Still gathering sources: checking which LDB3 papers are already cached here before searching the web.

Reading the rest of the OMIM text for CMD1C and LDB3, then searching for the mouse and functional studies.

Research report: Dilated Cardiomyopathy 1C (CMD1C; LDB3/ZASP/Cypher)

Date compiled: 2026-10-08. Target: MONDO:0011094, dilated cardiomyopathy 1C.

Before using this report: - The gene–disease link is weak. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel rates LDB3 as Limited for dominant DCM. It rates the recessive, loss-of-function form (DCM 2L, a separate entry) as Strong. The 2026 ClinGen reassessment (PMID:42708185) says so, and both ClinGen records are already cached in this repository. - Two PMIDs are often swapped. Vatta 2003 is PMID:14662268. Arimura 2004 is PMID:14660611. - Ontology IDs. The only CURIEs below are ones I confirmed this session from the draft entry, the ClinGen ingest file or the ClinGen cache. Every other ontology term is a label only. Look each one up (runoak or cache/*/terms.csv) before binding it. - Quotes. Abstract quotes were taken from PubMed efetch output, which a summarizing model relayed. Before using any of them as a snippet:, check it against the cached reference with just fetch-reference and just count-verified-snippets. - What is already cached. Of the papers below, only these are in references_cache/: PMID:15668942, 17097056, 42708185, 27532257, 30980206, 31771441, 33802723, 39337275, the two ClinGen records, and the GeneReviews DCM overview (NBK1309). Everything else needs fetching.

1. Disease information

Overview. CMD1C is an autosomal dominant dilated cardiomyopathy, with or without left ventricular noncompaction (LVNC). It is attributed to heterozygous missense variants in LDB3, the gene for ZASP/Cypher. That protein is a PDZ–LIM scaffold at the sarcomeric Z-disc in heart and skeletal muscle.

OMIM #601493 is titled "Cardiomyopathy, dilated, 1C, with or without left ventricular noncompaction". The same OMIM entry also covers: - LVNC3 (left ventricular noncompaction 3) - CMH24 (familial hypertrophic cardiomyopathy 24)

The OMIM clinical synopsis lists: - Heart: left ventricular dilation; noncompaction, hypertrophy or a sigmoid septum in some patients; congestive heart failure; ventricular arrhythmia and sudden cardiac death in some patients. - Biopsy: moderate to marked myocyte hypertrophy, mild to moderate endocardial fibrosis, and focal myocyte disarray.

Identifiers

Synonyms: CMD1C; dilated cardiomyopathy 1C with or without LVNC; LDB3-related (ZASP-related, Cypher-related) dilated cardiomyopathy; zaspopathy (cardiac form).

Source type. All of this information comes from published families and cohorts and from disease-level resources (OMIM, ClinGen). No EHR or registry-derived data exist.

Sources: OMIM 601493 mirror; Disease Ontology DOID:0110423.

2. Etiology

Causal factor. Heterozygous germline missense variants in LDB3 (OMIM .0004–.0006, .0009) are the cause.

Vatta et al. 2003 (PMID:14662268) screened 100 probands with left ventricular dysfunction and found five missense mutations in six of them. None of the mutations was present in 200 controls. Their quoted result: "Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM." Their conclusion: "These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis." - OMIM summarizes the carriers as 2 with DCM alone and 4 with DCM plus LVNC. One secondary source describes the cohort differently, so confirm the split against the full text.

How strong is the gene–disease evidence?

The 2026 ClinGen reassessment (PMID:42708185, cached) states: "Four previously evaluated genes were curated for both AD and AR MOIs: JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong)."

Variants that have been questioned. - D117N (OMIM .0007) did not segregate with disease in Bedouin families and is common in the population (Levitas 2016, PMID:26419279). The quoted conclusion: "our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation". - The population-scale reassessment of cardiomyopathy genes (Walsh 2017, PMID:27532257, cached) is the expected source for the absence of a case excess for LDB3. I have not checked its full text for an LDB3-specific figure.

Risk and modifier factors. - LDB3 polymorphisms have been studied as modifiers of clinical presentation and ICD outcomes (Wang 2019, PMID:31379146). This is association data only. - Oligogenic cases. One young-onset DCM case with sudden cardiac death carried LDB3 p.M456R together with MYH6 and SYNE1 variants (Zhao 2021, PMID:33949037). Separately, one Barth syndrome family carried a TAZ variant and an LDB3 variant together (Marziliano 2007, PMID:17394203). - Environmental risk factors. None are documented. - Protective factors. None are documented. - Gene–environment interactions. None are documented. One case report describes subtle cardiac involvement in LDB3-related myopathy that was unmasked after COVID-19 (Gadaleta 2025, PMID:40626683). This is anecdotal.

3. Phenotypes

The evidence comes from small family series, so frequencies are only qualitative ("some patients", per OMIM).

Quality of life. No LDB3-specific data exist. Burden follows the usual course of DCM: heart failure symptoms (NYHA class), arrhythmia, ICD shocks and transplantation.

4. Genetic and molecular information

Gene. LDB3, also called ZASP, CYPHER or KIAA0613; hgnc:15710; OMIM 605906. - The protein has an N-terminal PDZ domain, an internal ZASP-like motif (ZM, which binds actin) and three C-terminal LIM domains (which bind PKC). - Alternative splicing produces short isoforms without LIM domains and long isoforms with them, in cardiac-specific and skeletal-specific classes (Huang 2003, PMID:12499364).

Variants. HGVS numbering differs between OMIM and RefSeq: OMIM's S196L is p.Ser189Leu on NM_007078, and T213I is Thr206Ile.

• Variant type: missense, germline.
• Proposed effect: gain of function or altered binding (D626N increases PKC affinity), not haploinsufficiency. Heterozygous parents of the biallelic loss-of-function cases appear unaffected (PMID:36253531; PanelApp Australia), which argues against haploinsufficiency as the dominant mechanism.
• ClinVar. Classifications are mostly VUS or conflicting; p.Ser189Leu has 13 submissions (ClinVarMiner).
• Not established: gnomAD frequencies for each variant (I did not retrieve them), epigenetic contributions, and any chromosomal abnormality.

5. Environmental information

There are no known environmental, lifestyle or infectious causes. The general DCM cofactors (alcohol, cardiotoxic chemotherapy, myocarditis, pregnancy) would plausibly unmask disease, but no LDB3-specific study supports this. If the entry needs an environmental: block, mark it uncited.

6. Mechanism and pathophysiology

Causal chain (each step marked demonstrated or inferred):

1. A heterozygous LDB3 missense variant changes ZASP/Cypher in the PDZ region, the exon 4 region (S189L, T206I) or the LIM region (D626N). (Human genetics, PMID:14662268.)
2. This alters ZASP's protein interactions:
3. (2a) D626N increases LIM-domain affinity for PKC. Quote: "the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C" (PMID:14660611, in vitro).
4. (2b) S189L and T206I reduce binding of PGM1. Quote: "ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress" (PMID:19377068, in vitro).
5. (2c) ZASP is an A-kinase anchoring protein (AKAP) that is phosphorylated by PKA at Ser265 and Ser296 (PMID:23996002). DCM variants may disturb PKA signalling (phosphoproteomics, PMID:34966794).
6. This leads to Z-disc and cytoskeletal disorganization. Transfected mutant ZASP produced cytoskeletal disarray (PMID:14662268, in vitro). Knockout mice show fragmented Z-lines: Cypher "functions as a linker-strut to maintain cytoskeletal structure during contraction" (PMID:11696561, mouse).
7. This leads to impaired force transmission and maladaptive stress signalling in cardiomyocytes. Cardiac knockouts show increased ERK and Stat3 activity (PMID:19028670). Loss of the long isoforms disturbs calcineurin–NFAT and PKC signalling (PMID:21303826). Cypher deficiency destabilizes F-actin and impairs MRTFA–SRF-driven cardiomyocyte maturation (PMID:39113806). Knockdown causes apoptosis through Akt/p38 MAPK (PMID:32922198, in vitro). These are mostly loss-of-function models; applying them to dominant missense variants is an inference.
8. Branch, electrical: ZASP sits in a complex with cardiac ion channels. S196L knock-in mice develop "cardiac conduction defects and atrioventricular block" (PMID:20852297), which leads to arrhythmia and sudden death.
9. Branch, developmental (inferred): abnormal compaction of the ventricular myocardium leads to LVNC. Cypher and its homolog ENH are needed for cardiac development (PMID:25944877, mouse).
10. Cardiomyocyte loss, hypertrophy and fibrosis lead to LV dilation and systolic dysfunction (DCM), which leads to heart failure.

Suggested terms (labels only; verify IDs). - GO: sarcomere organization; Z disc (cellular component); actin filament organization; protein kinase C binding; protein kinase A binding; cardiac muscle contraction; regulation of cardiac conduction. - CL: cardiac muscle cell (cardiomyocyte); skeletal muscle fiber, for MFM4. - Molecular profiling: no CMD1C omics datasets were found. One forensic RNA-seq study reported abnormal LDB3 splicing in sudden cardiac death (PMID:31419596).

7. Anatomy

• Primary site: heart, specifically the left ventricular myocardium and the interventricular septum.
• Secondary site: skeletal muscle in the allelic spectrum.
• Tissue and cell level: cardiac muscle tissue and cardiomyocytes.
• Subcellular level: Z disc, I band, costamere.
• Distribution: cardiac involvement is global, biventricular or left-dominant. Myopathy in MFM4 is bilateral and distal-predominant.

8. Timing

• Onset: variable, from childhood to late adulthood. D626N was a late-onset familial case (PMID:14660611).
• Course: insidious onset, chronic, and progressive into heart failure.
• Remission: no spontaneous remission. Remodelling may partly reverse on guideline-directed medical therapy (GDMT); there are no LDB3-specific data.
• Contrast with the recessive form: biallelic loss of function (DCM 2L) causes severe disease in infancy and childhood, sometimes in the fetus, and is often lethal (PMID:36253531).

9. Inheritance and population

• Inheritance: autosomal dominant with incomplete, age-dependent penetrance and variable expression (DCM, LVNC or HCM within the same allelic group).
• Prevalence: unknown. LDB3 is a rare contributor to DCM. The 6% yield in Vatta's cohort was not replicated in later large studies, which is reflected in the Limited classification.
• Founder effects: the founder haplotype reported for LDB3 belongs to the A165V distal myopathy (PMID:17337483), not to CMD1C.
• Population data: probands have been reported from US, Japanese, Chinese and Bedouin populations. No sex ratio data exist.

10. Diagnostics

Clinical workup - Echocardiography and cardiac MRI (LV dilation, LVEF, noncompaction ratio, late gadolinium enhancement) - ECG and Holter monitoring (conduction disease, ventricular arrhythmia) - NT-proBNP - Creatine kinase (CK) and neurological examination to screen for myopathy - Endomyocardial biopsy is rarely needed

Genetic testing - Use a multigene DCM panel or exome sequencing. LDB3 is on most panels but is rated amber for DCM on Genomics England PanelApp (PanelApp). - Report heterozygous LDB3 missense variants cautiously. Most are VUS, and the dominant gene–disease link is Limited.

Differential diagnosis - Other dilated cardiomyopathies (TTN, LMNA, RBM20, FLNC, BAG3) - Isolated LVNC (MYH7, MIB1) - ACTN2- and MYPN-related Z-disc cardiomyopathies - Myofibrillar myopathies (DES, CRYAB, MYOT, FLNC) - Barth syndrome

Screening: cascade screening of relatives with imaging and ECG, and genotyping only when the variant is classified actionable. GeneReviews' DCM overview (NBK1309, cached) is the general baseline.

11. Outcome and prognosis

There are no LDB3-specific survival data. Risks are those of DCM in general: progressive heart failure, ventricular arrhythmia, sudden cardiac death and transplantation. Severe early cases with sudden death have been reported (PMID:33949037). Without an LDB3-specific series, prognostic factors default to general DCM markers: LVEF, LGE scar and non-sustained VT.

12. Treatment

Care follows standard heart failure guidelines. There is no LDB3-targeted therapy. NCIT labels below are to be verified.

• Gene, RNA and cell therapies: none.
• Clinical trials: none specific to LDB3.
• Pharmacogenomics: none specific to LDB3.

13. Prevention

• Primary prevention: not applicable beyond preimplantation or prenatal options, which are rarely justified given the Limited evidence.
• Secondary prevention: cascade clinical surveillance of first-degree relatives.
• Tertiary prevention: GDMT, ICD to prevent sudden death, and avoidance of cardiotoxins and excess alcohol (general DCM advice).

14. Other species

• No naturally occurring LDB3 cardiomyopathy appears in the material I reviewed. I did not search OMIA.
• Orthologs: mouse Ldb3 (Cypher); zebrafish ldb3a/b (not reviewed); Drosophila Zasp52 (knockdown work, PMID:19603185; Zasp regulates integrin activation, PMID:22992465).

15. Model organisms

Main limitation. Almost all models remove the gene, which matches the recessive DCM 2L disorder. Only the S196L mouse tests a dominant CMD1C missense allele, and no iPSC model of a CMD1C allele has been published. This is a natural HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion for the entry.

Implications for the dismech entry

1. Draft description. The current text, "associated with heterozygous LDB3 variants", should state the ClinGen Limited (AD) classification. Copy it into gene_disease_validity from the cached CGGV record; don't assign it yourself.
2. The cached record (CGGV:assertion_7756e3c0-…-2025-03-21T040000.000Z) is mapped to the generic DCM term MONDO:0005021.
3. The ingest file instead shows a 2026-03-04 record mapped to MONDO:0011094, this entry's own disease term.
4. Fetch or rebuild that newer record before citing it.
5. Scope. Keep DCM 2L (biallelic loss of function) out of this entry or link it as a separate disease. HCM (CMH24) and LVNC3 are the same OMIM entry. A has_subtypes block, or notes covering the allelic spectrum, would fit.
6. References to fetch: PMID:14662268, 14660611, 19377068, 20852297, 11696561, 19028670, 21303826, 26419279, 16427346, 23996002, 39113806, 36253531.

Sources

• Vatta et al. 2003, JACC, PMID:14662268 — UMN record
• OMIM #601493 (mirror); OMIM *605906 LDB3 (mirror)
• Disease Ontology DOID:0110423
• GenCC submission
• ClinGen DCM GCEP 2026 reassessment, Circulation, PMID:42708185 (cached)
• Koopmann et al., biallelic LDB3 loss (PMC9823012), PMID:36253531
• PanelApp Australia, LDB3; Genomics England PanelApp, LDB3
• ClinVarMiner, p.Ser189Leu
• bioRxiv 2025 preprint, LDB3 in an Indian DCM cohort (not peer-reviewed)
• PubMed abstracts retrieved through NCBI E-utilities, cited by PMID throughout.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:22992465 (1 mention) - Zasp regulates integrin activation.
• shared terms: zasp

Weighed against this report's own most characteristic terms: dcm, ldb3, cardiac, disease, lvnc, ventricular, cmd1c, cached, cypher, gene, heart, death, dominant, variant, zasp, clingen, failure, sudden, missense, myopathy.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

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:

• DOID:0110423 (6 mentions) - the report calls it "Disease Ontology"; DOID calls it dilated cardiomyopathy 1C
• MONDO:0979236 (1 mention) - the report calls it "DCM 2L"; MONDO calls it cardiomyopathy, dilated, 2l

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:0016587 (1 mention) - the report calls it "ARVC"; MONDO calls it arrhythmogenic right ventricular cardiomyopathy, and lists "ARVD" among its other names

Prefixes with no resolver

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