2006 screen of the same 315 probands, and they are curated on the same evidence base for the
  same reason - the locus exists and is queried, not because the gene-disease relationship is
  settled.

  The single most important thing in the entry is the expert-panel verdict, and it differs from
  1U's. In March 2026 the ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel reported the
  PSEN2 - dilated cardiomyopathy 1V relationship as **Limited** under SOP10. Limited is a
  positive but weak tier: some human genetic evidence is scorable, and it is not enough. That is
  one tier better than PSEN1's **Disputed** at the sibling locus, and the difference is real
  rather than cosmetic - for PSEN1 the panel found no scorable human genetic evidence at all,
  whereas for PSEN2 it counted two missense variants in four probands across two studies. The
  panel nevertheless records that the genetic evidence points decreased over time, that both
  reported variants turn out to be too common in population reference data for a monogenic
  effect, and that no new human genetic evidence has emerged since the previous curation.

  The clinical phenotype also differs, and in the direction that matters for a family. Where the
  PSEN1 family showed complete penetrance and progressive disease ending in transplantation or
  death, the PSEN2 variant Ser130Leu - found in two families in the same screen - showed partial
  penetrance, milder disease and a more favourable prognosis. Any statement about penetrance here
  rests on two small pedigrees and is not a lifetime estimate.

  The mechanism is held loosely, as at the sibling locus, but the cardiac anchor is a different
  molecule. For PSEN1 the proposed route runs through the sarcoplasmic-reticulum calcium pump
  SERCA2a. For PSEN2 the specific cardiac interaction reported is with the ryanodine receptor
  RyR2 and its modulator sorcin, demonstrated by co-immunoprecipitation and colocalisation at the
  Z-lines in mouse heart. Presenilin-2 is expressed in myocardium, and its expression rises with
  hypoxia and glucose deprivation in cardiac cells and in failing canine myocardium - which is
  the expression work ClinGen names as supporting the relationship. What is missing is the step
  that would matter: no cardiomyocyte carrying Ser130Leu has ever been studied, and the one in
  vivo cardiac calcium phenotype - from a Psen2 knockout mouse - runs in the wrong direction,
  showing increased contractility and no dilatation. The causal chain below is therefore held
  inside a single ALTERNATIVE mechanistic hypothesis rather than asserted as the disease
  mechanism.

  Practically: a PSEN2 variant found in a patient with dilated cardiomyopathy is weak evidence
  and should not be reported as a molecular diagnosis on its own. The Limited classification is
  specific to the cardiac phenotype and says nothing about PSEN2's established role in
  early-onset familial Alzheimer disease.

parents:
- Familial Dilated Cardiomyopathy

prevalence:
- population: Dilated cardiomyopathy index patients screened for presenilin variants
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence exists for this locus and none can be estimated. The only
    frequency figures in the literature are yields within screened cohorts: two PSEN2 families
    out of 315 dilated-cardiomyopathy index patients in the founding study, and, on the expert
    panel's count across both reporting studies, two missense variants in four probands in
    total. Those are variant-detection rates in selected cohorts, not disease prevalences, and
    the Limited classification means they should not be read as one.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1
      and PSEN2.
    explanation: >-
      The size and design of the screen that produced the CMD1V families, which is the
      denominator behind the two-family yield.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single
      PSEN2 missense mutation (Ser130Leu) was found in two other families.
    explanation: >-
      The numerator: two PSEN2 families. The PSEN1 family in the same sentence is the separate
      locus CMD1U and is not counted here.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Two missense variants have been reported in 4 probands in two studies (Li et al. PMID:
      17186461, Gianni et al. PMID: 20194882).
    explanation: >-
      The expert panel's own count of the reported cases across the whole literature, which is
      the largest number anyone has assembled for this locus.

progression:
- phase: Nonpenetrant carrier state
  notes: >-
    Unlike the sibling PSEN1 locus, where the founding paper describes complete penetrance,
    the PSEN2 variant is explicitly reported with partial penetrance: carriers in the two
    reported families were not uniformly affected. No penetrance_percentage is recorded on the
    inheritance block, because a penetrance statement drawn from two small pedigrees with age
    censoring is a family observation rather than a population estimate.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable
      prognosis.
    explanation: >-
      The reported penetrance of the CMD1V variant, and the sentence that separates this locus
      clinically from CMD1U.
- phase: Symptomatic dilated cardiomyopathy
  notes: >-
    Where the disease did manifest it was reported as milder than at the PSEN1 locus, with a
    more favourable prognosis - the founding paper contrasts it directly with the progressive
    PSEN1 course that ended in transplantation or death. No case series, follow-up study or
    outcome data exist for this locus beyond that sentence, so nothing more specific about the
    trajectory can be stated.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable
      prognosis.
    explanation: >-
      The only statement of clinical course available for this locus, quoted for the severity
      and prognosis clauses rather than the penetrance one.

pathophysiology:

- name: PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A heterozygous germline PSEN2 missense variant, Ser130Leu, reported in two dilated
    cardiomyopathy families in the founding screen and segregating with disease in them.
    Presenilin-2 is expressed in myocardium as well as brain, so a cardiomyocyte-autonomous
    lesion is anatomically possible.

    What the variant does to presenilin-2 in a cardiomyocyte has never been measured. There is
    no structural or biochemical characterisation of Ser130Leu in cardiac tissue, no Ser130Leu
    cardiomyocyte model, and no directional statement available about gamma-secretase activity
    in the heart of a carrier. The node is therefore typed as the proposed initiating lesion
    and given no modifier and no functional_impact_category: neither loss nor gain of function
    has been shown for this allele in this tissue, and FunctionalImpactEnum has no value that
    would be honest here.

    A second PSEN2 allele has been reported in myocardial disease and is placed at the same
    point in the chain rather than given its own node: the missense variant Arg62His, found in
    two of twenty sporadic idiopathic dilated-cardiomyopathy patients whose presenilin genes
    were sequenced. It is a different allele in different, non-familial patients, and it is
    recorded because the expert panel counts it as one of the two variants behind the Limited
    classification.
  genes:
  - preferred_term: PSEN2
    term:
      id: hgnc:9509
      label: PSEN2
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genetic_context:
    gene:
      preferred_term: PSEN2
      term:
        id: hgnc:9509
        label: PSEN2
    allele_type: MISSENSE
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous germline PSEN2 p.Ser130Leu, reported in two dilated-cardiomyopathy families.
      No functional_impact_category is assigned because the functional consequence of this
      allele has not been determined in cardiac tissue or in a cardiomyocyte model.
  downstream:
  - target: Dysregulated Cardiomyocyte Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - psen2_calcium_handling_dcm
    description: >-
      The proposed first step. Its support is calcium signalling measured in cultured skin
      fibroblasts from carriers, not in cardiomyocytes, so the intermediates between the
      variant and a myocardial calcium defect are unknown.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both mutations segregated with DCM and heart failure.
    explanation: >-
      The segregation observation in the index families that produced the CMD1U and CMD1V
      locus assignments.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The presenilins are also expressed in the heart and are critical to cardiac development.
    explanation: >-
      The anatomical premise that makes a cardiomyocyte-autonomous presenilin lesion possible
      at all. INDIRECT because expression in a tissue does not establish that this variant acts
      there.
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The coding region and promoters of PSEN1 and PSEN2 were sequenced in 20 patients with
      iDCM.
    explanation: >-
      The design of the second study the expert panel counts, in which the PSEN2 Arg62His
      allele was found. INDIRECT for this node because those were sporadic idiopathic cases,
      not CMD1V families, and the allele is not Ser130Leu.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      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
    explanation: >-
      The expert panel's reason for holding this relationship at Limited rather than raising
      it. Recorded on the initiating node because it bears on whether this node exists at all.

- name: Dysregulated Cardiomyocyte Calcium Handling
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proposed effector step: disturbed intracellular calcium regulation in the
    cardiomyocyte. Three observations point at it, and none was made in a cardiomyocyte
    carrying the CMD1V allele.

    First, cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers in the founding
    families showed altered calcium signalling. Fibroblasts are an accessible surrogate, not a
    contractile cell, and the paper reports the abnormality without asserting a myocardial
    equivalent.

    Second, and this is where the PSEN2 story diverges from its PSEN1 sibling, presenilin-2
    physically associates with the cardiac ryanodine receptor RyR2 and with sorcin, its
    modulator - shown by co-immunoprecipitation in mouse heart and by colocalisation at the
    Z-lines. Where the PSEN1 cardiac work implicates the sarcoplasmic-reticulum calcium pump
    SERCA2a, the PSEN2 work implicates the release channel. Both are calcium handling; they are
    not the same lesion.

    Third, the presenilin sequencing study in sporadic disease concluded that presenilin
    missense mutations may alter the interaction of these proteins with the
    excitation-contraction coupling machinery.

    The node carries no direction. The interaction results are physical associations rather
    than rates, the only in vivo cardiac measurement comes from a knockout mouse and points
    towards increased rather than decreased calcium release, and the human sources say
    "altered". The biological process below is therefore tagged DYSREGULATED: choosing
    INCREASED or DECREASED would be an invention.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: RyR2 ryanodine-sensitive calcium-release channel activity
    term:
      id: GO:0005219
      label: ryanodine-sensitive calcium-release channel activity
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  downstream:
  - target: Ventricular Remodeling and Chamber Dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - psen2_calcium_handling_dcm
    description: >-
      Impaired excitation-contraction coupling as a chronic cardiomyocyte insult driving
      adverse remodeling. This edge is the general cardiomyopathy chain rather than a
      CMD1V-specific finding; nothing in the PSEN2 literature measures it.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation
      carriers.
    explanation: >-
      The only functional measurement made in cells from CMD1V carriers. Graded IN_VITRO
      because the measurement was made in cultured cells, and INDIRECT because skin fibroblasts
      are a surrogate tissue: it supports a calcium phenotype in carrier cells, not in
      myocardium.
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other
      in HEK-293 cells overexpressing these proteins or in mouse hearts.
    explanation: >-
      The physical association that makes calcium handling, rather than amyloid, the proposed
      route for this locus - and specifically the release channel rather than the SERCA2a pump
      implicated at the sibling locus. Quoted with the source's own typography.
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin
      at the Z-lines.
    explanation: >-
      Places the interaction at the calcium-release apparatus of the cardiomyocyte rather than
      leaving it as a biochemical result in a lysate.
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Additionally, missense mutations in the PSEN1 and PSEN2 genes alter presenilin expression
      and may alter its interaction with proteins involved in excitation-contraction coupling.
    explanation: >-
      The authors' proposal of exactly this node, from the study of sporadic idiopathic cases.
      INDIRECT because it is a stated possibility about a different allele in different
      patients, not a measurement in a CMD1V carrier.

- name: Ventricular Remodeling and Chamber Dilatation
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Adverse structural remodeling of the left ventricle - chamber dilatation with wall
    thinning - as the shared final common path of the cardiomyopathies. Nothing in the CMD1V
    literature characterises remodeling in a PSEN2 carrier heart specifically: there is no
    histology, no fibrosis quantification and no imaging series. The node is curated because
    the reported clinical phenotype is dilated cardiomyopathy and this is the step that word
    names, and it conforms to the shared module rather than claiming disease-specific detail.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  downstream:
  - target: Systolic Dysfunction and Heart Failure
    causal_link_type: DIRECT
    description: >-
      Chamber dilatation with impaired contraction is by definition the dilated
      cardiomyopathy phenotype and the substrate for pump failure.
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      The clinical phenotype is the imaging expression of this tissue-level state: a dilated
      left ventricle with impaired systolic function is what this node names, observed on
      echocardiography. Definitional rather than a separately evidenced causal step.
  evidence:
  - reference: DOI:10.1093/ehjqcco/qcae109
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    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: >-
      Cited to anchor the node in the recognised disease class rather than to make a mechanistic
      claim: a systematic review of dilated-cardiomyopathy guidelines reports cross-guideline
      consensus on the disease definition and on the imaging that establishes it, which is what
      this node names. INDIRECT because it is about dilated cardiomyopathy generally, not
      remodeling in a PSEN2 carrier - of which nothing has been reported.

- name: Systolic Dysfunction and Heart Failure
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Falling ejection fraction and clinical heart failure. This is the clinical endpoint of the
    entity and the only part of the chain observed directly in CMD1V patients. Note the
    qualifier the sources support is weaker here than at the sibling locus: the reported course
    in the PSEN2 families was milder, with a more favourable prognosis, and no transplantation
    or death is reported for this locus.
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      The symptomatic clinical syndrome of the pump failure this node describes. Definitional
      rather than a separately evidenced causal step.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart
      failure and implicate novel mechanisms of myocardial disease.
    explanation: >-
      The founding study's conclusion, naming heart failure as the reported endpoint. Note it
      says "associated with", which is a weaker claim than the locus name implies.

- name: Stress-Responsive Myocardial Presenilin-2 Expression
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Presenilin-2 is present in myocardium and its level moves with cardiac stress: it is
    detectable in cultured cardiac cells and in adult rat heart, rises with glucose deprivation
    and hypoxia in cardiac cells, and is increased in the failing myocardium of dogs with heart
    failure, where a contractility-modulation therapy that improves ventricular function
    normalises it again.

    This node is kept outside the disease's causal chain deliberately, and no downstream edge is
    drawn from it. It is the expression work the ClinGen panel names as supporting the
    gene-disease relationship, so it belongs in the entry; but every observation in it is
    correlative and none involves a PSEN2 variant. The direction of causality is exactly what is
    unresolved - presenilin-2 rising in a failing heart is at least as consistent with a
    response to failure as with a cause of it, and the canine result, in which the increase
    reverses when ventricular function improves, reads more naturally as the former.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:12468103
    reference_title: "Presenilins in the heart: presenilin-2 expression is increased by low glucose and by hypoxia in cardiac cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Presenilin-2 (PS2) was detected in the cultured heart cells.
    explanation: >-
      Establishes the presence of presenilin-2 in cardiac cells, which is the premise of this
      node. Graded IN_VITRO because the measurement was made in a cultured cardiac cell line.
  - reference: PMID:12468103
    reference_title: "Presenilins in the heart: presenilin-2 expression is increased by low glucose and by hypoxia in cardiac cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      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.
    explanation: >-
      The stress-responsiveness this node names, with the measured magnitudes. This is one of
      the two expression studies the ClinGen panel cites as supporting the relationship.
  - reference: PMID:20443895
    reference_title: "Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Compared with NL, the expression of S100A1, sorcin, and HRC was decreased, whereas the
      expression of PS2 was increased in untreated HF dogs.
    explanation: >-
      Presenilin-2 expression is altered in failing myocardium in vivo - the second expression
      study the panel cites. Graded MODEL_ORGANISM because it is a canine heart-failure model.
  - reference: PMID:20443895
    reference_title: "Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      CCM therapy normalized the expression of S100A1, sorcin, and PS2 but not of HRC.
    explanation: >-
      The reversal that makes the direction of causality unclear: a therapy that improves
      ventricular function returns presenilin-2 towards normal, which is what a marker of
      failure would do. INDIRECT because it bears on how to read the expression change rather
      than on any PSEN2 variant.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This gene-disease relationship is supported by expression studies (Mohuczy et al. PMID:
      12468103, Gupta et al. PMID: 20443895).
    explanation: >-
      The panel's own statement that these two studies are what supports the relationship
      experimentally, which is why this node is curated at all.

mechanistic_hypotheses:
- hypothesis_group_id: psen2_calcium_handling_dcm
  hypothesis_label: Presenilin-2 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
  status: ALTERNATIVE
  description: >-
    The only mechanistic model proposed for CMD1V: a PSEN2 variant perturbs presenilin-2 in the
    cardiomyocyte, which disturbs sarcoplasmic-reticulum calcium handling - plausibly through
    the presenilin-2 association with RyR2 and sorcin - and the resulting
    excitation-contraction defect drives dilatation and pump failure.

    It is recorded as ALTERNATIVE, not CANONICAL, because the disease it explains carries only
    Limited gene-disease validity and because every support falls short of the claim. Carrier
    calcium signalling was measured in skin fibroblasts. The RyR2 and sorcin interaction was
    demonstrated in mouse heart and in a heterologous cell line, not in a carrier. No
    cardiomyocyte carrying Ser130Leu has ever been studied.

    Worse for the model than any of that: the one in vivo cardiac phenotype attributable to
    losing presenilin-2 points the wrong way. Psen2 knockout mice show increased contractility
    and larger calcium transients, with no hypertrophy or fibrosis - not the failing, dilating
    ventricle this entry is named for. That does not refute the hypothesis, since the CMD1V
    allele is a missense variant whose functional consequence is unknown and need not resemble
    deletion, but it does mean the mechanism cannot simply be read off the knockout.

    The model is nevertheless worth keeping, because it is amyloid-independent and stated as
    such in the sources, which distinguishes it from the neuronal presenilin literature and
    makes it falsifiable: an isogenic Ser130Leu human iPSC-cardiomyocyte line with
    calcium-transient and RyR2-flux readouts would settle it in either direction.
  evidence:
  - reference: PMID:37176125
    reference_title: "Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DCM may not be related to impaired APP cleavage by gamma secretase, suggesting that
      PSEN1 (and PSEN2) could impact heart failure through an amyloid-independent mechanism
    explanation: >-
      A review's statement of the amyloid-independent framing this hypothesis adopts, naming
      PSEN2 explicitly, and the reason the neuronal amyloid literature is excluded from the
      entry.
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taken together, our results suggest that PS2 plays an important role in cardiac
      excitation-contraction coupling by interacting with RyR2.
    explanation: >-
      The authors' conclusion, which is the strongest available statement that presenilin-2 has
      a real role in cardiomyocyte calcium handling - the premise this hypothesis needs.
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased
      compared with that in their littermate controls.
    explanation: >-
      The result that cuts against this hypothesis and is quoted so the entry does not overstate
      it: removing presenilin-2 from a mouse heart makes it contract better, not worse, which is
      the opposite of the direction a dilated cardiomyopathy mechanism requires.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This gene-disease relationship is supported by expression studies (Mohuczy et al. PMID:
      12468103, Gupta et al. PMID: 20443895).
    explanation: >-
      The expert panel's account of what does survive: expression work, which is where the
      myocardial presenilin-2 results sit. Quoted to show this hypothesis rests on the evidence
      class ClinGen credits rather than on the genetic evidence it discounts.

phenotypes:

- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    Left ventricular enlargement with impaired systolic function, unexplained by ischaemic,
    valvular, hypertensive or congenital causes. This is the defining and effectively the only
    phenotype of the entity: the entire reported clinical description of CMD1V is two families'
    cardiomyopathy, reported as milder than at the sibling PSEN1 locus.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  diagnostic: true
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single
      PSEN2 missense mutation (Ser130Leu) was found in two other families.
    explanation: >-
      Identifies the families in which the dilated-cardiomyopathy phenotype defining this locus
      was observed.
  notes: >-
    No frequency band is assigned, and no clinical_course qualifier either. The denominator is
    two pedigrees in a single paper, so a FrequencyEnum value would present a family observation
    as a disease-level frequency; and unlike the sibling locus, where the course is described as
    progressive, the only course statement available for CMD1V is that the disease was milder
    with a more favourable prognosis, which does not support PROGRESSIVE.

- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Symptomatic pump failure following the dilatation. Reported for this locus as milder than at
    the PSEN1 locus and with a more favourable prognosis; no transplantation or death is
    described in the CMD1V families.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart
      failure and implicate novel mechanisms of myocardial disease.
    explanation: >-
      The founding study's own conclusion sentence, naming heart failure alongside dilated
      cardiomyopathy as the reported phenotype for both presenilin loci.
  notes: >-
    No frequency band assigned, for the same reason as the dilated-cardiomyopathy phenotype:
    the only denominator available is two pedigrees.

genetic:

- name: PSEN2
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PSEN2
    term:
      id: hgnc:9509
      label: PSEN2
  association: >-
    PSEN2 encodes presenilin-2, a catalytic subunit of the gamma-secretase intramembrane
    protease and a paralogue of PSEN1. Its relationship with dilated cardiomyopathy was proposed
    in 2006 on the strength of two families carrying Ser130Leu, found in a screen of 315
    dilated-cardiomyopathy index patients, together with altered calcium signalling in carrier
    skin fibroblasts. A second missense allele, Arg62His, was later reported in two of twenty
    sporadic idiopathic cases.

    ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel first evaluated PSEN2 for
    dilated cardiomyopathy in December 2019, re-evaluated it under SOP10 in October 2024, and
    the classification did not change: **Limited**, re-reported March 2026. The panel counts two
    missense variants in four probands across two studies as the whole human genetic evidence
    base, records that the genetic evidence points decreased over time, and notes that both
    reported variants have since been found too frequently in population reference data for a
    monogenic pathogenic effect.

    The relationship is typed UNKNOWN rather than CAUSATIVE or DISPUTED, and the choice is
    deliberate in both directions. CAUSATIVE would assert what the panel declines to assert -
    Limited explicitly means the evidence does not establish the relationship. DISPUTED would
    import the sibling locus's verdict: the enum's own description binds DISPUTED to ClinGen
    "Disputed" or "Refuted", and PSEN2 is neither. Limited sits between the two, and UNKNOWN -
    "the relationship between the gene and the disease is unclear or not yet classified" - is
    the closest honest value the enum offers. The precise classification is recorded in the
    external_assertions block and in the evidence below, which is where a reader should look
    rather than relying on this coarse slot.

    The verdict is specific to the cardiac phenotype. PSEN2's relationship with early-onset
    familial Alzheimer disease is not in question and is a separate matter from this entry.
  variants:
  - name: PSEN2 p.Ser130Leu
    description: >-
      The founding CMD1V allele. A heterozygous missense substitution replacing serine with
      leucine, reported in two dilated-cardiomyopathy families with partial penetrance and
      milder disease than the PSEN1 allele found in the same screen. The original paper
      describes it at the nucleotide level in a historical transcript convention; that
      description is not restated here because it cannot be converted to modern HGVS without
      transcript confirmation.
  - name: PSEN2 p.Arg62His
    description: >-
      The second PSEN2 missense allele the expert panel counts, reported in two of twenty
      sporadic idiopathic dilated-cardiomyopathy patients rather than in a CMD1V family. It is
      recorded here because it forms part of the evidence base behind the Limited
      classification, not because it is a CMD1V allele. In the same report it did not segregate
      with disease status in the Alzheimer families in which it was also examined.
  evidence:
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 |
      Dilated Cardiomyopathy Gene Curation Expert Panel
    explanation: >-
      The current expert-panel classification row, curated against this exact MONDO term. This
      is the single most important item in the entry for anyone interpreting a PSEN2 variant in
      a cardiomyopathy patient.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      There is limited evidence to support this gene-disease relationship.
    explanation: >-
      The panel's conclusion about the strength of the relationship, and the reason
      relationship_type is not CAUSATIVE.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN2 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2006
      (Li et al. PMID: 17186461).
    explanation: >-
      Confirms the panel curated the same founding paper this entry is built on, so the Limited
      verdict and the entry's evidence base are about the same claim.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1
      and PSEN2.
    explanation: >-
      The screen that produced the original gene-disease claim, and the larger part of its human
      genetic evidence base.
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Thus, the E318G and R62H missense substitutions may play an important role in the
      pathogenesis of a subset of patients with iDCM by modulating different functions of the
      presenilin proteins.
    explanation: >-
      The second study's proposal for the PSEN2 Arg62His allele it reported. INDIRECT because it
      is a stated possibility about sporadic idiopathic cases rather than a demonstration, and
      the allele is not the CMD1V one.
  notes: >-
    The Arg62His allele is curated as a variant under this gene record rather than as its own
    genetic record, because it is the panel's second counted variant but was not found in a
    CMD1V family. Note the same report states it did not segregate with Alzheimer affection
    status in the Alzheimer families examined, which is a point about that allele's pathogenicity
    generally rather than about dilated cardiomyopathy.

external_assertions:
- name: ClinGen PSEN2-dilated cardiomyopathy 1V gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
  description: >-
    The ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal
    dominant PSEN2 - dilated cardiomyopathy 1V relationship as Limited. The curation is against
    MONDO:0013373 itself, so it is about this entity rather than about dilated cardiomyopathy in
    general. First evaluated December 2019, re-evaluated under SOP v10 in October 2024 with no
    change, approved by the working group in May 2025, report dated 2026-03-04. Its evidence
    summary is specific about the shape of the evidence: two missense variants in four probands
    across two studies, both variants too common in population reference data, no new human
    genetic evidence since the previous curation, and experimental support resting on two
    expression studies.

    This is one tier above the Disputed classification the same panel gives PSEN1 for dilated
    cardiomyopathy 1U on the same report date - a difference worth preserving, since for PSEN1
    the panel found no scorable human genetic evidence at all.
  evidence:
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      The overall genetic evidence points decreased over time.
    explanation: >-
      The direction of travel of the evidence between curations, which is the panel's own
      summary of why the classification did not improve.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      In summary, there is a lack of new supporting evidence in the period since the previous
      curation.
    explanation: >-
      Records that the relationship has not strengthened in the twenty years since it was
      proposed, which is the substance of the Limited verdict.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More evidence is needed to support the relationship of PSEN2 with AD DCM.
    explanation: >-
      Quoted so the Limited classification is not read as a rejection. The panel asks for more
      evidence rather than ruling the relationship out, which is why this entry curates the
      locus.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While Li et al. demonstrated limited segregation and functional evidence for the missense
      variant identified in their study
    explanation: >-
      The panel's characterisation of what the founding study actually established for this
      allele - limited segregation and functional evidence - which is the positive evidence that
      distinguishes Limited from the sibling locus's Disputed.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous transmission in the two reported families, and the mode of inheritance ClinGen
    curated the relationship under. The founding paper describes partial penetrance for the
    PSEN2 variant, in contrast to complete penetrance for the PSEN1 variant at the sibling
    locus. No penetrance_percentage is recorded: a penetrance statement drawn from two small
    pedigrees, with younger carriers still unaffected, is not a population estimate, and
    recording a number would give it a precision the source does not have.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable
      prognosis.
    explanation: >-
      The reported penetrance of the CMD1V allele, quoted for the penetrance clause. Partial
      penetrance is the feature that distinguishes this locus's inheritance from the sibling
      locus's.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 |
      Dilated Cardiomyopathy Gene Curation Expert Panel
    explanation: >-
      Records the mode of inheritance the expert panel curated the relationship under,
      alongside the classification.

diagnosis:
- name: Echocardiographic Diagnosis of Dilated Cardiomyopathy
  description: >-
    The phenotype is established on imaging - a dilated left ventricle with impaired systolic
    function and no ischaemic, valvular or load-related explanation - before any genetic
    question arises. Nothing about CMD1V changes this step, and there is no PSEN2-specific
    diagnostic feature: no cardiac imaging, biopsy or biomarker finding distinguishes a PSEN2
    carrier from any other dilated cardiomyopathy.
  evidence:
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews overview's statement that it defines proband evaluation for this disease
      class.

- name: Natriuretic Peptide, Troponin and Multimodality Cardiac Imaging
  description: >-
    The laboratory and imaging workup that establishes the phenotype. A 2025 systematic review
    of dilated-cardiomyopathy guidelines found cross-guideline consensus on B-type natriuretic
    peptides and high-sensitivity troponin in laboratory testing and on multimodality
    cardiovascular imaging for initial diagnosis. None of this is PSEN2-specific, which is
    itself worth recording: it means the diagnosis of this entity rests entirely on sequencing
    plus pedigree.
  evidence:
  - reference: DOI:10.1093/ehjqcco/qcae109
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    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: >-
      The elements of the diagnostic workup that guidelines agree on. INDIRECT because the
      review is about dilated cardiomyopathy generally; nothing in it is specific to this locus.

- name: Multigene Cardiomyopathy Panel Testing
  description: >-
    Genetic testing is by panel or exome. For PSEN2 the point is interpretation rather than
    efficiency: with the gene-disease relationship classified Limited, a PSEN2 variant found in
    a dilated-cardiomyopathy proband is weak evidence and should not carry the weight of a
    molecular diagnosis on its own. The panel's specific observation - that both reported
    variants are too common in population reference data for a monogenic effect - applies
    directly to interpreting a new one.

    Limited is nevertheless a positive tier rather than a contested one, so this is a weaker
    caution than the sibling PSEN1 locus warrants. A PSEN2 finding in a proband with a
    compatible family history is worth pursuing; it is not on its own an answer.
  evidence:
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN2 | HGNC:9509 | dilated cardiomyopathy 1V | MONDO:0013373 | AD | Limited | SOP10 |
      Dilated Cardiomyopathy Gene Curation Expert Panel
    explanation: >-
      The classification that governs how much weight a PSEN2 result should carry in this
      setting.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      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
    explanation: >-
      The population-frequency observation that should inform interpretation of any new PSEN2
      variant found in this setting.

treatments:

- name: Guideline-Directed Heart Failure Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Management of CMD1V is management of dilated cardiomyopathy: there is no PSEN2-directed
    therapy, no trial in this population, and no reason to expect genotype-specific treatment
    while the genotype-phenotype relationship carries only Limited validity. Treatment follows
    the contemporary heart-failure pathway, which acts on the remodeling and pump-failure end of
    the chain rather than on any presenilin lesion.

    The agents listed below are the standard classes of guideline-directed medical therapy for
    heart failure with reduced ejection fraction, recorded so the treatment is queryable by drug
    identity. They are not a CMD1V-specific regimen and no source names them for this locus.
    Beta-blockers belong in the same list but are not recorded as a therapeutic_agent, because
    the NCI Thesaurus build configured here has no drug-class term for them that could be
    verified.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin receptor-neprilysin inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Systolic Dysfunction and Heart Failure
    description: >-
      Acts on the clinical endpoint, not on the proposed molecular mechanism. Nothing in the
      standard regimen targets presenilin-2 or the calcium node above it.
  evidence:
  - reference: PMID:35379503
    reference_title: "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      The recommendations present an evidence-based approach to managing patients with heart
      failure, with the intent to improve quality of care and align with patients' interests.
    explanation: >-
      The guideline this treatment defers to. INDIRECT because it is written for heart failure
      as a whole and says nothing about PSEN2 - which is the point: no PSEN2-specific regimen
      exists, so the general pathway is the treatment.

- name: Cardiac Surveillance of At-Risk Relatives
  therapeutic_modality: OTHER
  description: >-
    Serial cardiac assessment of first-degree relatives of an affected proband. For a
    partially penetrant, late-onset cardiomyopathy this is the intervention with the clearest
    rationale, because it detects dilatation before symptoms - and partial penetrance is exactly
    the setting in which a clinical rather than genotypic trigger matters, since an unaffected
    carrier may remain unaffected.

    Whether surveillance should be triggered by a PSEN2 variant specifically is a weaker
    question than at the sibling PSEN1 locus but still not settled: Limited validity does not
    support genotype-directed surveillance on a PSEN2 result alone. Clinical surveillance of
    relatives of an affected proband stands on the family history regardless of genotype.
  treatment_term:
    preferred_term: serial cardiac surveillance
    term:
      id: NCIT:C168126
      label: Cardiac Disease Screening
  target_mechanisms:
  - target: Ventricular Remodeling and Chamber Dilatation
    description: >-
      Detects remodeling early rather than modifying it; the benefit comes from starting
      heart-failure therapy before decompensation.
  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: >-
      The rationale for surveillance of at-risk relatives, stated by GeneReviews as one of the
      purposes of its dilated-cardiomyopathy overview: early detection before symptoms so
      treatment can start sooner.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable
      prognosis.
    explanation: >-
      The partial penetrance that makes clinical rather than genotype-driven surveillance the
      sensible framing here. INDIRECT because the sentence describes the reported families, not
      a surveillance study.

animal_models:
- name: Presenilin-2 knockout mouse (cardiac phenotype)
  species: Mouse
  genotype: Psen2 germline knockout (PS2KO)
  publication: PMID:16204356
  genes:
  - preferred_term: PSEN2
    term:
      id: hgnc:9509
      label: PSEN2
  description: >-
    Mice lacking presenilin-2, characterised specifically for cardiac phenotype rather than for
    Alzheimer biology. The animals develop normally with no hypertrophy or fibrosis, but
    invasive haemodynamics show increased contractility, and isolated papillary muscle shows
    larger calcium transients and higher peak tension. The study goes on to show that
    presenilin-2 interacts with sorcin and the cardiac ryanodine receptor RyR2 and colocalises
    with them at the Z-lines.

    This is the only in vivo work directed at the presenilin-2 cardiac question, and it is
    curated here as the molecular anchor for the calcium node while being explicit that its
    phenotype runs opposite to dilated cardiomyopathy.
  modeled_mechanisms:
  - target: Dysregulated Cardiomyocyte Calcium Handling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Establishes that presenilin-2 is a real participant in cardiomyocyte calcium handling in
      the intact heart, through a defined interaction with RyR2 and sorcin - the mechanistic
      premise this entry's hypothesis rests on.
    limitations: >-
      The allele is a germline deletion, while CMD1V is a heterozygous missense variant whose
      functional consequence has never been determined; a knockout therefore cannot be assumed
      to model it. More importantly the direction is wrong: knockout hearts contract better,
      with larger calcium transients and no hypertrophy, fibrosis or dilatation, which is the
      opposite of the phenotype this entity is named for. The model was not built on, or tested
      against, the Ser130Leu allele, and no claim about the human disease mechanism rests on it.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's quantity is calcium transient amplitude and contractility in a
        presenilin-2-null heart. The node's quantity is disturbed calcium handling caused by a
        missense allele, which need not act by loss of function.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Murine cardiomyocyte calcium handling and heart rate differ substantially from human,
        and no human carrier cardiomyocyte has been studied for comparison.
    readouts:
    - name: Peak amplitude of calcium transients in isolated papillary muscle
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: INCREASED
      interpretation: >-
        The calcium measurement that ties presenilin-2 to cardiomyocyte calcium handling in
        vivo - and the one whose direction is opposite to what a dilated cardiomyopathy
        mechanism would predict.
      evidence:
      - reference: PMID:16204356
        reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients
          and peak tension were significantly higher in PS2KO mice than those in their
          littermate controls.
        explanation: >-
          The calcium and tension measurements behind this readout, with their direction.
    - name: Cardiac hypertrophy and fibrosis
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: UNCHANGED
      interpretation: >-
        A negative structural result, recorded because it is what makes this model a poor
        analogue of the human entity: losing presenilin-2 does not remodel the mouse heart.
      evidence:
      - reference: PMID:16204356
        reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis.
        explanation: >-
          The absence of structural remodeling in the knockout heart.
  - target: Ventricular Remodeling and Chamber Dilatation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model does not reproduce the structural phenotype the human entity is named for:
      mice lacking presenilin-2 develop no dilatation, no hypertrophy and no fibrosis, and
      their hearts contract better than controls. This is the central model-fidelity problem
      for the locus, recorded structurally rather than left in prose.
    limitations: >-
      A germline knockout is not a Ser130Leu knock-in, so this negative does not rule the
      mechanism out - a heterozygous missense allele could act by gain of function, dominant
      negativity, or a presenilin-2 function the deletion does not isolate. It does establish
      that simple loss of presenilin-2 is insufficient to produce dilated cardiomyopathy in the
      mouse.
    evidence:
    - reference: PMID:16204356
      reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis.
      explanation: >-
        The measured absence of the remodeling phenotype in the knockout, which is what this
        negative link records.
  evidence:
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taken together, our results suggest that PS2 plays an important role in cardiac
      excitation-contraction coupling by interacting with RyR2.
    explanation: >-
      The authors' conclusion, which is the claim that makes this model informative for this
      entry: presenilin-2 has a genuine role in cardiomyocyte calcium handling.
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      PS2 is ubiquitously expressed in various tissues including hearts.
    explanation: >-
      The expression premise for studying this animal's heart at all. INDIRECT because
      expression is not a disease mechanism.

discussions:

- discussion_id: psen2_dcm_gene_validity
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is PSEN2 a dilated cardiomyopathy gene, or is CMD1V an OMIM locus resting on two families
    and a variant that turns out to be too common?
  attaches_to:
  - genetic#PSEN2
  - disease#Dilated Cardiomyopathy 1V
  rationale: >-
    Twenty years after the founding report the human evidence is two families from the original
    screen plus two sporadic patients carrying a different allele, and the expert panel counts
    four probands in total. ClinGen has looked at it three times - 2019, 2024, 2026 - and each
    time called it Limited, on the ground that both reported disease-causing variants are too
    common in population reference data for a monogenic effect, and that nothing new has
    appeared.

    The counter-argument is stronger here than at the sibling PSEN1 locus, and that asymmetry is
    the interesting part. The panel credits the founding study with limited segregation and
    functional evidence for this allele - where for PSEN1 it found no scorable human genetic
    evidence at all - and there is a defined cardiac interaction partner for presenilin-2 in
    RyR2 and sorcin. Limited is a positive tier: it means some evidence exists and more is
    needed, not that the relationship is contested.

    This is recorded as an open controversy rather than resolved in either direction because
    the deciding work - a modern population-frequency and case-control reassessment of PSEN2 in
    a large dilated-cardiomyopathy cohort, or a cardiomyocyte model of Ser130Leu - has not been
    done. It matters practically: it determines whether PSEN2 belongs on a
    dilated-cardiomyopathy panel.
  evidence:
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      No new human genetic evidence has emerged since the last curation.
    explanation: >-
      The specific deficiency the classification rests on: the evidence base has not grown
      between curations.
  - reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
    reference_title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While Li et al. demonstrated limited segregation and functional evidence for the missense
      variant identified in their study
    explanation: >-
      The counter-argument in the panel's own words: unlike the sibling locus, this one has
      some scorable positive evidence, which is what puts it a tier higher.
  proposed_experiments:
  - experiment_id: psen2_dcm_case_control_burden
    name: Modern population-frequency and case-control reassessment of PSEN2 in dilated cardiomyopathy
    description: >-
      Genotype PSEN2 across a large sequenced dilated-cardiomyopathy cohort and compare variant
      burden against a matched population reference, testing directly the observation the
      Limited classification rests on.
    would_support:
    - pathophysiology#PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
    supporting_outcome:
    - >-
        Excess of rare, conserved PSEN2 missense variants in cases over ancestry-matched
        population controls, with Ser130Leu rare enough to be compatible with a monogenic
        effect.
    would_refute:
    - pathophysiology#PSEN2 Ser130Leu Missense Variant in Cardiomyocytes
    refuting_outcome:
    - >-
        No case-control burden difference, and reported disease-causing alleles present in
        population reference data at frequencies incompatible with a rare dominant
        cardiomyopathy.

- discussion_id: psen2_knockout_direction_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    The only in vivo cardiac phenotype for presenilin-2 loss is increased contractility with no
    dilatation. Does the proposed calcium mechanism actually point towards dilated
    cardiomyopathy?
  attaches_to:
  - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
  - mechanistic_hypotheses#psen2_calcium_handling_dcm
  rationale: >-
    Every piece of evidence for the calcium mechanism at this locus comes from the wrong cell,
    the wrong genotype, or the wrong direction. Carrier calcium signalling was measured in
    cultured skin fibroblasts, which are not contractile. The RyR2 and sorcin interaction was
    demonstrated in mouse heart and in a heterologous overexpression system, not in a carrier.
    And the one functional cardiac phenotype - from Psen2 knockout mice - shows increased
    contractility, larger calcium transients and no hypertrophy, fibrosis or dilatation.

    That last point is the substance of this mismatch and is worth stating precisely. It is not
    a refutation: CMD1V is a heterozygous missense allele, and a missense variant need not
    behave like a deletion - it could be a gain of function, a dominant negative, or act on a
    presenilin-2 function the knockout does not isolate. But it does mean the mechanism cannot
    be read off the knockout, and any account that treats "presenilin-2 dysfunction impairs
    cardiomyocyte calcium handling and the heart dilates" as established is asserting a
    direction that the only in vivo experiment contradicts.

    This is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap because the evidence is not
    absent - the model exists, is well characterised and is internally sound. What is missing is
    any demonstration that it composes into the human disease mechanism in the relevant genotype
    and direction.
  evidence:
  - reference: PMID:16204356
    reference_title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased
      compared with that in their littermate controls.
    explanation: >-
      The directional mismatch this discussion is about, in the source's own words.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation
      carriers.
    explanation: >-
      Names the tissue in which the carrier calcium phenotype was actually observed, which is
      the other half of the mismatch: a surrogate cell rather than a cardiomyocyte.
  proposed_experiments:
  - experiment_id: psen2_s130l_ipsc_cardiomyocyte_calcium
    name: Isogenic PSEN2 Ser130Leu human iPSC-cardiomyocyte calcium phenotyping
    description: >-
      Introduce Ser130Leu into a human iPSC line by genome editing, differentiate to
      cardiomyocytes alongside the isogenic wild-type parent, and measure calcium transients,
      sarcoplasmic-reticulum calcium load, RyR2-mediated leak and contractility.
    would_support:
    - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
    supporting_outcome:
    - >-
        Altered calcium transient kinetics and impaired contractility in the Ser130Leu
        cardiomyocytes relative to the isogenic control, in the direction of reduced rather than
        enhanced systolic performance.
    would_refute:
    - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
    refuting_outcome:
    - >-
        Calcium transients, sarcoplasmic-reticulum load and contractility indistinguishable from
        the isogenic wild-type control.

differential_diagnoses:
- name: Dilated Cardiomyopathy 1U
  description: >-
    The PSEN1 locus, and the sibling of this one in the most literal sense: both were defined by
    the same 2006 screen of the same 315 probands. PSEN1 Asp333Gly was found in one family with
    complete penetrance, aggressive disease and an outcome of transplantation or death. ClinGen's
    Dilated Cardiomyopathy Gene Curation Expert Panel classifies PSEN1 for dilated cardiomyopathy
    1U as Disputed - one tier below this entry's Limited, on the same review date - because it
    found no scorable human genetic evidence at all. dismech curates CMD1U as a separate entry.
  distinguishing_features:
  - >-
    Different gene (PSEN1, hgnc:9508) and a more severe reported phenotype with complete
    penetrance and a progressive course. The two cannot be told apart clinically; only
    sequencing separates them.
  evidence:
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PSEN1 mutation was associated with complete penetrance and progressive disease that
      resulted in the necessity of cardiac transplantation or in death.
    explanation: >-
      The clinical contrast between the two presenilin loci as reported in the paper that
      defined both, quoted from the PSEN1 side.

- name: Idiopathic Dilated Cardiomyopathy
  description: >-
    Dilated cardiomyopathy with no identified cause, which is what a CMD1V patient has if the
    PSEN2 attribution is not accepted. This is not an academic alternative: with the relationship
    at Limited and both reported variants too common in population data, it is the diagnosis
    implied for many PSEN2 carriers with the phenotype. Note also that the second PSEN2 allele
    the expert panel counts was itself found in idiopathic rather than familial cases, so the
    boundary between the two categories is where part of this locus's evidence base sits.
  distinguishing_features:
  - >-
    Absence of a family history or of a segregating variant. Given how weak the genetic evidence
    is, the practical boundary between this and CMD1V is the pedigree at least as much as the
    genotype.
  evidence:
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The coding region and promoters of PSEN1 and PSEN2 were sequenced in 20 patients with
      iDCM.
    explanation: >-
      Establishes that part of the presenilin cardiac evidence base was assembled in idiopathic,
      not familial, cases - and in a cohort of twenty.

notes: >-
  **Companion to Dilated Cardiomyopathy 1U.** This entry was written as the deliberate sibling
  of dismech's CMD1U (PSEN1, MONDO:0013371), which noted that this stub was open and shared its
  entire primary evidence base - same paper, same screen - differing in ClinGen verdict and in
  penetrance. Both of those differences are curated here rather than assumed: Limited against
  Disputed, and partial penetrance with milder disease against complete penetrance and a course
  ending in transplantation or death. The 1U file was not modified by this PR.

  Two places where copying the sibling entry would have been wrong, and was avoided. First,
  cardiac transplantation is curated as a treatment in 1U because the founding paper reports it
  as the outcome in that family; it is **not** curated here, because the same paper reports a
  more favourable prognosis for the PSEN2 families and no transplantation or death. Second, the
  dilated-cardiomyopathy phenotype in 1U carries clinical_course: PROGRESSIVE; here it does not,
  for the same reason. An implantable defibrillator is likewise not curated: 1U includes it to
  record that guidelines disagree about prophylactic criteria, and repeating that general point
  at a milder locus with no reported arrhythmic phenotype would add nothing this entry can
  source.

  **Separating the cardiac from the amyloid literature.** PSEN2 is far better known as a
  familial Alzheimer disease gene, and almost none of that work is about this disease. The
  Limited verdict applies to the cardiac phenotype only. Every citation in this file was checked
  to be about heart tissue, heart cells, or a cardiomyopathy cohort. The one review cited
  (PMID:37176125) is titled for PSEN1 but is quoted only where it speaks to PSEN2, and the
  quoted sentence names PSEN2 explicitly.

  **Where this entry's mechanism differs from the sibling's.** 1U's calcium route runs through
  SERCA2a, on the strength of a presenilin-1/SERCA2a co-immunoprecipitation in explanted
  myocardium. The PSEN2 cardiac interaction reported in the literature is with RyR2 and sorcin
  instead, so the molecular_functions binding here is the ryanodine-sensitive calcium-release
  channel rather than the P-type calcium transporter. Both are calcium handling and neither has
  been demonstrated for the disease allele, but they are different claims and are curated as
  such.

  **The expression node is deliberately outside the causal chain.** ClinGen names two expression
  studies as the experimental support for this relationship, so they are curated - but a
  presenilin-2 level that rises in failing myocardium and falls again when function improves is
  at least as consistent with a marker of failure as with a cause of it. The node carries no
  downstream edge for that reason.

  **Independent check on the ClinGen frequency argument.** The panel states that both reported
  variants are too frequent in population reference data. Looked up directly in gnomAD v4
  through the public API on 2026-09-05, PSEN2 p.Ser130Leu (rs63750197, 1-226885570-C-T) is
  present at an exome allele frequency of 1.3e-03 (1,830 of 1,461,780 alleles) and a genome
  allele frequency of 7.1e-04 - roughly one carrier in every four hundred people, which is far
  too common for a monogenic dominant cause of a rare cardiomyopathy and is considerably more
  common than the PSEN1 Asp333Gly allele at the sibling locus. This lookup is recorded here as
  a check on the reasoning rather than cited as evidence, because a database query is not a
  quotable publication; the evidence items in this entry rest on the ClinGen record.

  **What was deliberately not curated.** No biochemical, histopathology, imaging, dataset,
  clinical-trial or environmental section: nothing PSEN2-specific exists for any of them. No
  phenotype beyond dilated cardiomyopathy and heart failure - the founding abstract, which is
  all the cache holds, mentions no other cardiac finding for these families. No experimental
  models section: no human cardiomyocyte or organoid system carrying a PSEN2 cardiomyopathy
  allele has been reported, which is precisely the gap recorded in the HUMAN_MODEL_MISMATCH
  discussion.

  The general dilated-cardiomyopathy and heart-failure sources that are cited - the guideline
  systematic review, the 2022 heart failure guideline and the GeneReviews overview - are used
  only where the claim really is about the disease class, and are marked INDIRECT where they
  support a locus-adjacent claim. No general-class source is used to make a claim about PSEN2.

  **Deep research provenance.** The Edison/falcon provider returned HTTP 402 (account out of
  credits), so the run was repeated through the repository's recorded fallback mechanism, which
  produced the report under the claude_code provider and stamped the fallback in its frontmatter.
  No provider was substituted by hand.

references:
- reference: PMID:17186461
  title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
- reference: PMID:20194882
  title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
- reference: PMID:16204356
  title: "Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling."
- reference: PMID:12468103
  title: "Presenilins in the heart: presenilin-2 expression is increased by low glucose and by hypoxia in cardiac cells."
- reference: PMID:20443895
  title: "Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals."
- reference: PMID:37176125
  title: "Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease."
- reference: PMID:35379503
  title: "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
- reference: DOI:10.1093/ehjqcco/qcae109
  title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z
  title: "PSEN2 / dilated cardiomyopathy 1V (Limited)"
📚

References & Deep Research

References

10
PMID:17186461
Mutations of presenilin genes in dilated cardiomyopathy and heart failure.
No top-level findings curated for this source.
PMID:20194882
Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:16204356
Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.
No top-level findings curated for this source.
PMID:12468103
Presenilins in the heart: presenilin-2 expression is increased by low glucose and by hypoxia in cardiac cells.
No top-level findings curated for this source.
PMID:20443895
Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals.
No top-level findings curated for this source.
PMID:37176125
Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease.
No top-level findings curated for this source.
PMID:35379503
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
No top-level findings curated for this source.
DOI:10.1093/ehjqcco/qcae109
Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations
No top-level findings curated for this source.
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

**Companion to Dilated Cardiomyopathy 1U.** This entry was written as the deliberate sibling of dismech's CMD1U (PSEN1, MONDO:0013371), which noted that this stub was open and shared its entire primary evidence base - same paper, same screen - differing in ClinGen verdict and in penetrance. Both of those differences are curated here rather than assumed: Limited against Disputed, and partial penetrance with milder disease against complete penetrance and a course ending in transplantation or death. The 1U file was not modified by this PR. Two places where copying the sibling entry would have been wrong, and was avoided. First, cardiac transplantation is curated as a treatment in 1U because the founding paper reports it as the outcome in that family; it is **not** curated here, because the same paper reports a more favourable prognosis for the PSEN2 families and no transplantation or death. Second, the dilated-cardiomyopathy phenotype in 1U carries clinical_course: PROGRESSIVE; here it does not, for the same reason. An implantable defibrillator is likewise not curated: 1U includes it to record that guidelines disagree about prophylactic criteria, and repeating that general point at a milder locus with no reported arrhythmic phenotype would add nothing this entry can source. **Separating the cardiac from the amyloid literature.** PSEN2 is far better known as a familial Alzheimer disease gene, and almost none of that work is about this disease. The Limited verdict applies to the cardiac phenotype only. Every citation in this file was checked to be about heart tissue, heart cells, or a cardiomyopathy cohort. The one review cited (PMID:37176125) is titled for PSEN1 but is quoted only where it speaks to PSEN2, and the quoted sentence names PSEN2 explicitly. **Where this entry's mechanism differs from the sibling's.** 1U's calcium route runs through SERCA2a, on the strength of a presenilin-1/SERCA2a co-immunoprecipitation in explanted myocardium. The PSEN2 cardiac interaction reported in the literature is with RyR2 and sorcin instead, so the molecular_functions binding here is the ryanodine-sensitive calcium-release channel rather than the P-type calcium transporter. Both are calcium handling and neither has been demonstrated for the disease allele, but they are different claims and are curated as such. **The expression node is deliberately outside the causal chain.** ClinGen names two expression studies as the experimental support for this relationship, so they are curated - but a presenilin-2 level that rises in failing myocardium and falls again when function improves is at least as consistent with a marker of failure as with a cause of it. The node carries no downstream edge for that reason. **Independent check on the ClinGen frequency argument.** The panel states that both reported variants are too frequent in population reference data. Looked up directly in gnomAD v4 through the public API on 2026-09-05, PSEN2 p.Ser130Leu (rs63750197, 1-226885570-C-T) is present at an exome allele frequency of 1.3e-03 (1,830 of 1,461,780 alleles) and a genome allele frequency of 7.1e-04 - roughly one carrier in every four hundred people, which is far too common for a monogenic dominant cause of a rare cardiomyopathy and is considerably more common than the PSEN1 Asp333Gly allele at the sibling locus. This lookup is recorded here as a check on the reasoning rather than cited as evidence, because a database query is not a quotable publication; the evidence items in this entry rest on the ClinGen record. **What was deliberately not curated.** No biochemical, histopathology, imaging, dataset, clinical-trial or environmental section: nothing PSEN2-specific exists for any of them. No phenotype beyond dilated cardiomyopathy and heart failure - the founding abstract, which is all the cache holds, mentions no other cardiac finding for these families. No experimental models section: no human cardiomyocyte or organoid system carrying a PSEN2 cardiomyopathy allele has been reported, which is precisely the gap recorded in the HUMAN_MODEL_MISMATCH discussion. The general dilated-cardiomyopathy and heart-failure sources that are cited - the guideline systematic review, the 2022 heart failure guideline and the GeneReviews overview - are used only where the claim really is about the disease class, and are marked INDIRECT where they support a locus-adjacent claim. No general-class source is used to make a claim about PSEN2. **Deep research provenance.** The Edison/falcon provider returned HTTP 402 (account out of credits), so the run was repeated through the repository's recorded fallback mechanism, which produced the report under the claude_code provider and stamped the fallback in its frontmatter. No provider was substituted by hand.

Create: dilated cardiomyopathy 1V · 2026-09-06T00:35:46Z · View source

Created the PSEN2 companion entry to Dilated_Cardiomyopathy_1U (issue 11069), mirroring its contested-locus treatment: ClinGen DCM GCEP classification Limited (CGGV:assertion_9e20579f-efc7-4ccd-8653-85c0aafe788f-2026-03-04T170000.000Z, verified from the ClinGen structured source and cached via just clingen-rebuild --id after the pinned CSV drifted upstream; manifest not repinned, single record built from the fresh download), partial penetrance and milder course per Li 2006 (PMID:17186461), RyR2/sorcin calcium anchor per Takeda 2005 (PMID:16204356) including a FAILS_TO_RECAPITULATE link for the PS2-knockout mouse, the two ClinGen-credited expression studies (PMID:12468103, PMID:20443895), and the Arg62His allele from Gianni 2010 (PMID:20194882). Mechanism held in a single ALTERNATIVE hypothesis; expression node kept outside the causal chain. Deep research: falcon returned HTTP 402 (out of credits); the repo fallback mechanism produced the report via claude_code with fell_back provenance stamped. preflight-dr: WARN only (rival PSEN1 at 32 percent, expected sibling-locus contrast); gene-drift check PSEN2=37 vs PSEN1=12. Validation: just validate PASS, count-verified-snippets 55/55 incl. --unskip-prefix DOI, validate-terms PASS, check-folded-hyphens/snippet-length/title-snippets/snippet-grading/duplicate-keys/entity-refs/causal-targets/qualifier-terms/enum-values all PASS, validate-disorders PASS. Branch fast-forwarded to origin/main mid-curation to clear a stale-baseline title-snippet finding in an untouched file. gnomAD v4 S130L frequency recorded in notes as a reasoning check, not evidence.

Claude Code ▸
1. Disease Information
claude-fable-5[1m], claude-haiku-4-5-20251001 11 citations 2026-09-05T18:29:25.159309

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.

System ID Note
OMIM (phenotype) 613697 "CARDIOMYOPATHY, DILATED, 1V; CMD1V"
OMIM (gene) 600759 PSEN2; the S130L allele is 600759.0008
MONDO MONDO:0013373 "dilated cardiomyopathy 1V" (confirmed in ClinGen validity table)
HGNC HGNC:9509 (repo convention: hgnc:9509) PSEN2
Orphanet No CMD1V-specific code; subsumed under the familial isolated DCM umbrella (ORPHA:154)
ICD-10 / ICD-11 I42.0 / BC43.0 (dilated cardiomyopathy, not locus-specific)
MeSH D002311 (Cardiomyopathy, Dilated — umbrella)
UMLS/GTR condition C3150958 NIH Genetic Testing Registry

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).

Phenotype Type Onset Severity/course Frequency in carriers Suggested HPO
Dilated cardiomyopathy Clinical sign (imaging) Adult (36–55 y) Milder than CMD1U; progressive Partial penetrance — not all carriers affected HP:0001644 Dilated cardiomyopathy
Left ventricular dilatation Imaging sign Adult Progressive In affected carriers HP:4000141 Left ventricular dilatation
Reduced LV ejection fraction Imaging/functional Adult Variable In affected carriers HP:0012664 Reduced left ventricular ejection fraction
Congestive heart failure Clinical syndrome Adult "milder disease, and a more favorable prognosis" than PSEN1 disease Subset of affected HP:0001635 Congestive heart failure
Exertional dyspnea, palpitations (generic DCM symptomatology) Symptoms Adult Variable Not itemized per-carrier HP:0002875, HP:0001962
Unaffected carrier state — — — ≥1 mutation-positive relative with normal cardiovascular screening (OMIM) HP:0003829 (Typified by incomplete penetrance — current HP label)

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.

Intervention Notes Suggested NCIT
Guideline-directed medical therapy (ACEi/ARB/ARNI, beta-blockers, MRA, SGLT2 inhibitors, diuretics) Standard HFrEF pharmacotherapy NCIT:C15986 Pharmacotherapy (+ CHEBI/NCIT therapeutic_agent per drug)
ICD / CRT device therapy Standard indications; no locus-specific arrhythmia signal reported Device pattern per repo convention (action term + device qualifier)
Heart transplantation End-stage disease; notably not the reported course in the PSEN2 families (unlike CMD1U) NCIT:C15289 Organ Transplantation
Cardiac contractility modulation (CCM) Investigational HF electrotherapy; mechanistic contact point only — CCM normalized PS2/S100A1/sorcin expression in failing dog LV (PMID:20443895) —
Genetic counseling Required framing: Limited validity; variant carriage ≠ diagnosis NCIT:C15240 Genetic Counseling

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

Model Key finding Recapitulation of CMD1V
Psen2-knockout mouse (Takeda 2005, PMID:16204356) Viable; "cardiac contractility in PS2KO mice increased"; higher Ca²⁺ transients and peak tension; PS2–sorcin–RyR2 interaction; Z-line colocalization Fails to recapitulate — opposite contractile direction, no dilatation, no fibrosis. This is the central model-fidelity problem for the locus (FAILS_TO_RECAPITULATE, with the caveat that a knockout is not an S130L knock-in)
Psen1/Psen2 double-knockout mouse Un-looped heart at E8.5–9.0; presenilins essential for cardiac morphogenesis (PSEN1 single KO: VSD, DORV, PA stenosis) Developmental-essentiality context only; not a DCM model
Carrier dermal fibroblasts (human, in vitro; PMID:17186461) Altered calcium signaling; elevated resting [Ca²⁺] Supports the Ca²⁺ hypothesis one tissue removed from myocardium
Rat H9c2 cardiac cells (PMID:12468103) PS2 induced by hypoxia + glucose deprivation Expression-level support only
Failing-heart dog (PMID:20443895) PS2 increased in HF LV; normalized by CCM Expression-level support only; not a genetic model
Isolated mouse cardiomyocytes + Aβ oligomers (PMID:20194882) Oligomers acutely raise systolic Ca²⁺ transient Tests the proteostasis branch, not PSEN2 variants

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.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 4
Terms named correctly 1
Terms named as a different term 1
Terms whose name is worth a second look 2

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.