Dilated Cardiomyopathy 1M (CMD1M; MONDO:0011840): Research Report

Prepared 2026-10-08 for the dismech entry kb/disorders/Dilated_Cardiomyopathy_1M.yaml.

Provenance and limits. - Quoted text. The abstract quotes for PMID:12507422, PMID:14567970, PMID:18505755, PMID:30681346, PMID:39132495 and PMID:38666070 come from the repository's own references_cache/ files. They are safe to use as snippets. - Paraphrased text. Claims attributed to PMID:9039266, PMID:20044516, PMID:19412328, PMID:10555147 and PMID:31406109 were paraphrased from web search results. None of these is cached yet. Run just fetch-reference and take the quote from the cache before using any of them as evidence. - ClinGen. The ClinGen DCM curation was read from the live ClinGen website (assertion dated 2026-03-04). It is not in the local cache. - Ontology IDs. The repo rule is "never write a CURIE from memory". Every ontology CURIE below is marked as either confirmed, meaning seen in a source during this research, or verify, meaning it must be checked with a lookup before binding.

Executive summary: the entity is weakly supported

CMD1M is an OMIM provisional phenotype. It is listed as "?Cardiomyopathy, dilated, 1M" (MIM:607482) and attributed to heterozygous variants in CSRP3. CSRP3 encodes muscle LIM protein (MLP), on chromosome 11p15.1.

The DCM association is weak, while the same gene's association with hypertrophic cardiomyopathy is Definitive:

The ClinGen DCM curation scores 0.4 genetic points: - Hershberger 2008 p.Gly72Arg; Trachoo 2022 p.Glu191Lys; Zimmerman 2010 p.Ala50Thr and p.Thr179Ala, at 0.1 each. - Mohapatra 2003 p.Lys69Arg scored 0, as a possible phenocopy. - Case–control data from Walsh 2017 and Mazzarotto 2020 scored 0, because neither showed enrichment of CSRP3 variants in DCM cases.

It scores 3.5 experimental points, from the MLP-knockout mouse (Arber 1997) and the T-cap interaction defect (Knöll 2002). ClinGen's conclusion is that "there is limited convincing genetic evidence that has directly implicated this gene in human disease" and that "More evidence is needed to support the relationship of CSRP3 and AD DCM."

One web search result (a GenCC summary) said the 2025 re-evaluation changed the tier to "no known disease relationship". The live ClinGen report contradicts this: it says the tier stayed Limited. Use ClinGen.

The founding variant, W4R (p.Trp4Arg), is a common European polymorphism. It occurs in up to ~1% of Caucasians and in gnomAD heterozygotes, including at least one homozygote. Two studies weaken it as a cause of DCM: - It did not segregate with DCM in the Mohapatra 2003 family (PMID:14567970). - Geier et al. 2008 found it at similar rates in DCM cases (3/652), HCM cases (2/354) and controls (2/533) (PMID:18505755 era work, reported via OMIM and PanelApp).

Genomics England PanelApp lists CSRP3 as red (low evidence) for DCM.

Curation implications: 1. A gene_disease_validity assertion of LIMITED, classified_by: CLINGEN, AD, with the ClinGen DCM assertion ID. Run just clingen-rebuild --id <CGGV id> first so it can be cited. 2. Keep relationship_type off CAUSATIVE. CAUSATIVE means Definitive or Strong, and just check-gene-validity would flag it as overstated. 3. A KNOWLEDGE_GAP discussion on whether CMD1M exists as a distinct Mendelian DCM. 4. Much of the mechanistic and model literature is DCM in the knockout mouse, while human CSRP3 disease is mainly HCM. That is a HUMAN_MODEL_MISMATCH.

1. Disease information

• Definition. Autosomal dominant dilated cardiomyopathy attributed to heterozygous missense variants in CSRP3/MLP, a Z-disc and costamere LIM-only protein involved in sensing cardiomyocyte stretch. Clinically it is non-syndromic DCM: left ventricular dilation and systolic dysfunction leading to heart failure.
• Identifiers:
• MONDO:0011840 "dilated cardiomyopathy 1M" (confirmed: existing YAML and ClinGen).
• OMIM #607482, provisional "?" (confirmed).
• Gene: CSRP3, OMIM 600824, hgnc:2472* (confirmed, ClinGen).
• Not verified: a separate Orphanet code (likely only the umbrella "familial isolated DCM"), and ICD-10 I42.0 for dilated cardiomyopathy.
• Synonyms. CMD1M; Cardiomyopathy, dilated, 1M; CSRP3-related dilated cardiomyopathy; MLP-related DCM.
• Allelic disorder. Hypertrophic cardiomyopathy 12 (CMH12, MIM:612124) is caused by CSRP3 and is better established.
• Data basis. Aggregated disease-level resources (OMIM, ClinGen) and small case series. There are no EHR cohorts.

2. Etiology

• Causal factor. Heterozygous germline CSRP3 missense variants. The reported variants are W4R, K69R, G72R, A50T, T179A and E191K.
• Genetic risk and modifiers. W4R behaves as a common, low-penetrance or benign variant in humans. In mice it causes dose-dependent cardiomyopathy (PMID:20044516). Variants in interaction partners have been proposed as modifiers or co-contributors, but this is unproven:
• TCAP (hgnc:11610): ClinGen rates it Disputed for HCM (cached CGGV c35abc20).
• ACTN2: Mohapatra reported an ACTN2 Q9R variant that disrupts MLP binding.
• Environmental factors. No specific exposures are documented. In mice, catecholamine stress reveals the W4R phenotype ("lost almost all contractile reserve"; PMID:20044516, paraphrased). This is a model-level gene–environment interaction, plausibly relevant to adrenergic load in humans. It is an inference, not demonstrated in humans.
• Protective factors. None documented in humans. In mice, removing phospholamban rescued MLP−/− DCM (PMID:10555147). That is a genetic rescue in the mouse, not a protective human variant.

3. Phenotypes

The human data come from roughly 10 or fewer probands, so frequencies cannot be estimated.

Quality of life: no CMD1M-specific data. DCM-related heart failure generally lowers NYHA class and health-related quality of life.

4. Genetic and molecular information

• Gene. CSRP3 at 11p15.1, 6 exons spanning ~20 kb (Knöll 2002, via OMIM). It encodes a 194-aa protein with two LIM domains, expressed only in striated muscle.

Variants reported in DCM:

• Classification. ClinVar treats CSRP3 DCM variants mostly as VUS. One ClinVar record notes that "loss of function of CSRP3 has not been clearly established as a mechanism of disease".
• Origin and mechanism. All reported variants are germline. The functional class is unclear:
• Partial loss of function or destabilisation: reduced MLP protein in W4R mice; HCM mutants destabilised (PMID:18505755).
• Interaction loss: T-cap, α-actinin-2.
• In schema terms, PARTIAL_LOSS_OF_FUNCTION is the most defensible category, labelled as inferred.
• Inheritance across the CSRP3 spectrum. Biallelic CSRP3 truncating variants cause adult HCM (6 reported cases; PMID:38666070). ClinGen accordingly curates CSRP3–HCM as semi-dominant (PMID:39132495).
• Not reported. Epigenetic or chromosomal mechanisms: none.

5. Environmental information

None reported. No infectious, toxic or lifestyle causes. Adrenergic and pressure stress unmask the phenotype in model systems only (section 2).

6. Mechanism and pathophysiology

Causal chain:

1. A heterozygous CSRP3 missense variant (e.g. W4R in the N-terminus; K69R next to LIM1) leads to reduced MLP abundance or stability and/or loss of binding to partners: T-cap/telethonin at the Z-disc (W4R; PMID:12507422) and α-actinin-2 (K69R; PMID:14567970). Demonstrated in vitro and in mice. In-patient protein destabilisation has been shown only for HCM variants.
2. The loss of the Z-disc MLP/T-cap complex impairs cardiomyocyte mechanical stretch sensing. Knöll 2002: "a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery" (PMID:12507422; MLP−/− mice and cells).
3. Defective stretch-responsive signalling and cytoarchitecture result in cytoskeletal and sarcomeric disorganisation and abnormally compliant myocardium. In MLP−/− mice, newborn hearts are "abnormally soft" with "dramatic disruption of cardiomyocyte cytoarchitecture" before hypertrophy (PMID:9039266, paraphrase). Increased nuclear localisation of the mutant protein may change transcriptional co-regulation (W4R mice; PMID:20044516). This is inferred.
4. Branch: calcium cycling. Chronic phospholamban–SERCA2a inhibition in the MLP-deficient heart drives progressive dilation; phospholamban ablation rescues it (PMID:10555147; mouse). MLP-null human ESC-derived cardiomyocytes show abnormal Ca²⁺ handling (PMID:31406109).
5. These changes lead to eccentric remodelling and LV dilation with systolic dysfunction (DCM), and then heart failure. In humans, the outcome depends on genotype and context: the same pathway more often gives HCM (PMID:18505755), and W4R mice and MLP-null hESC-cardiomyocytes develop HCM-like phenotypes. That is the central human–model mismatch.

Suggested terms: - GO processes (verify): cellular response to mechanical stimulus (GO:0071260); sarcomere organization (GO:0045214); regulation of calcium ion transport / regulation of the force of heart contraction; cardiac muscle hypertrophy. - GO cellular components: Z disc (GO:0030018, verify); costamere; nucleus. - Cell type: cardiac muscle cell / cardiomyocyte (CL:0000746, verify). - Proteins: MLP/CSRP3 (hgnc:2472, confirmed); T-cap/TCAP (hgnc:11610, confirmed); α-actinin-2/ACTN2 (verify); β-spectrin and zyxin are also reported partners. - Molecular profiling: no CMD1M-specific transcriptomic or proteomic datasets were found. RNA-seq exists for Mlp-C58G knock-in mice, an HCM variant model (Oxford Cardioscience).

7. Anatomical structures

• Primary: heart, left ventricle (UBERON:0002084 heart left ventricle, verify), myocardium, endocardium (EFE case).
• Secondary: possibly skeletal muscle (mild myopathy, HCM and mouse data); systemic effects of heart failure.
• Subcellular: Z-disc, costamere, sarcolemma, nucleus.
• Laterality: bilateral or global ventricular involvement.

8. Temporal development

• Onset. Adult in most reports; one paediatric DCM/EFE case (K69R).
• Course. Progressive, from insidious systolic dysfunction to symptomatic heart failure. No staging or natural history specific to CMD1M exists; use DCM/heart-failure staging (ACC/AHA A–D). In mice the W4R phenotype is age- and dose-dependent.

9. Inheritance and population

• Inheritance. Autosomal dominant, as asserted by OMIM and ClinGen (HP:0000006 Autosomal dominant inheritance, verify).
• Penetrance. Low or incomplete: W4R in controls and failure to segregate. Expressivity is variable across the DCM and HCM spectrum.
• Prevalence. Unknown, and extremely rare if the entity is real. The W4R allele is up to ~1% in Europeans, so population carrier frequency greatly exceeds disease frequency, which argues against high penetrance.
• Not reported: founder effects, anticipation, sex bias, consanguinity role.

10. Diagnostics

• Imaging and function: echocardiography or cardiac MRI for LV dilation and reduced EF; ECG and Holter for arrhythmia; NT-proBNP or BNP as a heart-failure biomarker.
• Genetic testing: DCM multigene panels or exome sequencing.
• CSRP3 is on many DCM panels but should not be reported diagnostically for DCM at a Limited classification.
• Variants should be interpreted against gnomAD frequency. W4R is too common to be causal on its own.
• Exclude Definitive/Strong DCM genes first: TTN, LMNA, MYH7, TNNT2, RBM20, FLNC, BAG3, DSP and others (Jordan et al. 2021, Circulation).
• Differential diagnosis:
• CSRP3-HCM (CMH12) progressing to a burnt-out, dilated phase.
• Other genetic DCMs.
• Ischemic, myocarditic, toxic (alcohol, anthracycline) and peripartum DCM.
• Left ventricular noncompaction.
• Screening: cascade echocardiographic screening of first-degree relatives, as for any familial DCM.

11. Outcome and prognosis

There are no CMD1M-specific survival data. Expect the course of non-ischemic DCM: risk of heart failure progression, ventricular arrhythmia, sudden death and transplantation. Prognostic markers are generic: LVEF, LGE on cardiac MRI, NYHA class, natriuretic peptides.

12. Treatment

All treatment is standard guideline-directed DCM and heart-failure therapy. Nothing is genotype-specific.

Pharmacotherapy. Suggested NCIT treatment term: Pharmacotherapy NCIT:C15986, which CLAUDE.md lists. Suggested agents (CHEBI IDs must be looked up): - β-blockers (e.g. carvedilol, metoprolol, bisoprolol) - ACE inhibitor, ARB, or sacubitril/valsartan - Mineralocorticoid receptor antagonists (spironolactone, eplerenone) - SGLT2 inhibitors (dapagliflozin, empagliflozin) - Diuretics

Devices and surgery: - ICD and CRT: bind to a clinical-action term such as Surgical Procedure NCIT:C15329, with the device carried as a qualifier, per the repo's device convention. - Heart transplantation (Organ Transplantation, NCIT:C15289).

Other: Genetic Counseling (NCIT:C15240).

Experimental: no CSRP3-targeted trials. Phospholamban/SERCA2a modulation is a preclinical concept from the MLP−/− rescue (PMID:10555147). The SERCA2a gene-therapy trials (CUPID) were not CSRP3-specific.

13. Prevention

• Primary: none.
• Secondary: cascade family screening and surveillance echocardiography.
• Tertiary: guideline-directed therapy and ICD for sudden-death prevention.
• Counseling: genetic counseling should state the weak gene–disease validity, and that predictive testing for CSRP3 DCM variants is not clinically actionable.

14. Other species and natural disease

No naturally occurring CSRP3-linked cardiomyopathy was found in OMIA during this search (OMIA not queried directly).

Orthologs: mouse Csrp3 (MGI:1330824, from OMIM's links) and zebrafish csrp3 (ZFIN ZDB-GENE-041010-119). MLP is conserved across vertebrates as a muscle LIM protein.

15. Model organisms

Key quotable abstract snippets (verified in references_cache/)

• PMID:12507422 (Knöll 2002, MODEL_ORGANISM/IN_VITRO, with a human variant):
• "a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization"
• "We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure."
• PMID:14567970 (Mohapatra 2003):
• "We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R)." (HUMAN_CLINICAL)
• "the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered" (IN_VITRO)
• REFUTE for W4R causality: "In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family."
• Background quote: "An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure."
• PMID:18505755 (Geier 2008): "Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations."
• PMID:39132495 (ClinGen HCM reappraisal): "CSRP3 was curated for a semi-dominant mode of inheritance (definitive)."
• PMID:38666070: "biallelic PTVs in CSRP3 are seemingly associated with HCM in adults (based on six reported cases)"

Sources

• ClinGen CSRP3 gene page and the CSRP3–DCM 1M Limited report (2026-03-04)
• Local cache: references_cache/CGGV_assertion_012b9b15… (CSRP3–HCM Definitive), CGGV_assertion_c35abc20… (TCAP–HCM Disputed), PMID_12507422, PMID_14567970, PMID_18505755, PMID_30681346, PMID_39132495, PMID_38666070, PMID_27532257
• OMIM *600824 CSRP3 (mirror)
• GenCC CSRP3 submission; its "no known relationship" claim conflicts with ClinGen
• PanelApp Australia – CSRP3, DCM panel
• Knöll 2010, A Common MLP Variant Is Associated With Cardiomyopathy (PMID:20044516)
• Arber 1997 MLP-knockout mouse (PMID:9039266), MGI record
• Minamisawa 1999 phospholamban rescue (PMID:10555147)
• Hershberger 2008 (PMID:19412328)
• Li 2019 MLP-deficient hESC-cardiomyocytes (PMID:31406109)
• Indian DCM cohort, CSRP3 preprint (medRxiv 2021)
• Mlp-C58G knock-in RNA-seq (Oxford)
• Jordan et al. 2021 ClinGen DCM gene assessment (UCL Discovery)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

Terms the report names something else

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

• HP:0001635 (1 mention) - the report calls it "verify"; HP calls it Congestive heart failure
• HP:0001706 (1 mention) - the report calls it "verify"; HP calls it Endocardial fibroelastosis
• HP:0001712 (1 mention) - the report calls it "verify"; HP calls it Left ventricular hypertrophy

Terms whose name is worth a second look

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

• MONDO:0011840 (3 mentions) - the report calls it "CSRP3 – dilated cardiomyopathy 1M"; MONDO calls it dilated cardiomyopathy 1M
• MONDO:0005045 (1 mention) - the report calls it "CSRP3 – hypertrophic cardiomyopathy"; MONDO calls it hypertrophic cardiomyopathy

Prefixes with no resolver

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