👪

Inheritance

1

Autosomal dominant HP:0000006

Heterozygous transmission in the single reported family, and the mode of inheritance ClinGen curated the disputed relationship under. The founding paper describes complete penetrance for the PSEN1 variant, in contrast to partial penetrance for the PSEN2 variant at the sibling locus. No penetrance_percentage is recorded: a penetrance statement drawn from a handful of adult carriers in one pedigree, 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 (1 reference)

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z SUPPORT Other

Records the mode of inheritance the expert panel curated the relationship under, alongside the classification.

◈

Mechanistic Hypotheses

1

Presenilin-1 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling

psen1_calcium_handling_dcm ALTERNATIVE

Evidence balance 4 support

The only mechanistic model proposed for CMD1U: a PSEN1 variant perturbs presenilin-1 in the cardiomyocyte, which disturbs sarcoplasmic-reticulum calcium handling - plausibly through the presenilin-1/SERCA2a association - and the resulting excitation-contraction defect drives dilatation and pump failure. It is recorded as ALTERNATIVE, not CANONICAL, because the disease it explains is itself disputed. Two supports exist and both fall short of the claim: carrier calcium signalling was measured in skin fibroblasts, and the PSEN1/SERCA2a co-immunoprecipitation came from idiopathic dilated cardiomyopathy hearts carrying promoter variants rather than the CMD1U allele. No cardiomyocyte carrying Asp333Gly has ever been studied. The model is nevertheless worth keeping, because it is amyloid-independent and is stated as such in the sources. That distinguishes it from the neuronal PSEN1 literature and makes it falsifiable: an isogenic D333G human iPSC-cardiomyocyte line with calcium-transient and SERCA2a-activity readouts would settle it in either direction.

Pathograph links

PSEN1 Asp333Gly 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 CMD1U-specific finding; nothing in the PSEN1 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, and the reason the neuronal amyloid literature is excluded from the entry.

PMID:37176125 SUPPORT Other

"PSEN1 D333G was transfected into HEK293 cells but did not result in an alteration in the Ab42/Ab40 ratio."

The experimental result behind that framing: the CMD1U allele itself does not shift the amyloid-beta ratio in a heterologous cell line, which is a negative result against an amyloidogenic mechanism rather than positive evidence for a calcium one.

PMID:20194882 SUPPORT Human Clinical

"Aβ level was tested by immunohistochemistry in our samples and no difference in Aβ expression was present in iDCM compared to controls."

The second negative result against an amyloid mechanism, and the one made in the right tissue: amyloid-beta was measured in human dilated-cardiomyopathy myocardium and did not differ from controls. Supports this hypothesis by eliminating its competitor rather than by demonstrating calcium involvement.

+ 1 more reference

?

Discussions and Knowledge Gaps

3

Is PSEN1 a dilated cardiomyopathy gene at all, or is CMD1U an OMIM locus built on a single unreplicated family?

CONTROVERSY OPEN psen1_dcm_gene_validity

Attached to

genetic#PSEN1 disease#Dilated Cardiomyopathy 1U

Twenty years after the founding report there is still one family, one paper, and no independent pedigree. ClinGen's expert panel has now looked at the evidence three times - 2020, 2025, 2026 - and each time called it Disputed, on the ground that the reported disease-causing variants are too common in population data to be monogenic causes. The counter-argument is not nothing. The panel explicitly says its evidence neither supports nor refutes the relationship, and the founding pedigree's segregation was real. Absence of replication in a locus nobody has looked for since is weak evidence of absence. This is recorded as an open controversy rather than resolved in either direction because the deciding experiment - a modern population-frequency and case-control reassessment of PSEN1 in a large dilated-cardiomyopathy cohort, or a cardiomyocyte model of Asp333Gly - has not been done. It matters practically: it determines whether PSEN1 belongs on a dilated-cardiomyopathy panel.

Proposed experiments

Modern population-frequency and case-control reassessment of PSEN1 in dilated cardiomyopathy

psen1_dcm_case_control_burden

Genotype PSEN1 across a large sequenced dilated-cardiomyopathy cohort and compare variant burden against a matched population reference, testing directly the observation the ClinGen classification rests on.

Would support

pathophysiology#PSEN1 Asp333Gly Missense Variant in Cardiomyocytes

Would refute

pathophysiology#PSEN1 Asp333Gly Missense Variant in Cardiomyocytes

Supporting outcome

Excess of rare, conserved PSEN1 missense variants in cases over ancestry-matched population controls, with Asp333Gly 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.

The rs177415 association above is deliberately confined to this discussion rather than curated as a genetic record. Even taken at face value it is a susceptibility signal of small effect, not a monogenic locus, and a single unreplicated candidate-gene association at P = 0.039 is the genre of finding least likely to survive replication. Curating it as a genetic record would make the CMD1U evidence base look broader than it is.

Show evidence (2 references)

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

"Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 29th, 2025As a result, the classification did not change."

Shows the Disputed verdict survived a fresh review rather than being a stale 2020 call. The sentence is quoted as it appears in the ClinGen record, including the missing sentence break after the date.

PMID:21656036 SUPPORT INDIRECT Human Clinical

"Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette smoking, and gender, confirmed the association between that SNP rs177415 of the presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669; P = 0.039)."

The one other line of human evidence connecting PSEN1 to dilated cardiomyopathy, quoted so the effect size and the p-value are visible. INDIRECT because a common-variant susceptibility signal of this size is a different claim from a monogenic locus and cannot settle the controversy in either direction.

The calcium mechanism proposed for CMD1U was measured in skin fibroblasts and in non-CMD1U myocardium. Does it hold in a cardiomyocyte carrying Asp333Gly?

HUMAN MODEL MISMATCH OPEN psen1_dcm_calcium_evidence_tissue_mismatch

Attached to

pathophysiology#Dysregulated Cardiomyocyte Calcium Handling mechanistic_hypotheses#psen1_calcium_handling_dcm

Every piece of evidence for the calcium mechanism comes from the wrong cell, the wrong genotype, or both. Carrier calcium signalling was measured in cultured skin fibroblasts, which are not contractile and do not use SERCA2a. The presenilin-1/SERCA2a co-immunoprecipitation was done in myocardium from sporadic idiopathic dilated cardiomyopathy patients carrying promoter variants, not the CMD1U allele. The oligomer calcium experiment perturbed cardiomyocytes with protein oligomers rather than with a PSEN1 variant. And the mouse work deletes the gene rather than introducing the missense allele, and yields a diastolic, small-ventricle phenotype rather than a dilated one. One study comes close and is worth being precise about. PSEN1 delta-exon-9 patient iPSC-derived cardiomyocytes, compared against isogenic controls, show a sarcoplasmic-reticulum calcium leak - the right cell type, a clean genetic comparison, and a dissected mechanism. But delta-exon-9 is a familial Alzheimer disease allele, not Asp333Gly, and the donors were dementia patients. It therefore narrows the mismatch rather than resolving it: a PSEN1 variant can disturb calcium in a human cardiomyocyte, which was not previously shown, but nothing says this variant does. This is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap because the evidence is not absent - five distinct experimental results exist and each is internally sound. What is missing is any demonstration that they compose into the human disease mechanism in the relevant cell and genotype.

Proposed experiments

Isogenic PSEN1 Asp333Gly human iPSC-cardiomyocyte calcium phenotyping

psen1_d333g_ipsc_cardiomyocyte_calcium

Introduce Asp333Gly 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 and SERCA2a activity, together with contractility.

Would support

pathophysiology#Dysregulated Cardiomyocyte Calcium Handling

Would refute

pathophysiology#Dysregulated Cardiomyocyte Calcium Handling

Supporting outcome

Altered calcium transient kinetics and reduced sarcoplasmic-reticulum calcium handling in the Asp333Gly cardiomyocytes relative to the isogenic control, with impaired contractility.

Refuting outcome

Calcium transients, sarcoplasmic-reticulum load and contractility indistinguishable from the isogenic wild-type control.

Show evidence (2 references)

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 mismatch this discussion is about.

PMID:38851626 SUPPORT INDIRECT In Vitro

"Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart diseases."

Establishes what this study's donors were: patients with an Alzheimer-causing PSEN1 allele. Quoted here rather than a result sentence because the allele is the whole reason the study narrows this mismatch without closing it.

Is the cardiac phenotype reported for PSEN1 dilated at all, given that the most recent case report describes hypertrophic cardiomyopathy?

OPEN QUESTION OPEN psen1_cardiac_phenotype_breadth

Attached to

phenotypes#Dilated Cardiomyopathy

A 2026 case report describes a heterozygous PSEN1 variant in a man with nonobstructive hypertrophic cardiomyopathy and later ventricular fibrillation, framed by its authors as expanding the cardiac phenotype of PSEN1. That is a different variant and a different cardiomyopathy - hypertrophic, not dilated - so it is no evidence for CMD1U and is not curated as such. It is recorded because it bears on how the whole PSEN1 cardiac literature should be read. When single case reports attach a gene to hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy exome cohorts in turn, each on tiny numbers, the pattern is more consistent with a much-sequenced gene accruing incidental variants than with a coherent cardiac disease entity. That reading is the same one ClinGen's population-frequency argument arrives at from a different direction.

Show evidence (1 reference)

PMID:42236188 SUPPORT INDIRECT Human Clinical

"This report suggests an expansion of the phenotypic spectrum associated with PSEN1 variants and highlights the need for further investigation of potential cardiac manifestations in PSEN1 variant carriers."

The report's own claim, quoted to show what it does and does not establish. INDIRECT because the phenotype is hypertrophic cardiomyopathy in a carrier of a different variant, so it speaks to the breadth of PSEN1 cardiac claims rather than to CMD1U.

⚙

Pathophysiology

5

PSEN1 Asp333Gly Missense Variant in Cardiomyocytes

Mechanism confidence: Hypothetical

A heterozygous germline PSEN1 missense variant, Asp333Gly, in the large hydrophilic cytoplasmic loop between transmembrane domains six and seven of presenilin-1. Presenilin-1 is expressed in myocardium as well as brain, so a cardiomyocyte-autonomous lesion is anatomically possible, and the founding study reported the variant segregating with aggressive dilated cardiomyopathy in one family. What the variant does to presenilin-1 in a cardiomyocyte has never been measured. There is no structural or biochemical characterisation of D333G in cardiac tissue, no D333G 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: FunctionalImpactEnum has no value that would be honest here, since neither loss nor gain of function has been shown for this allele in this tissue. A second, independent PSEN1 lesion has been described in myocardium and is placed at the same point in the chain: two promoter-region variants found in sporadic idiopathic dilated cardiomyopathy that reduce presenilin-1 transcription and protein in the myocardium. These are a different genetic mechanism in different patients, not the CMD1U allele, and they are recorded here because they are the expression evidence ClinGen names as the only surviving support for a PSEN1-heart relationship.

Presenilin-1 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling

Cardiomyocyte CL:0000746

PSEN1 hgnc:9508

Genetic context PSEN1 hgnc:9508 allele_type: MISSENSE variant_origin: GERMLINE zygosity: HETEROZYGOUS

Heterozygous germline PSEN1 p.Asp333Gly, reported in a single dilated-cardiomyopathy family. 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.

Show evidence (3 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:20194882 SUPPORT INDIRECT Human Clinical

"Consistently, these variants decreased the expression of PS1 protein in the myocardium"

Direct demonstration that PSEN1 sequence variation can reduce presenilin-1 protein in human myocardium. INDIRECT for this node because the variants concerned are promoter variants in sporadic idiopathic dilated cardiomyopathy, not the CMD1U Asp333Gly allele.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

"All of the variants reported as disease-causing have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets."

The expert panel's reason for disputing that any reported PSEN1 variant, this one included, is a monogenic cause of dilated cardiomyopathy. Recorded on the initiating node because it bears on whether this node exists at all.

Dysregulated Cardiomyocyte Calcium Handling

Mechanism confidence: Hypothetical

The proposed effector step: disturbed intracellular calcium regulation in the cardiomyocyte. Two separate observations point at it, and neither was made in a cardiomyocyte carrying the CMD1U 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, presenilin-1 co-immunoprecipitates with SERCA2a, the cardiac sarcoplasmic-reticulum calcium ATPase, in explanted idiopathic dilated cardiomyopathy hearts. That is a physical association in human myocardium and is the most cardiac-specific molecular result in this literature. It is an interaction, not a rate: no measurement of SERCA2a activity in a PSEN1-variant heart exists, so the node carries no direction. The biological process below is tagged DYSREGULATED rather than INCREASED or DECREASED for that reason - the sources say "altered", and choosing a direction would be an invention.

Presenilin-1 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling

Cardiomyocyte CL:0000746

calcium ion transmembrane transport GO:0070588 ↕ DYSREGULATED

SERCA2a P-type calcium transporter activity GO:0005388

left ventricle UBERON:0002084

Experimental models

PSEN1 delta-exon-9 patient iPSC-derived cardiomyocytes IPSC DERIVED MODEL Demonstrates that a PSEN1 variant produces a specific, mechanistically characterised calcium-handling defect in human cardiomyocytes, which is the class of result this node needs and has otherwise never had.

Animal models

Drosophila dPsn cardiac knockdown and overexpression Fruit fly partially recapitulates Links a change in presenilin level to altered expression of the calcium-handling machinery and to a dilating, arrhythmic heart in the same animal - the only in vivo system in which the calcium arm of this entry's hypothesis and a dilated phenotype have been observed together.

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 CMD1U-specific finding; nothing in the PSEN1 literature measures it.

Show evidence (3 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 CMD1U 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:20194882 SUPPORT In Vitro

"Importantly, PS1 co-immunoprecipitated with the cardiac isoform of the SR Ca2+-ATPase pump SERCA2a"

A physical association between presenilin-1 and the cardiac SERCA isoform, demonstrated in explanted human myocardium, which is the mechanistic reason calcium handling rather than amyloid is the proposed route. Graded IN_VITRO because a co-immunoprecipitation is a biochemical assay on tissue lysate, not a clinical observation.

PMID:20194882 SUPPORT INDIRECT In Vitro

"We also showed that oligomers alter myocyte Ca(2+) homeostasis."

Establishes that a calcium-handling defect is achievable in cardiomyocytes in this disease context. INDIRECT because the perturbation is a protein oligomer applied to cultured myocytes, not a PSEN1 variant, so it supports the plausibility of the node rather than the PSEN1 route to it.

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 CMD1U literature characterises remodeling in a PSEN1 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

left ventricle UBERON:0002084

Downstream

Progressive Systolic Dysfunction and Heart Failure Chamber dilatation with impaired contraction is by definition the dilated cardiomyopathy phenotype and the substrate for progressive pump failure.

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 PSEN1 carrier - of which nothing has been reported.

Progressive Systolic Dysfunction and Heart Failure

Falling ejection fraction and clinical heart failure, progressing in the reported family to transplantation or death. This is the clinical endpoint of the entity and the only part of the chain observed directly in CMD1U patients.

left ventricle UBERON:0002084

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 observed clinical endpoint in the index family.

Cardiac Sarcomeric and Intercalated-Disc Disorganisation

Mechanism confidence: Hypothetical

A structural cardiomyocyte lesion reported only in mice. Deleting Psen1 from the murine cardiovascular system produces fewer muscle fibres, widened sarcomeric Z-lines, shortened sarcomeres and loosened gap junctions between neighbouring cardiomyocytes, and complete Psen1 nullity causes perinatal death with ventricular dilatation and septal defects. This node is kept separate from the calcium node and outside the disease's main causal chain on purpose. Every observation behind it comes from deleting the gene, and CMD1U is a heterozygous missense allele of unknown functional consequence. A knockout phenotype tells you what presenilin-1 does in the mouse heart; it does not tell you what Asp333Gly does in a human one, and the authors of that work say the mechanism of PSEN1 in cardiomyopathy remains unresolved. No downstream edge is drawn from it into the human chain for that reason.

Cardiomyocyte CL:0000746

sarcomere organization GO:0045214 ⚠ ABNORMAL

Animal models

Cardiovascular-restricted Psen1 conditional knockout mouse Mouse partially recapitulates Deleting Psen1 from the mouse cardiovascular system reproduces a cardiomyocyte structural lesion and a functional cardiac deficit, establishing that presenilin-1 is required for normal cardiomyocyte architecture in vivo.

Show evidence (3 references)

PMID:28617969 SUPPORT Model Organism

"PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes."

The ultrastructural phenotype of adult cardiac Psen1 deletion in mouse, which is the whole basis for this node.

PMID:28617969 SUPPORT Model Organism

"Cardiovascular loss of function of PSEN1 induced by Sm22a-Cre or Myh6-Cre/ER/tamoxifen also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions between neighboring cardiomyocytes."

The intercalated-disc component of the same murine phenotype, obtained with cardiovascular- and cardiomyocyte-restricted deletion.

PMID:28617969 NO_EVIDENCE Model Organism

"However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved."

The same authors' own statement of what was unresolved when they began, quoted so this node is not read as a mechanism for the human disease. NO_EVIDENCE because the sentence reports the absence of a settled mechanism rather than an experimental result for or against one.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

2

Dilated Cardiomyopathy Cardiovascular HP:0001644

Course: PROGRESSIVE

No frequency band is assigned. The HPO annotations for MONDO:0013371 give this phenotype at 100%, but the denominator is the three genotyped affected relatives of one pedigree in a single paper; a FrequencyEnum value would present a family observation as a disease-level frequency.

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 family in which the dilated-cardiomyopathy phenotype defining this locus was observed.

Congestive Heart Failure Cardiovascular HP:0001635

Course: PROGRESSIVE

No frequency band assigned, for the same reason as the dilated-cardiomyopathy phenotype: the only denominator available is a single pedigree.

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. Note it says "associated with", which is a weaker claim than the locus name implies.

🧬

Genetic Associations

1

PSEN1 (PSEN1 encodes presenilin-1, the catalytic subunit of the gamma-secretase intramembrane protease. Its relationship with dilated cardiomyopathy was proposed in 2006 on the strength of one family carrying Asp333Gly, found in a screen of 315 dilated-cardiomyopathy index patients, together with altered calcium signalling in carrier skin fibroblasts. That claim has not strengthened in twenty years, and the expert reappraisal went the other way. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel first evaluated PSEN1 for dilated cardiomyopathy in 2020, re-evaluated it under SOP10 in 2025, and the classification did not change: **Disputed**, re-reported March 2026. The panel's reasoning is that the reported disease-causing variants turn out to be too common in population reference data for a monogenic pathogenic effect, leaving no scorable human genetic evidence, so the relationship rests on expression studies alone. The relationship is therefore typed DISPUTED rather than CAUSATIVE. That is a deliberate departure from the OMIM-defined entity this file curates, which asserts causation; where the ontology and the expert panel disagree, this entry follows the panel and says so. Disputed is not the same as refuted. The panel's own summary says the evidence neither supports nor refutes the role of PSEN1 in dilated cardiomyopathy and that the relationship is unclear - so this entry does not claim PSEN1 has been shown not to cause dilated cardiomyopathy. It claims the question is open and currently answered against. The verdict is specific to the cardiac phenotype. PSEN1's relationship with early-onset autosomal dominant Alzheimer disease is not in question and is curated separately in dismech, as are PSEN1's roles in cerebral amyloid angiopathy and hidradenitis suppurativa.)

Gene: PSEN1 hgnc:9508 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (5 references)

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

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 PSEN1 variant in a cardiomyopathy patient.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

"Therefore, there is no scorable human genetic evidence."

The panel's conclusion about the genetic evidence specifically, and the reason relationship_type is DISPUTED rather than CAUSATIVE.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z SUPPORT Other

"In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of PSEN1 and DCM."

Quoted so the Disputed classification is not read as stronger than the source supports. The panel explicitly declines to rule the relationship out, which is why this entry curates the locus rather than proposing it be discarded.

+ 2 more references

Variants (1)

PSEN1 p.Asp333Gly

The founding CMD1U allele. A heterozygous missense substitution replacing a conserved acidic aspartate with glycine in the cytoplasmic loop between transmembrane domains six and seven, reported in a single family. 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.

🗃️

External Assertions

1

ClinGen PSEN1-dilated cardiomyopathy 1U gene-disease validity assertion

ClinGen gene disease validity CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z

The ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal dominant PSEN1 - dilated cardiomyopathy 1U relationship as Disputed. The curation is against MONDO:0013371 itself, so it is about this entity rather than about dilated cardiomyopathy in general. First evaluated 2020, re-evaluated under SOP10 in May 2025 with no change, report dated 2026-03-04. Its evidence summary is unusually specific about why: the reported disease-causing variants are too common in population reference data, so there is no scorable human genetic evidence, and the assertion rests on expression studies.

The panel's evidence summary cites the supporting expression study as "Gianni et al., 2010, PMID: 2019488". That identifier is one digit short of PMID:20194882, the Gianni 2010 Circulation paper on protein aggregates and presenilin variants in idiopathic dilated cardiomyopathy, which matches the author, year and description exactly. This entry cites the full, correct identifier; the truncated form is left as-is inside the quoted snippets because a snippet belongs to its source.

Show evidence (3 references)

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

"The relationship of PSEN1 with DCM is unclear and therefore classified as disputed."

The panel's conclusion sentence.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z REFUTE Other

"There is a lack of robust human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation."

The specific deficiency the classification rests on, stated separately from the population-frequency observation that produced it.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z SUPPORT Other

"PSEN1 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2006 (Li et al., 2006, PMID: 17186461)."

Confirms that the panel curated the same founding paper this entry is built on, so the Disputed verdict and the entry's evidence base are about the same claim.

💊

Medical Actions

4

Guideline-Directed Heart Failure Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 angiotensin receptor-neprilysin inhibitor NCIT:C190796 SGLT2 inhibitor NCIT:C98083

Platform: Small molecule

Management of CMD1U is management of dilated cardiomyopathy: there is no PSEN1-directed therapy, no trial in this population, and no reason to expect genotype-specific treatment while the genotype-phenotype relationship itself is disputed. 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 CMD1U-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:

Progressive Systolic Dysfunction and Heart Failure — Acts on the clinical endpoint, not on the proposed molecular mechanism. Nothing in the standard regimen targets presenilin-1 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 PSEN1 - which is the point: no PSEN1-specific regimen exists, so the general pathway is the treatment.

Cardiac Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

The endpoint intervention for refractory disease, and one that was actually reached in the reported family: the founding paper describes progressive disease resulting in the necessity of cardiac transplantation or in death.

Mechanism Target:

Progressive Systolic Dysfunction and Heart Failure — Replaces the failing organ; it does not address the proposed mechanism.

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."

Records that transplantation was the outcome in the index family, which is the only treatment observation that exists for this locus.

Cardiac Surveillance of At-Risk Relatives

Action: serial cardiac surveillance Ontology label: Supportive Care NCIT:C15747

Platform: Other

Serial cardiac assessment of first-degree relatives of an affected proband. For a late-onset cardiomyopathy this is the intervention with the clearest rationale, because it detects dilatation before symptoms. Whether surveillance should be triggered by a PSEN1 variant specifically is a different question and this entry answers it no: with the relationship Disputed, a PSEN1 result is not a basis for genotype-directed surveillance. 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.

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z SUPPORT Other

"Therefore, there is no scorable human genetic evidence."

The basis for declining to recommend genotype-directed surveillance on a PSEN1 result. Surveillance driven by family history is unaffected by this.

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Device therapy for the arrhythmic risk that accompanies a dilated, poorly contracting ventricle. It is included because it is part of dilated-cardiomyopathy management and because the guidelines disagree about it: a 2025 systematic review found the criteria for prophylactic defibrillator implantation to be one of the areas where dilated-cardiomyopathy guidelines vary, along with arrhythmic risk stratification generally. Nothing about a PSEN1 result should shift that decision in either direction. There is no reported arrhythmic phenotype for this locus and, with the gene-disease relationship disputed, no basis for treating a PSEN1 variant as the kind of high-risk genotype - LMNA, FLNC, RBM20 - that does modify defibrillator thresholds.

Mechanism Target:

Progressive Systolic Dysfunction and Heart Failure — Treats the arrhythmic consequence of the failing, dilated ventricle. It modifies neither the remodeling nor anything upstream of it.

Show evidence (1 reference)

DOI:10.1093/ehjqcco/qcae109 SUPPORT INDIRECT Other

"Nonetheless, notable areas of variation included the formation of multidisciplinary management teams, the role of cascade genetic testing, pathways for arrhythmic risk stratification, and the criteria for prophylactic defibrillator implantation."

Establishes that prophylactic defibrillator criteria are contested across dilated-cardiomyopathy guidelines, which is why this entry records the intervention without asserting a threshold. INDIRECT because the review addresses dilated cardiomyopathy as a class, not this locus.

🔬

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 CMD1U changes this step, and there is no PSEN1-specific diagnostic feature: no cardiac imaging, biopsy or biomarker finding distinguishes a PSEN1 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 PSEN1-specific: no biomarker, imaging feature or biopsy finding distinguishes a PSEN1 carrier from any other dilated cardiomyopathy, which is itself worth recording because 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 PSEN1 the point is not efficiency but interpretation: with the gene-disease relationship classified Disputed, a PSEN1 variant found in a dilated-cardiomyopathy proband should not be reported as a molecular diagnosis, and cascade testing of relatives on the strength of one is difficult to justify. The value of testing such a patient is to find a variant in a gene with real support. Whether PSEN1 belongs on an evidence-based dilated-cardiomyopathy panel at all is a live question that this entry does not settle.

Show evidence (1 reference)

CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z SUPPORT Other

The classification that governs how much weight a PSEN1 result should carry in this setting.

📈

Progression

2

Preclinical carrier state

Age: below approximately 35 years

In the single reported family, variant carriers below roughly the fourth decade were reported without cardiac disease while affected relatives spanned mid-adulthood to old age. The founding paper describes the PSEN1 mutation as completely penetrant, which is a statement about clinically evaluable adult relatives in one small pedigree rather than a lifetime penetrance estimate; with a handful of carriers and age censoring, no penetrance figure from this family is stable. No penetrance_percentage is recorded on the inheritance block for that reason.

Progressive symptomatic dilated cardiomyopathy

Once established, the reported course was progressive rather than stable, ending in cardiac transplantation or death in affected members of the index family. Whether that aggressive trajectory is a property of the variant or of the family is unknown, because no second family has been reported.

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 reported natural history in the index family, and the basis for describing the course as progressive.

📊

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 figure in the literature is a yield within a screened cohort: one PSEN1 family out of 315 dilated-cardiomyopathy index patients in the founding study. That is a variant-detection rate in a selected cohort, not a disease prevalence, and the ClinGen Disputed classification means it should not be read as one either.

Show evidence (2 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 only screen that has ever reported a CMD1U family, which is the denominator behind the single-family yield.

PMID:17186461 SUPPORT Human Clinical

"Heart failure usually results from dilated cardiomyopathy (DCM). ... We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were..."

Screening 315 DCM index patients identified a PSEN1 variant in one family and a PSEN2 variant in two other families. The report establishes family observations, not a population prevalence or the later clinical-validity classification.

🔀

Differential Diagnoses

2

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

Dilated Cardiomyopathy 1V

Overlapping Features The PSEN2 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. PSEN2 Ser130Leu was found in two families with milder disease, partial penetrance and a more favourable prognosis than the PSEN1 family. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies PSEN2 for dilated cardiomyopathy 1V as Limited - one tier better than PSEN1's Disputed, on the same review date. dismech does not yet curate CMD1V.

Distinguishing Features

Different gene (PSEN2, hgnc:9509) and a milder reported phenotype with partial penetrance. The two cannot be told apart clinically; only sequencing separates them.

Show evidence (1 reference)

PMID:17186461 SUPPORT Human Clinical

"The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis."

The clinical contrast between the two presenilin loci as reported in the paper that defined both.

Idiopathic Dilated Cardiomyopathy

Overlapping Features Dilated cardiomyopathy with no identified cause, which is what a CMD1U patient has if the PSEN1 attribution is not accepted. This is not an academic alternative: it is the diagnosis the ClinGen classification implies for most PSEN1 carriers with the phenotype. Notably, the myocardial presenilin-1 work that ClinGen credits as the surviving evidence was itself done in idiopathic cases rather than in CMD1U families.

Distinguishing Features

Absence of a family history or of a segregating variant. Given that no PSEN1 variant is currently scorable as genetic evidence, the practical boundary between this and CMD1U is the pedigree, not 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 the presenilin cardiac work most often cited for this locus was performed in idiopathic, not familial CMD1U, cases - and in a cohort of twenty.

🧫

Experimental Models

1

PSEN1 delta-exon-9 patient iPSC-derived cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes differentiated from induced pluripotent stem cells of patients carrying the PSEN1 exon 9 deletion, compared against isogenic controls. This is the only human cardiomyocyte system in which a PSEN1 variant has been studied, and it finds a sarcoplasmic-reticulum calcium leak that is not blocked by ryanodine-receptor or IP3-receptor inhibition, producing a diastolic calcium buildup near the perinuclear SR and less releasable calcium during systole. The allele is wrong for this entry. PSEN1 delta-exon-9 is a familial Alzheimer disease variant, not the CMD1U Asp333Gly allele, and the patients were ascertained for dementia. So this system does not resolve the tissue mismatch that this entry's central hypothesis rests on - it narrows it, by showing that a PSEN1 variant can disturb cardiomyocyte calcium in human cells, while leaving open whether the CMD1U allele does.

Organism

human NCBITaxon:9606

Publication

PMID:38851626

Pathograph links

Dysregulated Cardiomyocyte Calcium Handling partially recapitulates fidelity: low Demonstrates that a PSEN1 variant produces a specific, mechanistically characterised calcium-handling defect in human cardiomyocytes, which is the class of result this node needs and has otherwise never had.

Limitations: Different allele, different disease and different ascertainment: PSEN1 delta-exon-9 causes familial Alzheimer disease and these donors were not dilated-cardiomyopathy patients, so nothing here shows that Asp333Gly behaves the same way. The defect is an SR leak rather than the SERCA2a-uptake failure the human myocardial work implicates, and it left electrophysiological properties unchanged, so it is not obviously a route to a dilated phenotype. iPSC-derived cardiomyocytes are also immature relative to adult myocardium.

Readouts

Sarcoplasmic reticulum calcium leak against isogenic control

Direction: INCREASED

Interpretation: The core measurement, made against an isogenic control so the comparison is clean, and pharmacologically dissected: the leak survives blockade of both ryanodine and IP3 receptors, so it is not through either channel.

Show evidence (1 reference)

PMID:38851626 SUPPORT In Vitro

"When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased sarcoplasmic reticulum (SR) Ca2+ leak that was resistant to blockage of ryanodine receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP3Rs) by 2-ABP."

The leak measurement and the two pharmacological controls that exclude the obvious channels.

Electrophysiological properties of the cardiomyocytes

Direction: UNCHANGED

Interpretation: A negative result worth recording: the calcium leak did not change the cells' electrophysiology, so whatever this variant does to a cardiomyocyte it does not do it through the action potential.

Show evidence (1 reference)

PMID:38851626 SUPPORT In Vitro

"The SR Ca2+ leak did not affect electrophysiological properties of the hiPSC-CMs"

The measured absence of an electrophysiological effect.

Show evidence (1 reference)

PMID:38851626 SUPPORT In Vitro

"This demonstrates that PSEN1 ΔE9 induced SR Ca2+ leak has specific effects in iPSC-CMs, reflecting their unique structural and calcium signaling features."

The authors' conclusion that the leak is a cardiomyocyte-specific effect rather than a generic consequence of the variant, which is what makes this system informative for a cardiac entry at all. The sentence stating the leak's functional consequence - diastolic calcium buildup near the perinuclear SR with less releasable calcium during systole - is described in this entry's prose rather than quoted, because its bracketed calcium notation is stripped by the reference validator's bracket handling and so cannot be snippet-verified.

🐁

Animal Models

2

Drosophila dPsn cardiac knockdown and overexpression

Transgenic flies in which the single Drosophila presenilin ortholog is silenced or overexpressed, with cardiac function measured in living adults by optical coherence tomography. It was built specifically to ask what presenilin does in the heart after the human PSEN1 dilated-cardiomyopathy report, so unlike almost everything else in the presenilin literature it is not an Alzheimer model that happens to have a heart. Silencing produces an age-dependent increase in end-diastolic dimension - a dilating heart, the direction this entity is named for and the direction the mouse knockout does not give - together with slowed rate, arrhythmia, myofibril defects and mitochondrial impairment. The calcium result is what makes it relevant here: silencing dPsn raises dIP3R and lowers dSERCA expression, which is the fly counterpart of the presenilin-SERCA relationship proposed in human myocardium.

Species

Fruit fly

Genotype

Transgenic RNAi knockdown or overexpression of dPsn, the Drosophila presenilin ortholog

Publication

PMID:21524270

Pathograph links

Dysregulated Cardiomyocyte Calcium Handling partially recapitulates fidelity: low Links a change in presenilin level to altered expression of the calcium-handling machinery and to a dilating, arrhythmic heart in the same animal - the only in vivo system in which the calcium arm of this entry's hypothesis and a dilated phenotype have been observed together.

Limitations: The Drosophila heart is a linear contractile tube with no chambers, no valves in the mammalian sense and no coronary circulation, so "end-diastolic vertical dimension" is not a left ventricular volume and the resemblance to human dilatation is analogical. The manipulation is knockdown or overexpression of the whole gene rather than the CMD1U missense allele, and it is not even clear which direction models the human variant: the authors report opposite cardiac effects for silencing and overexpression. The calcium finding is transcript abundance by RT-PCR, not pump activity or a calcium transient, and dSERCA is the single fly SERCA rather than the cardiac SERCA2a isoform the human work implicates. The paper's own framing is that the mechanism was not understood.

Readouts

dSERCA and dIP3R transcript abundance in cardiac cells

Direction: ALTERED

Interpretation: The calcium-machinery readout, and the reason this model is attached to this node. The two transcripts move in opposite directions under dPsn silencing, so the direction is ALTERED rather than INCREASED or DECREASED.

Show evidence (1 reference)

PMID:21524270 SUPPORT Model Organism

"Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression."

The transcript measurements behind this readout, quoted with the source's own typography.

End-diastolic vertical dimension of the adult fly heart

Direction: INCREASED

Interpretation: A chamber-dilation analogue measured in a living animal, and the one place in the presenilin cardiac literature where reducing presenilin produces dilatation rather than the small-ventricle diastolic phenotype of the mouse.

Show evidence (1 reference)

PMID:21524270 SUPPORT Model Organism

"Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions."

The dimensional measurement and its direction, with the rate change reported alongside it.

Show evidence (2 references)

PMID:21524270 SUPPORT Model Organism

"Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis."

The authors' own conclusion, which is the claim that makes this model informative for this entry - and note it names two routes, calcium handling and Wnt signalling, of which only the first is curated here because only the first has any human cardiac counterpart.

PMID:21524270 SUPPORT Model Organism

"Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment."

The structural and arrhythmic phenotype, recorded because it appears in both directions of manipulation - which is part of why the model's fidelity to a specific human missense allele is rated LOW.

Cardiovascular-restricted Psen1 conditional knockout mouse

A panel of four genetically modified mouse lines deleting Psen1 constitutively or from the cardiovascular system and cardiomyocytes in the adult. Null animals die perinatally with retarded heart growth, ventricular dilatation, septal defects and valvular thickening; adult cardiovascular deletion produces sarcomeric and gap-junction ultrastructural abnormalities, spontaneous mortality and diastolic dysfunction. This is the only mouse work directed at the PSEN1-cardiomyopathy question rather than at Alzheimer disease. It is not a CMD1U model, and the entry does not treat it as one - the genes list carries PSEN1 because the lesion really is in that gene, but the lesion is deletion, not the CMD1U missense allele.

Species

Mouse

Genotype

Psen1 conditional deletion (Sm22a-Cre or Myh6-Cre/ER, tamoxifen-induced); Psen1 null

Genes

Psen1 hgnc:9508

Publication

PMID:28617969

Pathograph links

Cardiac Sarcomeric and Intercalated-Disc Disorganisation partially recapitulates fidelity: low Deleting Psen1 from the mouse cardiovascular system reproduces a cardiomyocyte structural lesion and a functional cardiac deficit, establishing that presenilin-1 is required for normal cardiomyocyte architecture in vivo.

Limitations: Three separate gaps between this model and CMD1U. The allele is a deletion, while CMD1U is a heterozygous missense variant whose functional consequence - loss, gain, or neither - has never been determined; a knockout therefore cannot be assumed to model it. The functional phenotype reported is diastolic dysfunction with decreased left ventricular volume, which is not the dilated phenotype the human entity is named for, and the paper separately notes ventricular dilatation only in the constitutive null, which dies perinatally. And the model was not built on, or tested against, the Asp333Gly allele. No claim about the human disease mechanism rests on it.

Readouts

Sarcomere Z-line width and sarcomere length in cardiomyocytes

Direction: ALTERED

Interpretation: Structural correlate of the disorganisation node: Z-lines widened and sarcomeres shortened in adult Psen1 knockout cardiomyocytes. Direction is ALTERED rather than INCREASED or DECREASED because the two measurements move in opposite directions.

Show evidence (1 reference)

PMID:28617969 SUPPORT Model Organism

"PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes."

The reported ultrastructural measurement behind this readout.

Left ventricular volume at end-systole and end-diastole

Direction: DECREASED

Interpretation: The functional consequence in this model is diastolic dysfunction with reduced ventricular volumes. Recorded because it is the opposite direction from the chamber dilatation the human entity is defined by, and that divergence is the main reason the model's fidelity is rated LOW.

Show evidence (1 reference)

PMID:28617969 SUPPORT Model Organism

"Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from birth to adulthood and led to diastolic heart dysfunction, including decreased volume of the left ventricle at the end-systolic and end-diastolic stages."

The functional phenotype of cardiovascular Psen1 deletion, including the direction of the ventricular volume change.

Show evidence (1 reference)

PMID:28617969 SUPPORT Model Organism

"PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular dilatation, septum defects, and valvular thickening."

Establishes that complete loss of presenilin-1 has a cardiac consequence in vivo, which is what makes this model informative about presenilin-1 in the heart at all.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1U
creation_date: "2026-08-31T18:00:00Z"
category: Mendelian
disease_term:
  preferred_term: dilated cardiomyopathy 1U
  term:
    id: MONDO:0013371
    label: dilated cardiomyopathy 1U
synonyms:
- CMD1U
- DCM1U
- cardiomyopathy, dilated, 1U
- dilated cardiomyopathy type 1U
- PSEN1-related dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in PSEN1
description: >-
  A numbered OMIM dilated-cardiomyopathy locus assigned to PSEN1, the catalytic subunit of
  gamma-secretase and the best-known early-onset Alzheimer disease gene. This entry exists
  because the locus exists and is queried, not because the gene-disease relationship is
  settled - and the single most important thing in it is that the relationship is not settled.

  In March 2026 the ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classified the
  PSEN1 - dilated cardiomyopathy 1U relationship as **Disputed** under SOP10, re-affirming a
  verdict first reached in 2020 and re-reviewed in 2025. Disputed sits one tier above Refuted.
  The panel's stated reason is specific and checkable: every variant reported as disease-causing
  has since been found in population reference data at a frequency incompatible with a
  monogenic pathogenic effect, leaving no scorable human genetic evidence at all. What survives
  is expression work.

  The primary evidence is one paper. A 2006 screen of 315 dilated-cardiomyopathy index patients
  found a single PSEN1 missense variant, Asp333Gly, in one family, where it segregated with
  aggressive adult-onset disease ending in transplantation or death. The same screen produced
  PSEN2 Ser130Leu in two other families, which is the separate locus CMD1V. No independent
  CMD1U pedigree has been reported since.

  The mechanism proposed for the cardiac phenotype is not the amyloid cascade, and this entry
  keeps it that way deliberately. PSEN1 is surrounded by an enormous neuronal amyloid
  literature that has nothing to do with this locus, and two cardiac results argue directly
  against importing it: myocardium from idiopathic dilated cardiomyopathy patients showed no
  difference in amyloid-beta from controls, and D333G expressed in HEK293 cells did not shift
  the Abeta42/Abeta40 ratio. What is actually proposed is calcium: altered calcium signalling
  in cultured skin fibroblasts from carriers, and a physical association between presenilin-1
  and the cardiac sarcoplasmic-reticulum calcium pump SERCA2a in explanted iDCM hearts. Both
  observations are real; neither was made in a cardiomyocyte carrying D333G. The whole causal
  chain below is therefore held inside a single ALTERNATIVE mechanistic hypothesis rather than
  asserted as the disease mechanism.

  Practically: a PSEN1 variant found in a patient with dilated cardiomyopathy should not be
  treated as a molecular diagnosis, and cascade testing of relatives on the strength of one is
  difficult to justify. The Disputed classification is specific to the cardiac phenotype and
  says nothing about PSEN1's well-established role in early-onset Alzheimer disease, which
  dismech curates separately.

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 figure in the literature is a yield within a screened cohort: one PSEN1 family
    out of 315 dilated-cardiomyopathy index patients in the founding study. That is a
    variant-detection rate in a selected cohort, not a disease prevalence, and the ClinGen
    Disputed classification means it should not be read as one either.
  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 only screen that has ever reported a CMD1U family, which is
      the denominator behind the single-family yield.
  - reference: PMID:17186461
    reference_title: "Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart failure usually results from dilated cardiomyopathy (DCM). ... We hypothesized that
      mutations in presenilins may also be associated with DCM and that their discovery could
      provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index
      patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive
      for mutations underwent additional clinical, genetic, and functional studies. 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.
    explanation: >-
      Screening 315 DCM index patients identified a PSEN1 variant in one family and a PSEN2 variant
      in two other families. The report establishes family observations, not a population prevalence
      or the later clinical-validity classification.
progression:
- phase: Preclinical carrier state
  age_range: below approximately 35 years
  notes: >-
    In the single reported family, variant carriers below roughly the fourth decade were
    reported without cardiac disease while affected relatives spanned mid-adulthood to old
    age. The founding paper describes the PSEN1 mutation as completely penetrant, which is a
    statement about clinically evaluable adult relatives in one small pedigree rather than a
    lifetime penetrance estimate; with a handful of carriers and age censoring, no penetrance
    figure from this family is stable. No penetrance_percentage is recorded on the
    inheritance block for that reason.
- phase: Progressive symptomatic dilated cardiomyopathy
  notes: >-
    Once established, the reported course was progressive rather than stable, ending in
    cardiac transplantation or death in affected members of the index family. Whether that
    aggressive trajectory is a property of the variant or of the family is unknown, because
    no second family has been reported.
  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 reported natural history in the index family, and the basis for describing the
      course as progressive.

pathophysiology:

- name: PSEN1 Asp333Gly Missense Variant in Cardiomyocytes
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A heterozygous germline PSEN1 missense variant, Asp333Gly, in the large hydrophilic
    cytoplasmic loop between transmembrane domains six and seven of presenilin-1. Presenilin-1
    is expressed in myocardium as well as brain, so a cardiomyocyte-autonomous lesion is
    anatomically possible, and the founding study reported the variant segregating with
    aggressive dilated cardiomyopathy in one family.

    What the variant does to presenilin-1 in a cardiomyocyte has never been measured. There is
    no structural or biochemical characterisation of D333G in cardiac tissue, no D333G
    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: FunctionalImpactEnum has no value
    that would be honest here, since neither loss nor gain of function has been shown for this
    allele in this tissue.

    A second, independent PSEN1 lesion has been described in myocardium and is placed at the
    same point in the chain: two promoter-region variants found in sporadic idiopathic
    dilated cardiomyopathy that reduce presenilin-1 transcription and protein in the
    myocardium. These are a different genetic mechanism in different patients, not the CMD1U
    allele, and they are recorded here because they are the expression evidence ClinGen names
    as the only surviving support for a PSEN1-heart relationship.
  genes:
  - preferred_term: PSEN1
    term:
      id: hgnc:9508
      label: PSEN1
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genetic_context:
    gene:
      preferred_term: PSEN1
      term:
        id: hgnc:9508
        label: PSEN1
    allele_type: MISSENSE
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous germline PSEN1 p.Asp333Gly, reported in a single dilated-cardiomyopathy
      family. 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:
    - psen1_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:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Consistently, these variants decreased the expression of PS1 protein in the myocardium
    explanation: >-
      Direct demonstration that PSEN1 sequence variation can reduce presenilin-1 protein in
      human myocardium. INDIRECT for this node because the variants concerned are promoter
      variants in sporadic idiopathic dilated cardiomyopathy, not the CMD1U Asp333Gly allele.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      All of the variants reported as disease-causing 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 disputing that any reported PSEN1 variant, this one
      included, is a monogenic cause of dilated cardiomyopathy. 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. Two separate observations point at it, and neither was made in a
    cardiomyocyte carrying the CMD1U 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, presenilin-1 co-immunoprecipitates with SERCA2a, the cardiac sarcoplasmic-reticulum
    calcium ATPase, in explanted idiopathic dilated cardiomyopathy hearts. That is a physical
    association in human myocardium and is the most cardiac-specific molecular result in this
    literature. It is an interaction, not a rate: no measurement of SERCA2a activity in a
    PSEN1-variant heart exists, so the node carries no direction. The biological process below
    is tagged DYSREGULATED rather than INCREASED or DECREASED for that reason - the sources
    say "altered", and choosing a direction 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: SERCA2a P-type calcium transporter activity
    term:
      id: GO:0005388
      label: P-type calcium transporter 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:
    - psen1_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
      CMD1U-specific finding; nothing in the PSEN1 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 CMD1U 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:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, PS1 co-immunoprecipitated with the cardiac isoform of the SR Ca2+-ATPase
      pump SERCA2a
    explanation: >-
      A physical association between presenilin-1 and the cardiac SERCA isoform, demonstrated
      in explanted human myocardium, which is the mechanistic reason calcium handling rather
      than amyloid is the proposed route. Graded IN_VITRO because a co-immunoprecipitation is a
      biochemical assay on tissue lysate, not a clinical observation.
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      We also showed that oligomers alter myocyte Ca(2+) homeostasis.
    explanation: >-
      Establishes that a calcium-handling defect is achievable in cardiomyocytes in this
      disease context. INDIRECT because the perturbation is a protein oligomer applied to
      cultured myocytes, not a PSEN1 variant, so it supports the plausibility of the node rather
      than the PSEN1 route to it.

- 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 CMD1U
    literature characterises remodeling in a PSEN1 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: Progressive 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 progressive pump failure.
  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 PSEN1 carrier - of which nothing has been reported.

- name: Progressive 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, progressing in the reported family
    to transplantation or death. This is the clinical endpoint of the entity and the only part
    of the chain observed directly in CMD1U patients.
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  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 observed clinical endpoint in the index family.

- name: Cardiac Sarcomeric and Intercalated-Disc Disorganisation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A structural cardiomyocyte lesion reported only in mice. Deleting Psen1 from the murine
    cardiovascular system produces fewer muscle fibres, widened sarcomeric Z-lines, shortened
    sarcomeres and loosened gap junctions between neighbouring cardiomyocytes, and complete
    Psen1 nullity causes perinatal death with ventricular dilatation and septal defects.

    This node is kept separate from the calcium node and outside the disease's main causal
    chain on purpose. Every observation behind it comes from deleting the gene, and CMD1U is
    a heterozygous missense allele of unknown functional consequence. A knockout phenotype
    tells you what presenilin-1 does in the mouse heart; it does not tell you what Asp333Gly
    does in a human one, and the authors of that work say the mechanism of PSEN1 in
    cardiomyopathy remains unresolved. No downstream edge is drawn from it into the human
    chain for that reason.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28617969
    reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and
      reduced lengths of sarcomeres in cardiomyocytes.
    explanation: >-
      The ultrastructural phenotype of adult cardiac Psen1 deletion in mouse, which is the
      whole basis for this node.
  - reference: PMID:28617969
    reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiovascular loss of function of PSEN1 induced by Sm22a-Cre or Myh6-Cre/ER/tamoxifen
      also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions
      between neighboring cardiomyocytes.
    explanation: >-
      The intercalated-disc component of the same murine phenotype, obtained with
      cardiovascular- and cardiomyocyte-restricted deletion.
  - reference: PMID:28617969
    reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved.
    explanation: >-
      The same authors' own statement of what was unresolved when they began, quoted so this
      node is not read as a mechanism for the human disease. NO_EVIDENCE because the sentence
      reports the absence of a settled mechanism rather than an experimental result for or
      against one.

mechanistic_hypotheses:
- hypothesis_group_id: psen1_calcium_handling_dcm
  hypothesis_label: Presenilin-1 dysfunction causes dilated cardiomyopathy through disturbed cardiomyocyte calcium handling
  status: ALTERNATIVE
  description: >-
    The only mechanistic model proposed for CMD1U: a PSEN1 variant perturbs presenilin-1 in
    the cardiomyocyte, which disturbs sarcoplasmic-reticulum calcium handling - plausibly
    through the presenilin-1/SERCA2a association - and the resulting excitation-contraction
    defect drives dilatation and pump failure.

    It is recorded as ALTERNATIVE, not CANONICAL, because the disease it explains is itself
    disputed. Two supports exist and both fall short of the claim: carrier calcium signalling
    was measured in skin fibroblasts, and the PSEN1/SERCA2a co-immunoprecipitation came from
    idiopathic dilated cardiomyopathy hearts carrying promoter variants rather than the CMD1U
    allele. No cardiomyocyte carrying Asp333Gly has ever been studied.

    The model is nevertheless worth keeping, because it is amyloid-independent and is stated
    as such in the sources. That distinguishes it from the neuronal PSEN1 literature and makes
    it falsifiable: an isogenic D333G human iPSC-cardiomyocyte line with calcium-transient and
    SERCA2a-activity 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, and the
      reason the neuronal amyloid literature is excluded from the entry.
  - reference: PMID:37176125
    reference_title: "Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN1 D333G was transfected into HEK293 cells but did not result in an alteration in the
      Ab42/Ab40 ratio.
    explanation: >-
      The experimental result behind that framing: the CMD1U allele itself does not shift the
      amyloid-beta ratio in a heterologous cell line, which is a negative result against an
      amyloidogenic mechanism rather than positive evidence for a calcium one.
  - reference: PMID:20194882
    reference_title: "Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aβ level was tested by immunohistochemistry in our samples and no difference in Aβ
      expression was present in iDCM compared to controls.
    explanation: >-
      The second negative result against an amyloid mechanism, and the one made in the right
      tissue: amyloid-beta was measured in human dilated-cardiomyopathy myocardium and did not
      differ from controls. Supports this hypothesis by eliminating its competitor rather than by
      demonstrating calcium involvement.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This gene-disease assertion is supported by expression studies
    explanation: >-
      The expert panel's account of what does survive: expression work, which is where the
      myocardial presenilin-1 and SERCA2a results sit. Quoted to show this hypothesis rests on
      the only evidence class ClinGen credits, not 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 CMD1U is a single
    family's cardiomyopathy.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  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 family in which the dilated-cardiomyopathy phenotype defining this locus
      was observed.
  notes: >-
    No frequency band is assigned. The HPO annotations for MONDO:0013371 give this phenotype
    at 100%, but the denominator is the three genotyped affected relatives of one pedigree in
    a single paper; a FrequencyEnum value would present a family observation as a disease-level
    frequency.

- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Symptomatic pump failure following the dilatation, progressing in affected members of the
    index family to cardiac transplantation or death.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  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. Note it says "associated with", which is a
      weaker claim than the locus name implies.
  notes: >-
    No frequency band assigned, for the same reason as the dilated-cardiomyopathy phenotype:
    the only denominator available is a single pedigree.

genetic:

- name: PSEN1
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PSEN1
    term:
      id: hgnc:9508
      label: PSEN1
  association: >-
    PSEN1 encodes presenilin-1, the catalytic subunit of the gamma-secretase intramembrane
    protease. Its relationship with dilated cardiomyopathy was proposed in 2006 on the
    strength of one family carrying Asp333Gly, found in a screen of 315 dilated-cardiomyopathy
    index patients, together with altered calcium signalling in carrier skin fibroblasts.

    That claim has not strengthened in twenty years, and the expert reappraisal went the other
    way. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel first evaluated PSEN1 for
    dilated cardiomyopathy in 2020, re-evaluated it under SOP10 in 2025, and the classification
    did not change: **Disputed**, re-reported March 2026. The panel's reasoning is that the
    reported disease-causing variants turn out to be too common in population reference data
    for a monogenic pathogenic effect, leaving no scorable human genetic evidence, so the
    relationship rests on expression studies alone.

    The relationship is therefore typed DISPUTED rather than CAUSATIVE. That is a deliberate
    departure from the OMIM-defined entity this file curates, which asserts causation; where
    the ontology and the expert panel disagree, this entry follows the panel and says so.

    Disputed is not the same as refuted. The panel's own summary says the evidence neither
    supports nor refutes the role of PSEN1 in dilated cardiomyopathy and that the relationship
    is unclear - so this entry does not claim PSEN1 has been shown not to cause dilated
    cardiomyopathy. It claims the question is open and currently answered against.

    The verdict is specific to the cardiac phenotype. PSEN1's relationship with early-onset
    autosomal dominant Alzheimer disease is not in question and is curated separately in
    dismech, as are PSEN1's roles in cerebral amyloid angiopathy and hidradenitis suppurativa.
  variants:
  - name: PSEN1 p.Asp333Gly
    description: >-
      The founding CMD1U allele. A heterozygous missense substitution replacing a conserved
      acidic aspartate with glycine in the cytoplasmic loop between transmembrane domains six
      and seven, reported in a single family. 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.
  evidence:
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      PSEN1 | HGNC:9508 | dilated cardiomyopathy 1U | MONDO:0013371 | AD | Disputed | 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 PSEN1 variant
      in a cardiomyopathy patient.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Therefore, there is no scorable human genetic evidence.
    explanation: >-
      The panel's conclusion about the genetic evidence specifically, and the reason
      relationship_type is DISPUTED rather than CAUSATIVE.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, the evidence presented for this gene-disease relationship does not provide
      convincing human genetic evidence in support of or refuting the role of PSEN1 and DCM.
    explanation: >-
      Quoted so the Disputed classification is not read as stronger than the source supports.
      The panel explicitly declines to rule the relationship out, which is why this entry
      curates the locus rather than proposing it be discarded.
  - 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 whole of its human
      genetic evidence base.
  - reference: PMID:37176125
    reference_title: "Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mutation was found in an African family in which one family member had AD, while the
      other six affected relatives were diagnosed with an aggressive heart disorder
    explanation: >-
      A later review's description of the index family, showing that the cardiac and the
      Alzheimer phenotypes were reported in different members of the same pedigree. That
      co-occurrence is the historical reason PSEN1 was screened in cardiomyopathy at all, and
      it is also the reason the two literatures are easy to conflate.
  notes: >-
    A separate candidate-gene association study reported a common PSEN1 SNP, rs177415,
    associated with dilated cardiomyopathy susceptibility in a 282-case, 306-control sample
    with an adjusted odds ratio of 1.30. It is not curated as a genetic record here. A single
    small unreplicated candidate-gene association is a different kind of claim from a
    monogenic locus, the effect size is at the edge of significance, and folding it in would
    make the CMD1U evidence base look broader than it is. It is recorded in a discussion
    instead.

external_assertions:
- name: ClinGen PSEN1-dilated cardiomyopathy 1U gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
  description: >-
    The ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal
    dominant PSEN1 - dilated cardiomyopathy 1U relationship as Disputed. The curation is
    against MONDO:0013371 itself, so it is about this entity rather than about dilated
    cardiomyopathy in general. First evaluated 2020, re-evaluated under SOP10 in May 2025 with
    no change, report dated 2026-03-04. Its evidence summary is unusually specific about why:
    the reported disease-causing variants are too common in population reference data, so
    there is no scorable human genetic evidence, and the assertion rests on expression studies.
  evidence:
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      The relationship of PSEN1 with DCM is unclear and therefore classified as disputed.
    explanation: >-
      The panel's conclusion sentence.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      There is a lack of robust human genetic evidence demonstrating this gene-disease
      relationship in the literature at the time of curation.
    explanation: >-
      The specific deficiency the classification rests on, stated separately from the
      population-frequency observation that produced it.
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN1 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM)
      in 2006 (Li et al., 2006, PMID: 17186461).
    explanation: >-
      Confirms that the panel curated the same founding paper this entry is built on, so the
      Disputed verdict and the entry's evidence base are about the same claim.
  notes: >-
    The panel's evidence summary cites the supporting expression study as "Gianni et al., 2010,
    PMID: 2019488". That identifier is one digit short of PMID:20194882, the Gianni 2010
    Circulation paper on protein aggregates and presenilin variants in idiopathic dilated
    cardiomyopathy, which matches the author, year and description exactly. This entry cites
    the full, correct identifier; the truncated form is left as-is inside the quoted snippets
    because a snippet belongs to its source.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous transmission in the single reported family, and the mode of inheritance
    ClinGen curated the disputed relationship under. The founding paper describes complete
    penetrance for the PSEN1 variant, in contrast to partial penetrance for the PSEN2 variant
    at the sibling locus. No penetrance_percentage is recorded: a penetrance statement drawn
    from a handful of adult carriers in one pedigree, 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: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN1 | HGNC:9508 | dilated cardiomyopathy 1U | MONDO:0013371 | AD | Disputed | 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 CMD1U changes this step, and there is no PSEN1-specific
    diagnostic feature: no cardiac imaging, biopsy or biomarker finding distinguishes a PSEN1
    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 PSEN1-specific: no biomarker,
    imaging feature or biopsy finding distinguishes a PSEN1 carrier from any other dilated
    cardiomyopathy, which is itself worth recording because 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 PSEN1 the point is not efficiency but
    interpretation: with the gene-disease relationship classified Disputed, a PSEN1 variant
    found in a dilated-cardiomyopathy proband should not be reported as a molecular diagnosis,
    and cascade testing of relatives on the strength of one is difficult to justify. The value
    of testing such a patient is to find a variant in a gene with real support.

    Whether PSEN1 belongs on an evidence-based dilated-cardiomyopathy panel at all is a live
    question that this entry does not settle.
  evidence:
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PSEN1 | HGNC:9508 | dilated cardiomyopathy 1U | MONDO:0013371 | AD | Disputed | SOP10 |
      Dilated Cardiomyopathy Gene Curation Expert Panel
    explanation: >-
      The classification that governs how much weight a PSEN1 result should carry in this
      setting.

treatments:

- name: Guideline-Directed Heart Failure Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Management of CMD1U is management of dilated cardiomyopathy: there is no PSEN1-directed
    therapy, no trial in this population, and no reason to expect genotype-specific treatment
    while the genotype-phenotype relationship itself is disputed. 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 CMD1U-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: Progressive Systolic Dysfunction and Heart Failure
    description: >-
      Acts on the clinical endpoint, not on the proposed molecular mechanism. Nothing in the
      standard regimen targets presenilin-1 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 PSEN1 - which is the point: no PSEN1-specific regimen
      exists, so the general pathway is the treatment.

- name: Cardiac Transplantation
  therapeutic_modality: SURGERY
  description: >-
    The endpoint intervention for refractory disease, and one that was actually reached in the
    reported family: the founding paper describes progressive disease resulting in the
    necessity of cardiac transplantation or in death.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Progressive Systolic Dysfunction and Heart Failure
    description: >-
      Replaces the failing organ; it does not address the proposed mechanism.
  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: >-
      Records that transplantation was the outcome in the index family, which is the only
      treatment observation that exists for this locus.

- name: Cardiac Surveillance of At-Risk Relatives
  therapeutic_modality: OTHER
  description: >-
    Serial cardiac assessment of first-degree relatives of an affected proband. For a
    late-onset cardiomyopathy this is the intervention with the clearest rationale, because it
    detects dilatation before symptoms.

    Whether surveillance should be triggered by a PSEN1 variant specifically is a different
    question and this entry answers it no: with the relationship Disputed, a PSEN1 result is
    not a basis for genotype-directed surveillance. 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:C15747
      label: Supportive Care
  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: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therefore, there is no scorable human genetic evidence.
    explanation: >-
      The basis for declining to recommend genotype-directed surveillance on a PSEN1 result.
      Surveillance driven by family history is unaffected by this.

- name: Implantable Cardioverter-Defibrillator
  therapeutic_modality: DEVICE
  description: >-
    Device therapy for the arrhythmic risk that accompanies a dilated, poorly contracting
    ventricle. It is included because it is part of dilated-cardiomyopathy management and because
    the guidelines disagree about it: a 2025 systematic review found the criteria for prophylactic
    defibrillator implantation to be one of the areas where dilated-cardiomyopathy guidelines
    vary, along with arrhythmic risk stratification generally.

    Nothing about a PSEN1 result should shift that decision in either direction. There is no
    reported arrhythmic phenotype for this locus and, with the gene-disease relationship disputed,
    no basis for treating a PSEN1 variant as the kind of high-risk genotype - LMNA, FLNC, RBM20 -
    that does modify defibrillator thresholds.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Progressive Systolic Dysfunction and Heart Failure
    description: >-
      Treats the arrhythmic consequence of the failing, dilated ventricle. It modifies neither
      the remodeling nor anything upstream of it.
  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: >-
      Nonetheless, notable areas of variation included the formation of multidisciplinary
      management teams, the role of cascade genetic testing, pathways for arrhythmic risk
      stratification, and the criteria for prophylactic defibrillator implantation.
    explanation: >-
      Establishes that prophylactic defibrillator criteria are contested across
      dilated-cardiomyopathy guidelines, which is why this entry records the intervention without
      asserting a threshold. INDIRECT because the review addresses dilated cardiomyopathy as a
      class, not this locus.

differential_diagnoses:
- name: Dilated Cardiomyopathy 1V
  description: >-
    The PSEN2 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. PSEN2 Ser130Leu was found in two families
    with milder disease, partial penetrance and a more favourable prognosis than the PSEN1
    family. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies PSEN2 for
    dilated cardiomyopathy 1V as Limited - one tier better than PSEN1's Disputed, on the same
    review date. dismech does not yet curate CMD1V.
  distinguishing_features:
  - >-
    Different gene (PSEN2, hgnc:9509) and a milder reported phenotype with partial penetrance.
    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 PSEN2 mutation showed partial penetrance, milder disease, and a more favorable
      prognosis.
    explanation: >-
      The clinical contrast between the two presenilin loci as reported in the paper that
      defined both.

- name: Idiopathic Dilated Cardiomyopathy
  description: >-
    Dilated cardiomyopathy with no identified cause, which is what a CMD1U patient has if the
    PSEN1 attribution is not accepted. This is not an academic alternative: it is the
    diagnosis the ClinGen classification implies for most PSEN1 carriers with the phenotype.
    Notably, the myocardial presenilin-1 work that ClinGen credits as the surviving evidence
    was itself done in idiopathic cases rather than in CMD1U families.
  distinguishing_features:
  - >-
    Absence of a family history or of a segregating variant. Given that no PSEN1 variant is
    currently scorable as genetic evidence, the practical boundary between this and CMD1U is
    the pedigree, not 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 the presenilin cardiac work most often cited for this locus was
      performed in idiopathic, not familial CMD1U, cases - and in a cohort of twenty.

animal_models:
- name: Drosophila dPsn cardiac knockdown and overexpression
  species: Fruit fly
  genotype: Transgenic RNAi knockdown or overexpression of dPsn, the Drosophila presenilin ortholog
  publication: PMID:21524270
  description: >-
    Transgenic flies in which the single Drosophila presenilin ortholog is silenced or
    overexpressed, with cardiac function measured in living adults by optical coherence
    tomography. It was built specifically to ask what presenilin does in the heart after the
    human PSEN1 dilated-cardiomyopathy report, so unlike almost everything else in the presenilin
    literature it is not an Alzheimer model that happens to have a heart.

    Silencing produces an age-dependent increase in end-diastolic dimension - a dilating heart,
    the direction this entity is named for and the direction the mouse knockout does not give -
    together with slowed rate, arrhythmia, myofibril defects and mitochondrial impairment. The
    calcium result is what makes it relevant here: silencing dPsn raises dIP3R and lowers dSERCA
    expression, which is the fly counterpart of the presenilin-SERCA relationship proposed in
    human myocardium.
  modeled_mechanisms:
  - target: Dysregulated Cardiomyocyte Calcium Handling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Links a change in presenilin level to altered expression of the calcium-handling machinery
      and to a dilating, arrhythmic heart in the same animal - the only in vivo system in which
      the calcium arm of this entry's hypothesis and a dilated phenotype have been observed
      together.
    limitations: >-
      The Drosophila heart is a linear contractile tube with no chambers, no valves in the
      mammalian sense and no coronary circulation, so "end-diastolic vertical dimension" is not a
      left ventricular volume and the resemblance to human dilatation is analogical. The
      manipulation is knockdown or overexpression of the whole gene rather than the CMD1U
      missense allele, and it is not even clear which direction models the human variant: the
      authors report opposite cardiac effects for silencing and overexpression. The calcium
      finding is transcript abundance by RT-PCR, not pump activity or a calcium transient, and
      dSERCA is the single fly SERCA rather than the cardiac SERCA2a isoform the human work
      implicates. The paper's own framing is that the mechanism was not understood.
    readouts:
    - name: dSERCA and dIP3R transcript abundance in cardiac cells
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: ALTERED
      interpretation: >-
        The calcium-machinery readout, and the reason this model is attached to this node. The
        two transcripts move in opposite directions under dPsn silencing, so the direction is
        ALTERED rather than INCREASED or DECREASED.
      evidence:
      - reference: PMID:21524270
        reference_title: "Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression;
          overexprerssion of dPsn led to reduced dRyR expression.
        explanation: >-
          The transcript measurements behind this readout, quoted with the source's own
          typography.
    - name: End-diastolic vertical dimension of the adult fly heart
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: INCREASED
      interpretation: >-
        A chamber-dilation analogue measured in a living animal, and the one place in the
        presenilin cardiac literature where reducing presenilin produces dilatation rather than
        the small-ventricle diastolic phenotype of the mouse.
      evidence:
      - reference: PMID:21524270
        reference_title: "Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced
          heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions.
        explanation: >-
          The dimensional measurement and its direction, with the rate change reported alongside
          it.
  evidence:
  - reference: PMID:21524270
    reference_title: "Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data provide novel evidence that changes in presenilin level leads to cardiac
      dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt
      signaling transduction, indicating a pathogenic role for presenilin mutations in DCM
      pathogenesis.
    explanation: >-
      The authors' own conclusion, which is the claim that makes this model informative for this
      entry - and note it names two routes, calcium handling and Wnt signalling, of which only
      the first is curated here because only the first has any human cardiac counterpart.
  - reference: PMID:21524270
    reference_title: "Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms
      accompanied by cardiomyofibril defects and mitochondrial impairment.
    explanation: >-
      The structural and arrhythmic phenotype, recorded because it appears in both directions of
      manipulation - which is part of why the model's fidelity to a specific human missense
      allele is rated LOW.

- name: Cardiovascular-restricted Psen1 conditional knockout mouse
  species: Mouse
  genotype: Psen1 conditional deletion (Sm22a-Cre or Myh6-Cre/ER, tamoxifen-induced); Psen1 null
  publication: PMID:28617969
  genes:
  - preferred_term: Psen1
    term:
      id: hgnc:9508
      label: PSEN1
  description: >-
    A panel of four genetically modified mouse lines deleting Psen1 constitutively or from the
    cardiovascular system and cardiomyocytes in the adult. Null animals die perinatally with
    retarded heart growth, ventricular dilatation, septal defects and valvular thickening;
    adult cardiovascular deletion produces sarcomeric and gap-junction ultrastructural
    abnormalities, spontaneous mortality and diastolic dysfunction.

    This is the only mouse work directed at the PSEN1-cardiomyopathy question rather than at
    Alzheimer disease. It is not a CMD1U model, and the entry does not treat it as one - the
    genes list carries PSEN1 because the lesion really is in that gene, but the lesion is
    deletion, not the CMD1U missense allele.
  modeled_mechanisms:
  - target: Cardiac Sarcomeric and Intercalated-Disc Disorganisation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Deleting Psen1 from the mouse cardiovascular system reproduces a cardiomyocyte
      structural lesion and a functional cardiac deficit, establishing that presenilin-1 is
      required for normal cardiomyocyte architecture in vivo.
    limitations: >-
      Three separate gaps between this model and CMD1U. The allele is a deletion, while CMD1U
      is a heterozygous missense variant whose functional consequence - loss, gain, or neither -
      has never been determined; a knockout therefore cannot be assumed to model it. The
      functional phenotype reported is diastolic dysfunction with decreased left ventricular
      volume, which is not the dilated phenotype the human entity is named for, and the paper
      separately notes ventricular dilatation only in the constitutive null, which dies
      perinatally. And the model was not built on, or tested against, the Asp333Gly allele.
      No claim about the human disease mechanism rests on it.
    readouts:
    - name: Sarcomere Z-line width and sarcomere length in cardiomyocytes
      target: Cardiac Sarcomeric and Intercalated-Disc Disorganisation
      direction: ALTERED
      interpretation: >-
        Structural correlate of the disorganisation node: Z-lines widened and sarcomeres
        shortened in adult Psen1 knockout cardiomyocytes. Direction is ALTERED rather than
        INCREASED or DECREASED because the two measurements move in opposite directions.
      evidence:
      - reference: PMID:28617969
        reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines
          and reduced lengths of sarcomeres in cardiomyocytes.
        explanation: >-
          The reported ultrastructural measurement behind this readout.
    - name: Left ventricular volume at end-systole and end-diastole
      target: Cardiac Sarcomeric and Intercalated-Disc Disorganisation
      direction: DECREASED
      interpretation: >-
        The functional consequence in this model is diastolic dysfunction with reduced
        ventricular volumes. Recorded because it is the opposite direction from the chamber
        dilatation the human entity is defined by, and that divergence is the main reason the
        model's fidelity is rated LOW.
      evidence:
      - reference: PMID:28617969
        reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from
          birth to adulthood and led to diastolic heart dysfunction, including decreased volume
          of the left ventricle at the end-systolic and end-diastolic stages.
        explanation: >-
          The functional phenotype of cardiovascular Psen1 deletion, including the direction of
          the ventricular volume change.
  evidence:
  - reference: PMID:28617969
    reference_title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular
      dilatation, septum defects, and valvular thickening.
    explanation: >-
      Establishes that complete loss of presenilin-1 has a cardiac consequence in vivo, which
      is what makes this model informative about presenilin-1 in the heart at all.

experimental_models:
- name: PSEN1 delta-exon-9 patient iPSC-derived cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:38851626
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: >-
    Cardiomyocytes differentiated from induced pluripotent stem cells of patients carrying the
    PSEN1 exon 9 deletion, compared against isogenic controls. This is the only human
    cardiomyocyte system in which a PSEN1 variant has been studied, and it finds a
    sarcoplasmic-reticulum calcium leak that is not blocked by ryanodine-receptor or
    IP3-receptor inhibition, producing a diastolic calcium buildup near the perinuclear SR and
    less releasable calcium during systole.

    The allele is wrong for this entry. PSEN1 delta-exon-9 is a familial Alzheimer disease
    variant, not the CMD1U Asp333Gly allele, and the patients were ascertained for dementia. So
    this system does not resolve the tissue mismatch that this entry's central hypothesis rests
    on - it narrows it, by showing that a PSEN1 variant can disturb cardiomyocyte calcium in
    human cells, while leaving open whether the CMD1U allele does.
  modeled_mechanisms:
  - target: Dysregulated Cardiomyocyte Calcium Handling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates that a PSEN1 variant produces a specific, mechanistically characterised
      calcium-handling defect in human cardiomyocytes, which is the class of result this node
      needs and has otherwise never had.
    limitations: >-
      Different allele, different disease and different ascertainment: PSEN1 delta-exon-9 causes
      familial Alzheimer disease and these donors were not dilated-cardiomyopathy patients, so
      nothing here shows that Asp333Gly behaves the same way. The defect is an SR leak rather
      than the SERCA2a-uptake failure the human myocardial work implicates, and it left
      electrophysiological properties unchanged, so it is not obviously a route to a dilated
      phenotype. iPSC-derived cardiomyocytes are also immature relative to adult myocardium.
    readouts:
    - name: Sarcoplasmic reticulum calcium leak against isogenic control
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: INCREASED
      interpretation: >-
        The core measurement, made against an isogenic control so the comparison is clean, and
        pharmacologically dissected: the leak survives blockade of both ryanodine and IP3
        receptors, so it is not through either channel.
      evidence:
      - reference: PMID:38851626
        reference_title: "Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca(2+)](i) distribution in human iPSC-derived cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased
          sarcoplasmic reticulum (SR) Ca2+ leak that was resistant to blockage of ryanodine
          receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP3Rs) by 2-ABP.
        explanation: >-
          The leak measurement and the two pharmacological controls that exclude the obvious
          channels.
    - name: Electrophysiological properties of the cardiomyocytes
      target: Dysregulated Cardiomyocyte Calcium Handling
      direction: UNCHANGED
      interpretation: >-
        A negative result worth recording: the calcium leak did not change the cells'
        electrophysiology, so whatever this variant does to a cardiomyocyte it does not do it
        through the action potential.
      evidence:
      - reference: PMID:38851626
        reference_title: "Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca(2+)](i) distribution in human iPSC-derived cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The SR Ca2+ leak did not affect electrophysiological properties of the hiPSC-CMs
        explanation: >-
          The measured absence of an electrophysiological effect.
  evidence:
  - reference: PMID:38851626
    reference_title: "Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca(2+)](i) distribution in human iPSC-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This demonstrates that PSEN1 ΔE9 induced SR Ca2+ leak has specific effects in iPSC-CMs,
      reflecting their unique structural and calcium signaling features.
    explanation: >-
      The authors' conclusion that the leak is a cardiomyocyte-specific effect rather than a
      generic consequence of the variant, which is what makes this system informative for a
      cardiac entry at all. The sentence stating the leak's functional consequence - diastolic
      calcium buildup near the perinuclear SR with less releasable calcium during systole - is
      described in this entry's prose rather than quoted, because its bracketed calcium notation
      is stripped by the reference validator's bracket handling and so cannot be snippet-verified.

discussions:

- discussion_id: psen1_dcm_gene_validity
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is PSEN1 a dilated cardiomyopathy gene at all, or is CMD1U an OMIM locus built on a single
    unreplicated family?
  attaches_to:
  - genetic#PSEN1
  - disease#Dilated Cardiomyopathy 1U
  rationale: >-
    Twenty years after the founding report there is still one family, one paper, and no
    independent pedigree. ClinGen's expert panel has now looked at the evidence three times -
    2020, 2025, 2026 - and each time called it Disputed, on the ground that the reported
    disease-causing variants are too common in population data to be monogenic causes.

    The counter-argument is not nothing. The panel explicitly says its evidence neither
    supports nor refutes the relationship, and the founding pedigree's segregation was real.
    Absence of replication in a locus nobody has looked for since is weak evidence of absence.

    This is recorded as an open controversy rather than resolved in either direction because
    the deciding experiment - a modern population-frequency and case-control reassessment of
    PSEN1 in a large dilated-cardiomyopathy cohort, or a cardiomyocyte model of Asp333Gly -
    has not been done. It matters practically: it determines whether PSEN1 belongs on a
    dilated-cardiomyopathy panel.
  evidence:
  - reference: CGGV:assertion_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
    reference_title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May
      29th, 2025As a result, the classification did not change.
    explanation: >-
      Shows the Disputed verdict survived a fresh review rather than being a stale 2020 call.
      The sentence is quoted as it appears in the ClinGen record, including the missing
      sentence break after the date.
  - reference: PMID:21656036
    reference_title: "Polymorphisms of presenilin-1 gene associate with dilated cardiomyopathy susceptibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette
      smoking, and gender, confirmed the association between that SNP rs177415 of the
      presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669;
      P = 0.039).
    explanation: >-
      The one other line of human evidence connecting PSEN1 to dilated cardiomyopathy, quoted so
      the effect size and the p-value are visible. INDIRECT because a common-variant
      susceptibility signal of this size is a different claim from a monogenic locus and cannot
      settle the controversy in either direction.
  notes: >-
    The rs177415 association above is deliberately confined to this discussion rather than
    curated as a genetic record. Even taken at face value it is a susceptibility signal of small
    effect, not a monogenic locus, and a single unreplicated candidate-gene association at
    P = 0.039 is the genre of finding least likely to survive replication. Curating it as a
    genetic record would make the CMD1U evidence base look broader than it is.
  proposed_experiments:
  - experiment_id: psen1_dcm_case_control_burden
    name: Modern population-frequency and case-control reassessment of PSEN1 in dilated cardiomyopathy
    description: >-
      Genotype PSEN1 across a large sequenced dilated-cardiomyopathy cohort and compare
      variant burden against a matched population reference, testing directly the observation
      the ClinGen classification rests on.
    would_support:
    - pathophysiology#PSEN1 Asp333Gly Missense Variant in Cardiomyocytes
    supporting_outcome:
    - >-
        Excess of rare, conserved PSEN1 missense variants in cases over ancestry-matched
        population controls, with Asp333Gly rare enough to be compatible with a monogenic effect.
    would_refute:
    - pathophysiology#PSEN1 Asp333Gly 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: psen1_dcm_calcium_evidence_tissue_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    The calcium mechanism proposed for CMD1U was measured in skin fibroblasts and in
    non-CMD1U myocardium. Does it hold in a cardiomyocyte carrying Asp333Gly?
  attaches_to:
  - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
  - mechanistic_hypotheses#psen1_calcium_handling_dcm
  rationale: >-
    Every piece of evidence for the calcium mechanism comes from the wrong cell, the wrong
    genotype, or both. Carrier calcium signalling was measured in cultured skin fibroblasts,
    which are not contractile and do not use SERCA2a. The presenilin-1/SERCA2a
    co-immunoprecipitation was done in myocardium from sporadic idiopathic dilated
    cardiomyopathy patients carrying promoter variants, not the CMD1U allele. The oligomer
    calcium experiment perturbed cardiomyocytes with protein oligomers rather than with a
    PSEN1 variant. And the mouse work deletes the gene rather than introducing the missense
    allele, and yields a diastolic, small-ventricle phenotype rather than a dilated one.

    One study comes close and is worth being precise about. PSEN1 delta-exon-9 patient
    iPSC-derived cardiomyocytes, compared against isogenic controls, show a
    sarcoplasmic-reticulum calcium leak - the right cell type, a clean genetic comparison, and a
    dissected mechanism. But delta-exon-9 is a familial Alzheimer disease allele, not Asp333Gly,
    and the donors were dementia patients. It therefore narrows the mismatch rather than
    resolving it: a PSEN1 variant can disturb calcium in a human cardiomyocyte, which was not
    previously shown, but nothing says this variant does.

    This is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap because the evidence is
    not absent - five distinct experimental results exist and each is internally sound. What
    is missing is any demonstration that they compose into the human disease mechanism in the
    relevant cell and genotype.
  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: >-
      Names the tissue in which the carrier calcium phenotype was actually observed, which is
      the mismatch this discussion is about.
  - reference: PMID:38851626
    reference_title: "Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca(2+)](i) distribution in human iPSC-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial
      Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart
      diseases.
    explanation: >-
      Establishes what this study's donors were: patients with an Alzheimer-causing PSEN1 allele.
      Quoted here rather than a result sentence because the allele is the whole reason the study
      narrows this mismatch without closing it.
  proposed_experiments:
  - experiment_id: psen1_d333g_ipsc_cardiomyocyte_calcium
    name: Isogenic PSEN1 Asp333Gly human iPSC-cardiomyocyte calcium phenotyping
    description: >-
      Introduce Asp333Gly 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 and SERCA2a activity, together with contractility.
    would_support:
    - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
    supporting_outcome:
    - >-
        Altered calcium transient kinetics and reduced sarcoplasmic-reticulum calcium handling
        in the Asp333Gly cardiomyocytes relative to the isogenic control, with impaired
        contractility.
    would_refute:
    - pathophysiology#Dysregulated Cardiomyocyte Calcium Handling
    refuting_outcome:
    - >-
        Calcium transients, sarcoplasmic-reticulum load and contractility indistinguishable from
        the isogenic wild-type control.

- discussion_id: psen1_cardiac_phenotype_breadth
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the cardiac phenotype reported for PSEN1 dilated at all, given that the most recent
    case report describes hypertrophic cardiomyopathy?
  attaches_to:
  - phenotypes#Dilated Cardiomyopathy
  rationale: >-
    A 2026 case report describes a heterozygous PSEN1 variant in a man with nonobstructive
    hypertrophic cardiomyopathy and later ventricular fibrillation, framed by its authors as
    expanding the cardiac phenotype of PSEN1. That is a different variant and a different
    cardiomyopathy - hypertrophic, not dilated - so it is no evidence for CMD1U and is not
    curated as such.

    It is recorded because it bears on how the whole PSEN1 cardiac literature should be read.
    When single case reports attach a gene to hypertrophic cardiomyopathy, dilated
    cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy exome cohorts in turn,
    each on tiny numbers, the pattern is more consistent with a much-sequenced gene accruing
    incidental variants than with a coherent cardiac disease entity. That reading is the same
    one ClinGen's population-frequency argument arrives at from a different direction.
  evidence:
  - reference: PMID:42236188
    reference_title: "Hypertrophic Cardiomyopathy and Sudden Cardiac Arrest Associated with a PSEN1 Variant: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      This report suggests an expansion of the phenotypic spectrum associated with PSEN1
      variants and highlights the need for further investigation of potential cardiac
      manifestations in PSEN1 variant carriers.
    explanation: >-
      The report's own claim, quoted to show what it does and does not establish. INDIRECT
      because the phenotype is hypertrophic cardiomyopathy in a carrier of a different variant,
      so it speaks to the breadth of PSEN1 cardiac claims rather than to CMD1U.

notes: >-
  **Separating the cardiac from the amyloid literature.** PSEN1 is one of the most-studied
  genes in medicine and almost none of that work is about this disease. dismech already curates
  PSEN1 in Alzheimer Disease, Early-Onset Autosomal Dominant Alzheimer Disease, Cerebral Amyloid
  Angiopathy and Hidradenitis Suppurativa; none of those is this entity, and the ClinGen
  Disputed verdict applies to this one only. Three specific decoys were identified and
  excluded: APP/PS1 double-transgenic mouse cardiac studies, which are Alzheimer models
  carrying a familial-AD PSEN1 allele plus mutant APP and report diastolic rather than dilated
  dysfunction; Alzheimer-cardiovascular shared-genetics and Mendelian-randomisation literature,
  which is population-genetic overlap rather than a monogenic cardiac entity; and neuronal
  gamma-secretase mechanism work generally. Every citation in this file was checked to be about
  heart tissue, heart cells, or a cardiomyopathy cohort. Two results in the cited sources argue
  against carrying amyloid biology across at all: myocardium from idiopathic dilated
  cardiomyopathy patients showed no difference in amyloid-beta from controls, and Asp333Gly did
  not shift the Abeta42/Abeta40 ratio when expressed in HEK293 cells.

  **Independent check on the ClinGen frequency argument.** The panel states that variants
  reported as disease-causing are too frequent in population reference data. Looked up directly
  in gnomAD v4 through the public API on 2026-08-31, PSEN1 p.Asp333Gly is present at an exome
  allele frequency of 2.1e-05 and a genome allele frequency of 2.3e-04 - roughly one carrier in
  a few thousand, which is far too common for a fully penetrant dominant cause of a rare
  cardiomyopathy. The neighbouring PSEN1 p.Glu318Gly, which the Gianni study also found in an
  idiopathic case, sits at 1.8 per cent and is a common polymorphism. These lookups are 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 PSEN1-specific exists for any of them.

  No phenotype beyond dilated cardiomyopathy and heart failure. The reason is narrower than "no
  frequency data": the two curated phenotypes are each backed by an exact quote from the Li 2006
  abstract, and that abstract - which is all the cache holds, the publisher blocking full text -
  mentions neither ejection fraction nor electrocardiography. HP:0012664 and HP:0003115 appear in
  the HPO annotations for MONDO:0013371 and in the deep-research report, but no cached source
  states them in words that could be quoted, and the HPO annotation itself traces to the same
  three-relative pedigree.

  The general dilated-cardiomyopathy and heart-failure sources that are cited - the guideline
  systematic review and the 2022 heart failure guideline - are used only where the claim really is
  about the disease class (what the workup consists of, what the treatment pathway is, that
  defibrillator criteria are contested) and are marked INDIRECT throughout. No general-class
  source is used to make a claim about PSEN1.

  The rs177415 candidate-gene association is cited in a discussion rather than curated as a
  genetic record.

  **Sibling locus.** stubs/Dilated_Cardiomyopathy_1V.yaml (PSEN2, MONDO:0013373) is open and
  shares this entry's entire primary evidence base - same paper, same screen - differing in
  ClinGen verdict (Limited rather than Disputed) and in penetrance. It is a natural companion
  and was left for a separate PR rather than folded in here.

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:28617969
  title: "Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction."
- reference: PMID:37176125
  title: "Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease."
- reference: PMID:42236188
  title: "Hypertrophic Cardiomyopathy and Sudden Cardiac Arrest Associated with a PSEN1 Variant: A Case Report."
- reference: PMID:21524270
  title: "Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction."
- reference: PMID:21656036
  title: "Polymorphisms of presenilin-1 gene associate with dilated cardiomyopathy susceptibility."
- reference: PMID:38851626
  title: "Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca(2+)](i) distribution in human iPSC-derived cardiomyocytes."
- 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_d71e8591-dece-4855-ae6c-d43e20cbf836-2026-03-04T170000.000Z
  title: "PSEN1 / dilated cardiomyopathy 1U (Disputed)"

📚

References & Deep Research