Dilated Cardiomyopathy 1C

Mendelian MONDO:0011094 Pathograph 21 Show in embeddings browser Dilated Cardiomyopathy Left Ventricular Noncompaction Hypertrophic Cardiomyopathy

Dilated cardiomyopathy 1C (CMD1C) is the autosomal dominant cardiomyopathy attributed to heterozygous missense variants in LDB3, which encodes ZASP (Cypher), a PDZ-LIM scaffold protein of the sarcomeric Z-disc in cardiac and skeletal muscle. The MONDO concept (MONDO:0011094; OMIM 601493) spans three allelic presentations: dilated cardiomyopathy with or without left ventricular noncompaction (CMD1C), left ventricular noncompaction (LVNC3), and hypertrophic cardiomyopathy (CMH24). The founding screen found five LDB3 missense variants in six of 100 probands with left ventricular dysfunction. Later reports added a late-onset familial D626N allele and Z-disc variants in hypertrophic cardiomyopathy probands. Cell and biochemical studies show that disease alleles disarrange the cytoskeleton and change ZASP binding to protein kinase C and phosphoglucomutase 1. A transgenic mouse expressing the S196L allele develops conduction defects and later ventricular dysfunction. The evidence base is small: ClinGen classifies the autosomal dominant LDB3-CMD1C relationship as Limited, rates LDB3 as Disputed for hypertrophic cardiomyopathy, and one reported allele (D117N) failed to segregate with disease. Biallelic loss-of-function LDB3 disease (dilated cardiomyopathy 2L) and LDB3 myofibrillar myopathy (zaspopathy) are separate entities.

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Inheritance

Autosomal dominant HP:0000006

Heterozygous missense alleles are reported in familial and sporadic cases. Segregation evidence is thin. In the D626N dilated cardiomyopathy family all affected siblings tested carried the variant. The D117N allele failed to segregate in two Bedouin families. One healthy heterozygous carrier is reported: the father of a Barth syndrome proband who also carried a TAZ variant transmitted the LDB3 T350I allele and is healthy, although he shows prominent left ventricular trabeculation. No study counts unaffected and affected carriers of a disease-associated allele, so penetrance is recorded as UNKNOWN.

Autosomal dominant inheritance Penetrance: UNKNOWN

Show evidence (4 references)

PMID:14660611 SUPPORT Human Clinical

"A family study of the patient showed that all affected siblings tested had the same mutation."

Co-occurrence of the heterozygous allele with disease in affected sibs is the strongest segregation datum in the cached record.

PMID:17394203 SUPPORT Human Clinical

"and one of paternal origin in the LDB3 gene"

The proband's LDB3 variant (T350I) was inherited from his father. The allele name in square brackets is left out because the validator treats square brackets as an editorial insertion.

PMID:17394203 SUPPORT Human Clinical

"The mother, brother and father are healthy; although the latter two show prominent left ventricle trabeculation without dysfunction."

The LDB3-carrying father is healthy, apart from trabeculation without dysfunction, so at least one heterozygous carrier is unaffected. This supports incomplete or age-dependent penetrance, but one carrier does not give a rate.

+ 1 more reference

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Subtypes

Dilated cardiomyopathy 1C, with or without left ventricular noncompaction

LDB3 hgnc:15710

The dilated presentation: left ventricular dilation with systolic dysfunction, with or without noncompaction. It carries the founding Vatta alleles and the late-onset Japanese D626N family. It has no separate term because it is the primary sense of MONDO:0011094, the entry's own disease term.

Show evidence (2 references)

PMID:14662268 SUPPORT Human Clinical

"Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM."

The founding screen identified LDB3 variants in probands with dilated cardiomyopathy or noncompaction. The cached abstract does not split the six probands between the two presentations.

PMID:14660611 SUPPORT Human Clinical

"A D626N mutation located within the third LIM domain was identified in a familial case but not found in the unrelated controls."

A second, independent dilated cardiomyopathy family carrying a heterozygous LDB3 LIM-domain variant.

Left ventricular noncompaction 3

LDB3 hgnc:15710

The noncompaction presentation. The founding screen included probands with isolated noncompaction, and the D626N allele seen in a Japanese dilated cardiomyopathy family was also found in two Japanese noncompaction families. No separate MONDO term exists for this presentation.

Show evidence (2 references)

PMID:16427346 SUPPORT Human Clinical

"A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC."

Documents the same LDB3 allele in families with noncompaction, showing that one allele can produce both the dilated and the noncompaction presentation.

PMID:14662268 SUPPORT Human Clinical

"These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis."

The founding report includes isolated noncompaction in the LDB3 spectrum.

Cardiomyopathy, familial hypertrophic, 24

LDB3 hgnc:15710

The hypertrophic presentation. It has no separate disease term because "cardiomyopathy, hypertrophic, 24" is an exact MONDO synonym of MONDO:0011094 itself. It rests on rare LDB3 variants in myofilament-negative hypertrophic cardiomyopathy probands. ClinGen rates LDB3 as Disputed for hypertrophic cardiomyopathy (see discussions).

Show evidence (2 references)

PMID:17097056 SUPPORT Human Clinical

"Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated Z-disc mutations involving residues highly conserved across species and absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1), and VCL (2)."

Six of 239 myofilament-negative hypertrophic cardiomyopathy probands carried rare LDB3 variants. Segregation was not reported in the abstract.

CGGV:assertion_1089e729-07ab-4d5b-8fed-1a2ad3f37fd2-2026-01-27T170000.000Z REFUTE Other

ClinGen's hereditary cardiovascular disease panel classifies LDB3 for hypertrophic cardiomyopathy (MONDO:0005045) as Disputed, which cuts against LDB3 as a cause of this presentation. It is a different MONDO term from this entry, so it is not recorded as gene-disease validity.

Discussions and Knowledge Gaps

Do dominant LDB3 missense alleles act through the same pathways that knockout mice reveal?

HUMAN MODEL MISMATCH OPEN dominant_mechanism_unresolved

Attached to

pathophysiology#Maladaptive Cardiomyocyte Stress Signalling pathophysiology#Z-Disc Cytoskeletal Disorganization animal_models#Global Cypher knockout mouse animal_models#Cardiac-specific Cypher knockout mouse

Nearly all mechanistic mouse work deletes Cypher or its isoforms. That matches recessive LDB3 disease. Heterozygous loss-of-function carriers in the recessive families were reported as asymptomatic. The one human allele tested biochemically for PKC binding (D626N) increases binding rather than removing it. The only allele-specific mouse is a transgenic overexpressor. So the signalling and Z-disc nodes are carried over from loss-of-function models, and no heterozygous knock-in or patient iPSC model tests them.

Show evidence (2 references)

PMID:36253531 SUPPORT Human Clinical

"suggesting that heterozygous missense variants in the LDB3 gene may be more deleterious than heterozygous loss-of-function variants in this gene."

Heterozygous loss-of-function carriers in the recessive families were asymptomatic (one set of parents declined examination). The authors infer that dominant disease is not simple haploinsufficiency.

PMID:14660611 SUPPORT In Vitro

"It was demonstrated by both assays that the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C"

Yeast two-hybrid and pull-down assays show the allele changes PKC binding directly.

Should the CMH24 hypertrophic presentation remain inside this concept when ClinGen disputes LDB3 for hypertrophic cardiomyopathy?

CONTROVERSY OPEN hcm_presentation_disputed

Attached to

has_subtypes#CMH24 phenotypes#Hypertrophic cardiomyopathy

MONDO lists cardiomyopathy, hypertrophic, 24 as an exact synonym of MONDO:0011094, so the entry keeps it. The supporting data are case-only: six LDB3 carriers among 239 myofilament-negative probands, with no segregation in the abstract. ClinGen's hereditary cardiovascular panel classified LDB3 for hypertrophic cardiomyopathy as Disputed in January 2026.

Show evidence (2 references)

CGGV:assertion_1089e729-07ab-4d5b-8fed-1a2ad3f37fd2-2026-01-27T170000.000Z SUPPORT Other

The current ClinGen tier for LDB3 in hypertrophic cardiomyopathy.

PMID:17097056 SUPPORT Human Clinical

The case-only evidence behind CMH24.

Which reported dominant LDB3 alleles are truly pathogenic?

CONTROVERSY OPEN variant_level_doubt

Attached to

genetic#LDB3

The D117N allele was first reported in two sporadic cases. It did not segregate in two Bedouin families. It was found on 11 of 210 Bedouin chromosomes (5.2%, an allele frequency, all heterozygous). The M456R case also carried MYH6 and SYNE1 variants. Most LDB3 missense variants on clinical panels are of uncertain significance, which fits the Limited classification.

Show evidence (3 references)

PMID:26419279 SUPPORT Human Clinical

"However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations."

Direct segregation evidence against one allele.

PMID:26419279 SUPPORT Human Clinical

"Eleven out of 210 chromosomes (5.2%) were found to carry p.(D117N) (all in heterozygous state)."

The variant is too common in the source population to cause a rare dominant disease.

PMID:33949037 SUPPORT Human Clinical

"The multiple heterozygous mutations of SYNE1, LDB3, and MYH6 may be associated with young and early-onset of DCM and SCD."

The LDB3 contribution cannot be separated from co-occurring variants.

Do CMD1C patients have subclinical skeletal myopathy, and how many zaspopathy patients develop cardiomyopathy?

KNOWLEDGE GAP OPEN cardiac_skeletal_overlap

Attached to

genetic#LDB3 differential_diagnoses#Myofibrillar myopathy 4

LDB3 causes both this cardiomyopathy and a dominant myofibrillar myopathy, curated separately in Myofibrillar_Myopathy. Cardiac involvement was found in 3 of 11 myopathy patients. The founding cardiac cohort measured muscle creatine kinase, but the cached abstract does not report the result. No cited study examined skeletal muscle systematically in cardiac probands. The two entries therefore overlap at the gene level without a measured shared-phenotype rate.

Show evidence (2 references)

PMID:15668942 SUPPORT Human Clinical

"We therefore searched for mutations in ZASP in 54 MFM patients and detected 3 heterozygous missense mutations in 11."

Denominator for the myopathy cohort (11 carriers, 3 with cardiac involvement).

PMID:14662268 SUPPORT Human Clinical

"In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement."

CK was measured in the cardiac cohort, but the result is not in the abstract.

How do heterozygous LDB3 variants produce noncompaction rather than, or as well as, dilation?

KNOWLEDGE GAP OPEN lvnc_mechanism_unknown

Attached to

phenotypes#Left ventricular noncompaction

The same D626N allele was reported with late-onset dilated cardiomyopathy in one family and with noncompaction in two others. No study explains how the variant affects trabecular compaction, so the edge to noncompaction is recorded with unknown intermediates.

Show evidence (1 reference)

PMID:16427346 SUPPORT Human Clinical

"A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC."

Same allele, different presentation.

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Pathophysiology

LDB3 Heterozygous Missense Variant

Mechanism confidence: Provisional

A heterozygous germline missense variant in LDB3 alters ZASP/Cypher, a Z-disc scaffold that binds alpha-actinin through its PDZ domain and protein kinase C through its C-terminal LIM domains. Reported alleles cluster in the cardiac-preferred exons 4 and 10 (S196L/S189L, T213I/T206I, I352M/I345M) or in the third LIM domain (D626N). Whether these act by gain of function, dominant interference or partial loss is unresolved, so the functional impact is recorded as UNKNOWN. Heterozygous loss-of-function carriers in the recessive families were reported as asymptomatic, which argues against simple haploinsufficiency.

Cardiomyocyte CL:0000746

LDB3 hgnc:15710

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN

protein kinase C binding GO:0005080 ⚠ ABNORMAL muscle alpha-actinin binding GO:0051371

Z disc GO:0030018

Downstream

Altered ZASP Signalling-Partner Binding Disease alleles change ZASP binding to protein kinase C (D626N, increased) and to phosphoglucomutase 1 (exon 4 and 10 alleles, reduced).

Z-Disc Cytoskeletal Disorganization Cells transfected with mutant ZASP show cytoskeletal disarray. The steps between the variant and the disarray are not defined.

Disturbed Cardiomyocyte Ion Currents In a transgenic mouse, cardiac expression of S196L ZASP altered L-type calcium and sodium currents. ZASP complexes with both channels.

Left ventricular noncompaction Heterozygous LDB3 variants are associated with noncompaction, but no study describes how they disturb ventricular compaction.

Hypertrophic cardiomyopathy Rare LDB3 variants are reported in hypertrophic cardiomyopathy probands. How a Z-disc variant would produce hypertrophy is not described. Whether LDB3 causes hypertrophic cardiomyopathy at all is disputed (see the CMH24 subtype and discussions).

Show evidence (4 references)

PMID:14662268 SUPPORT Human Clinical

"These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis."

The founding report's conclusion that LDB3 variants cause the disease.

PMID:19377068 SUPPORT BACKGROUND Human Clinical

"Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3 and both exons were expressed preferentially in the heart."

Places the reported dilated cardiomyopathy alleles in cardiac-preferred exons. This is the paper's framing of earlier human reports.

PMID:11696561 SUPPORT In Vitro

"In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components."

Grounds the alpha-actinin binding function of the normal protein at the Z-line.

+ 1 more reference

Altered ZASP Signalling-Partner Binding

Mechanism confidence: Provisional

Disease alleles change which partners ZASP holds at the Z-disc. D626N in the third LIM domain increases binding to protein kinase C. The exon 4 alleles S189L and T206I, and I345M in exon 10, reduce binding to phosphoglucomutase 1 (PGM1). Under stress, ZASP normally anchors PGM1 at the Z-disc. All of this comes from binding assays and cultured cardiomyocytes, not from patient tissue.

Cardiomyocyte CL:0000746

LDB3 hgnc:15710

protein kinase C binding GO:0005080 ↑ INCREASED

Downstream

Maladaptive Cardiomyocyte Stress Signalling Proposed link: changed PKC binding by the LIM domains could disturb PKC signalling. The only in vivo support is that mice lacking the LIM-containing long isoforms show PKC pathway changes. That is a deletion model, not a missense allele.

Left Ventricular Dilation and Systolic Dysfunction Both binding studies propose that the binding change contributes to dilated cardiomyopathy. Neither tests it in the heart.

Show evidence (2 references)

PMID:14660611 SUPPORT In Vitro

"It was demonstrated by both assays that the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C"

Yeast two-hybrid and pull-down assays show the allele changes PKC binding directly.

PMID:19377068 SUPPORT In Vitro

"Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another mutation in exon 10 (Ile345Met) reduced the binding to PGM1."

Binding assays show three dilated cardiomyopathy alleles reduce PGM1 binding.

Z-Disc Cytoskeletal Disorganization

Mechanism confidence: Provisional

ZASP is not needed to build the Z-disc but keeps it intact during contraction, acting as a linker-strut. Mutant ZASP disarranges the cytoskeleton of transfected cells. Loss of Cypher in mice fragments and disorganizes Z-lines in heart and skeletal muscle. No patient myocardium with a dominant CMD1C allele has been examined at this level in the cited sources.

Cardiomyocyte CL:0000746

sarcomere organization GO:0045214 ⚠ ABNORMAL

Z disc GO:0030018

Animal models

Global Cypher knockout mouse Mouse partially recapitulates Z-line maintenance fails without Cypher.

Downstream

Left Ventricular Dilation and Systolic Dysfunction In mice, cardiac loss of Cypher disrupts cardiomyocyte ultrastructure and produces dilated cardiomyopathy. The link from Z-disc failure to chamber dilation is shown only in loss-of-function models.

Maladaptive Cardiomyocyte Stress Signalling In Cypher-deficient mouse hearts, the Z-line defect comes with changed ERK, Stat3, calcineurin-NFAT, PKC and actin-MRTFA-SRF signalling.

Show evidence (2 references)

PMID:14662268 SUPPORT INDIRECT In Vitro

"In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP."

Transfection overexpresses the mutant protein in cultured cells, so this is an inference about the heterozygous heart, not a direct observation in patient myocardium.

PMID:11696561 SUPPORT INDIRECT Model Organism

"Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function."

Knockout mice define the normal Z-line maintenance role. They are a null model, closer to recessive LDB3 disease than to CMD1C.

Maladaptive Cardiomyocyte Stress Signalling

Mechanism confidence: Hypothetical

Cypher-deficient mouse hearts show several signalling changes: more ERK and Stat3 activity, abnormal calcineurin-NFAT and PKC signalling when the long isoforms are lost, and, through F-actin destabilization, less MRTFA-SRF driven cardiomyocyte maturation. These are all deletion models. Whether a heterozygous missense allele engages the same pathways in the human heart has not been tested, so the node is HYPOTHETICAL for CMD1C.

Cardiomyocyte CL:0000746

cardiomyocyte maturation GO:0055007 ⚠ ABNORMAL

Animal models

Cardiac-specific Cypher knockout mouse Mouse measures ERK and Stat3 signalling increase.

Cypher long-isoform knockout mouse Mouse partially recapitulates Calcineurin-NFAT and PKC pathway changes come before cardiomyopathy.

Downstream

Left Ventricular Dilation and Systolic Dysfunction The knockout studies propose that these pathways help drive progression to heart failure.

Show evidence (3 references)

PMID:19028670 SUPPORT Model Organism

"In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were augmented."

Signalling change in cardiac knockout mice.

PMID:39113806 SUPPORT Model Organism

"Mechanistically, Cypher deficiency resulted in the destabilization of F-actin and a notable increase in G-actin levels, thereby impeding the nuclear localisation of myocardin-related transcription factor A (MRTFA)"

Actin-MRTFA-SRF signalling defect in Cypher-depleted mouse cardiomyocytes.

PMID:39113806 SUPPORT Model Organism

"Cypher deletion led to impaired sarcomere isoform switch and morphological abnormalities in mitochondria, transverse-tubules, and intercalated discs."

Grounds the abnormal cardiomyocyte maturation annotation in Cypher-deleted mouse hearts.

Disturbed Cardiomyocyte Ion Currents

Mechanism confidence: Hypothetical

ZASP sits in a complex with the L-type calcium channel Cav1.2 and the sodium channel Nav1.5. In transgenic mice with cardiac expression of S196L, isolated cardiomyocytes have altered L-type calcium and sodium currents, and the mice develop conduction defects and atrioventricular block by 3 months. Human electrophysiological data for this mechanism are lacking.

Cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ⚠ ABNORMAL

Animal models

S196L transgenic mouse Mouse recapitulates Altered calcium and sodium currents in mutant cardiomyocytes.

Downstream

Ventricular arrhythmia The S196L model study proposes that altered channel complexes explain conduction defects and arrhythmia in LDB3 cardiomyopathy. No human electrophysiological study tests this.

Show evidence (2 references)

PMID:20852297 SUPPORT In Vitro

"The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca(v)1.2) and sodium (Na(v)1.5) channels."

Biochemical evidence that ZASP sits in an ion-channel complex.

PMID:20852297 SUPPORT Model Organism

"Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block."

In this model the conduction defects come before ventricular dysfunction.

Left Ventricular Dilation and Systolic Dysfunction

Mechanism confidence: Established

The defining tissue lesion of the dilated presentation: left ventricular enlargement with reduced systolic function. Probands were found by screening patients with left ventricular dysfunction. In the D626N family the disease came on late.

Cardiomyocyte CL:0000746

heart contraction GO:0060047 ↓ DECREASED

Left ventricle UBERON:0002084

Animal models

Cardiac-specific Cypher knockout mouse Mouse partially recapitulates Cardiac loss of Cypher is enough to cause dilated cardiomyopathy.

Cypher long-isoform knockout mouse Mouse partially recapitulates Late-onset course resembles the dominant human disease better than full deletion.

S196L transgenic mouse Mouse partially recapitulates Later onset of ventricular dysfunction after the conduction defect.

Downstream

Dilated cardiomyopathy Left ventricular dilation with systolic dysfunction is the clinical definition of dilated cardiomyopathy.

Show evidence (2 references)

PMID:14662268 SUPPORT Human Clinical

"We identified and screened 100 probands with left ventricular dysfunction."

The founding probands were ascertained for left ventricular dysfunction.

PMID:14660611 SUPPORT Human Clinical

"Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy."

Late-onset dilated cardiomyopathy in a D626N family.

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Pathograph

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

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Phenotypes

Dilated cardiomyopathy Cardiovascular HP:0001644

Sequelae: Congestive heart failure

Show evidence (2 references)

PMID:14662268 SUPPORT Human Clinical

"Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM."

Dilated cardiomyopathy in LDB3 variant carriers.

PMID:14660611 SUPPORT Human Clinical

"Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy."

Late-onset dilated cardiomyopathy in a D626N family.

Left ventricular noncompaction Cardiovascular HP:0030682

Show evidence (2 references)

PMID:16427346 SUPPORT Human Clinical

"A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC."

Noncompaction in four D626N carriers from two families.

PMID:14662268 SUPPORT Human Clinical

"These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis."

The founding report includes isolated noncompaction in the LDB3 spectrum.

Hypertrophic cardiomyopathy Cardiovascular HP:0001639

Sequelae: Ventricular septal hypertrophy

Show evidence (1 reference)

PMID:17097056 SUPPORT Human Clinical

Six LDB3 variant carriers among 239 hypertrophic cardiomyopathy probands.

Ventricular septal hypertrophy Cardiovascular HP:0005144

Show evidence (1 reference)

PMID:17097056 SUPPORT INDIRECT Human Clinical

"In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology."

Group-level finding for Z-disc hypertrophic cardiomyopathy. It is not broken down for LDB3 carriers alone.

Congestive heart failure Cardiovascular HP:0001635

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Heart failure. Symptoms include those of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion)."

General dilated cardiomyopathy synthesis from GeneReviews. No LDB3-specific heart failure series exists.

Ventricular arrhythmia Cardiovascular HP:0004308

Sequelae: Sudden cardiac death

Show evidence (1 reference)

PMID:33949037 SUPPORT Human Clinical

"In a Chinese Han family, the patient of 24 years old occurred with early-onset and DCM and died of SCD associated with ICD storms induced by repetitive ventricular tachycardia/fibrillation (VT/F)."

Ventricular tachycardia and fibrillation in a carrier of LDB3 p.M456R together with MYH6 and SYNE1 variants. It cannot be assigned to LDB3 alone.

Sudden cardiac death Cardiovascular HP:0001645

Show evidence (2 references)

PMID:20852297 SUPPORT BACKGROUND Human Clinical

"We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death."

The mouse paper's background recalls the human S196L family with sudden death. "LBD3" is the source's typo for LDB3.

PMID:33949037 SUPPORT Human Clinical

"The multiple heterozygous mutations of SYNE1, LDB3, and MYH6 may be associated with young and early-onset of DCM and SCD."

Oligogenic case; LDB3 is one of three candidate contributors.

🧬

Genetic Associations

LDB3 (Heterozygous missense variants; ClinGen Limited (autosomal dominant) for dilated cardiomyopathy 1C)

Gene: LDB3 hgnc:15710 gene page variant_origin: GERMLINE

Show evidence (2 references)

PMID:42708185 SUPPORT REVIEW SYNTHESIS Other

"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)."

The ClinGen expert panel's published summary of the split LDB3 classifications.

PMID:14662268 SUPPORT Human Clinical

"Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM."

Founding human genetic evidence.

💊

Medical Actions

Guideline-directed heart failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Standard heart failure therapy for symptomatic or asymptomatic left ventricular systolic dysfunction. No LDB3-specific trial or case series exists.

Mechanism Target:

Congestive heart failure — Treats heart failure; does not address the Z-disc lesion.

Show evidence (2 references)

PMID:35379503 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients."

General heart failure guideline, applied by extrapolation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"permit initiation of medical therapy aimed at preventing/delaying the morbidity of late-stage symptomatic disease"

GeneReviews supports early medical therapy in genetic dilated cardiomyopathy generally.

Implantable cardioverter-defibrillator

Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Considered for sudden death prevention under general cardiomyopathy criteria.

Mechanism Target:

Sudden cardiac death — Prevents arrhythmic death; does not modify the cardiomyopathy.

Show evidence (1 reference)

PMID:33949037 SUPPORT INDIRECT Human Clinical

"In a Chinese Han family, the patient of 24 years old occurred with early-onset and DCM and died of SCD associated with ICD storms induced by repetitive ventricular tachycardia/fibrillation (VT/F)."

Context only: an ICD was implanted in an LDB3 variant carrier with malignant arrhythmia. It did not prevent death, and the case is oligogenic, so it gives no LDB3-specific evidence of benefit.

Heart transplantation

Action: Heart Transplantation NCIT:C15246

Platform: Surgery

Option for end-stage heart failure under general criteria.

Mechanism Target:

Congestive heart failure — Replaces the failing heart.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counsel families on autosomal dominant inheritance, the Limited gene-disease classification, and the uncertainty of any one LDB3 missense variant. Offer cardiac surveillance of at-risk relatives.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"It is appropriate to clarify the clinical and genetic status of asymptomatic family members at risk for DCM prior to the onset of manifestations"

General GeneReviews family guidance for dilated cardiomyopathy.

🔬

Diagnosis

Cardiac imaging

Echocardiography or cardiac MRI measures left ventricular size and systolic function, shows noncompaction, and grades septal hypertrophy and contour.

Echocardiography Test NCIT:C16525

Show evidence (2 references)

PMID:14662268 SUPPORT Human Clinical

"Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination."

Clinical workup used in the founding cohort.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Enlargement is most commonly assessed in adults by either echocardiography or cardiac MRI."

General GeneReviews guidance on imaging in dilated cardiomyopathy.

Electrocardiography

Resting ECG, and Holter monitoring where indicated, to detect conduction disease and ventricular arrhythmia. The arrhythmia risk is suggested by the S196L family and the mouse model, but is not quantified in humans.

Electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:14662268 SUPPORT Human Clinical

"Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination."

ECG was part of the founding cohort's workup.

Creatine kinase screening for skeletal muscle involvement

Muscle creatine kinase was measured in the founding cohort to look for skeletal muscle involvement, since LDB3 is also a myofibrillar myopathy gene. The cached abstract does not report the result.

Creatine Kinase Measurement NCIT:C64489

Show evidence (1 reference)

PMID:14662268 SUPPORT Human Clinical

"In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement."

CK screening was part of the founding protocol.

Multigene cardiomyopathy panel or exome sequencing

LDB3 is tested on cardiomyopathy panels and exomes. Because ClinGen rates the dominant relationship as Limited, and one previously reported allele (D117N) did not segregate, report a heterozygous LDB3 missense variant with caution and test segregation in the family.

Genetic Testing NCIT:C15709

Show evidence (2 references)

CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z SUPPORT Other

The Limited tier is why a single LDB3 variant is weak diagnostic evidence.

PMID:26419279 SUPPORT Human Clinical

"However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations."

A reported LDB3 allele failed segregation, so segregation testing is needed.

Cascade screening of relatives

Clinical cardiac screening of first-degree relatives, with genetic testing when the familial variant is actionable. This is general dilated cardiomyopathy guidance, not LDB3-specific.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome"

General GeneReviews guidance for families with dilated cardiomyopathy.

📈

Progression

Adult-onset, progressive dilated disease

CMD1C Age: Mostly adult; late onset in the D626N family, age 24 at death in one oligogenic case

No LDB3-specific natural-history series exists. The D626N family had late onset. The oligogenic M456R case was 24 at sudden death. In general dilated cardiomyopathy, carriers may be asymptomatic for years before heart failure or arrhythmia.

Show evidence (2 references)

PMID:14660611 SUPPORT Human Clinical

"Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy."

Late onset in the D626N family.

PMID:36253531 SUPPORT BACKGROUND Human Clinical

"Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans."

Background summary of the dominant LDB3 phenotype as late-onset.

📊

Prevalence

Published LDB3 cardiomyopathy reports

Cases In Literature Ultra Rare

The cited primary reports describe about 16 heterozygous index cases. These are 6 probands from the founding 100-proband screen, 1 Japanese dilated cardiomyopathy family (D626N, from 96 patients), 2 Japanese noncompaction families (D626N, found in four members of two families with LVNC), 6 hypertrophic cardiomyopathy probands from 239 screened, and 1 oligogenic case that also carried MYH6 and SYNE1 variants. Two further LDB3 carriers are reported outside these counts: a Barth syndrome proband with a TAZ variant plus paternal LDB3 T350I, and one ARVC family (c.1051A>G), a disease ClinGen disputes for LDB3. The D117N allele was later shown not to segregate. It was first reported in two sporadic cases. The cached abstracts do not say whether those were among the founding six probands, so up to 2 of the ~16 index cases may rest on a refuted allele. Whether the two D626N noncompaction families are related to the D626N dilated family is not stated. GeneReviews attributes under 1% of dilated cardiomyopathy to LDB3. No population prevalence has been measured.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"LDB3 AD <1% Limited HCM; myofibrillar myopathy"

The GeneReviews gene table row for LDB3: autosomal dominant, under 1% of dilated cardiomyopathy, ClinGen Limited, allelic with hypertrophic cardiomyopathy and myofibrillar myopathy.

PMID:14662268 SUPPORT Human Clinical

"Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM."

The largest single set of index cases in the literature.

🔀

Differential Diagnoses

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

Dilated cardiomyopathy 2L Not Yet Curated MONDO:0979236

Overlapping Features The recessive LDB3 disease: biallelic loss-of-function variants cause severe dilated cardiomyopathy in infancy, childhood or the fetus, sometimes with noncompaction and myopathy. ClinGen rates it Strong (AR). It is a separate concept and not part of this entry.

Distinguishing Features

Biallelic truncating LDB3 variants rather than a single missense allele
Early-onset, often lethal pediatric disease

Show evidence (2 references)

PMID:36253531 SUPPORT Human Clinical

"Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism."

Defines the recessive LDB3 phenotype that this entry excludes.

CGGV:assertion_c9d89b2d-2761-47d5-a773-e592f8e6d1df-2026-03-04T170000.000Z SUPPORT Other

ClinGen classifies the recessive concept separately, as Strong.

Myofibrillar myopathy 4 Not Yet Curated MONDO:0012277

Overlapping Features Dominant LDB3 zaspopathy is a late-onset skeletal myofibrillar myopathy, curated under Myofibrillar_Myopathy. Cardiac involvement occurs in a minority, so a patient with cardiomyopathy and distal weakness may belong to this allelic disorder.

Distinguishing Features

Skeletal myopathy with distal-predominant weakness and myofibrillar pathology on biopsy
Alleles mostly in exon 6 (A147T, A165V) rather than the cardiac-preferred exons

Show evidence (1 reference)

PMID:15668942 SUPPORT Human Clinical

"Dominant inheritance was apparent in seven patients, cardiac involvement in three, and signs of peripheral neuropathy in five."

Cardiac involvement in 3 of 11 LDB3 myofibrillar myopathy patients.

Barth syndrome MONDO:0010543

Overlapping Features X-linked TAZ disease presenting with dilated cardiomyopathy and noncompaction in boys. One reported proband carried a TAZ variant together with an inherited LDB3 variant.

Distinguishing Features

X-linked inheritance with neutropenia, skeletal myopathy and 3-methylglutaconic aciduria

Show evidence (1 reference)

PMID:17394203 SUPPORT Human Clinical

"Barth syndrome is an X-linked recessive disorder caused by the tafazzin (TAZ) gene mutations and includes dilated cardiomyopathy (DCM) with left ventricular non-compaction, neutropenia, skeletal myopathy, abnormal mitochondria and 3-methylglutaconic aciduria."

Overlapping cardiac phenotype with distinguishing systemic features.

Arrhythmogenic right ventricular cardiomyopathy MONDO:0016587

Overlapping Features Left-dominant arrhythmogenic cardiomyopathy can present as dilated cardiomyopathy. An LDB3 variant was also reported in one ARVC family. ClinGen classifies LDB3 for ARVC as Disputed.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant left ventricular involvement may present as DCM"

GeneReviews names ARVC as a dilated cardiomyopathy mimic.

CGGV:assertion_8ebdc3e8-2e0a-4a5e-8906-8e616d14008b-2019-09-12T160000.000Z SUPPORT Other

ClinGen's ARVC panel disputes LDB3 as an ARVC gene.

PMID:25041374 SUPPORT Human Clinical

"A heterozygous missense mutation in LDB3 c.1051A>G was identified."

The single ARVC family report involving LDB3.

🐁

Animal Models

Global Cypher knockout mouse

Homozygous loss of both Cypher isoforms causes a severe congenital myopathy with fragmented, disorganized Z-lines in skeletal and cardiac muscle, and death soon after birth.

Species

Mouse

Genotype

Ldb3 (Cypher) null, homozygous

Publication

PMID:11696561

Pathograph links

Z-Disc Cytoskeletal Disorganization partially recapitulates fidelity: low observes: cellular Z-line maintenance fails without Cypher.

Limitations: A homozygous null allele models recessive LDB3 disease, not a dominant missense allele, and the lethal skeletal myopathy dominates.

Divergences from the human mechanism

cause unrepresented qualifying

The human cause is one heterozygous missense allele. The model removes both copies, so it cannot show any gain-of-function or dominant effect of the variant protein.

species mismatch qualifying

Neonatal mouse striated muscle shows the defect. Adult human myocardium with a dominant allele has not been studied at the same level.

Show evidence (1 reference)

PMID:11696561 SUPPORT Model Organism

"Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles."

Shows the severity and skeletal predominance of the null phenotype.

Cardiac-specific Cypher knockout mouse

Cardiac deletion, in development or in adult myocardium, causes severe dilated cardiomyopathy with ultrastructural disruption and death before 23 weeks. ERK and Stat3 activity is increased.

Species

Mouse

Genotype

Cardiomyocyte-restricted and adult-inducible Ldb3 deletion

Publication

PMID:19028670

Pathograph links

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate observes: organism Cardiac loss of Cypher is enough to cause dilated cardiomyopathy.

Limitations: Loss of function on both alleles. It is much more severe and earlier than the late-onset dominant human disease.

Divergences from the human mechanism

cause unrepresented qualifying

The deletion removes the protein, but CMD1C alleles are missense variants that keep the protein and change its binding.

Show evidence (1 reference)

PMID:19028670 SUPPORT Model Organism

"A similar phenotype was observed in inducible cardiac-specific CKO mice in which Cypher was specifically ablated in adult myocardium."

Adult deletion also causes the dilated phenotype, so it is not only developmental.

Maladaptive Cardiomyocyte Stress Signalling measures fidelity: low observes: cellular ERK and Stat3 signalling increase.

Limitations: Signalling was measured in deletion hearts, not in hearts with a missense allele.

Show evidence (1 reference)

PMID:19028670 SUPPORT Model Organism

"In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were augmented."

Signalling readout in the model.

Cypher long-isoform knockout mouse

Losing only the long isoforms causes late-onset dilated cardiomyopathy with fibrosis and calcification. It is preceded by Z-line defects and changed calcineurin-NFAT and PKC signalling. Losing only the short isoforms has no effect.

Species

Mouse

Genotype

Selective deletion of LIM-domain-containing Cypher long isoforms

Publication

PMID:21303826

Pathograph links

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate observes: organism Late-onset course resembles the dominant human disease better than full deletion.

Limitations: Isoform deletion, not a missense allele; the mice also have growth retardation and partial neonatal lethality.

Divergences from the human mechanism

cause unrepresented qualifying

The model removes the LIM-domain isoforms. The human D626N allele keeps them and increases their PKC affinity.

Show evidence (1 reference)

PMID:21303826 SUPPORT Model Organism

"Surviving mutants exhibited growth retardation and late-onset dilated cardiomyopathy, which was associated with cardiac fibrosis and calcification, leading to premature adult mortality."

Late-onset dilated phenotype in the isoform model.

Maladaptive Cardiomyocyte Stress Signalling partially recapitulates fidelity: low observes: cellular Calcineurin-NFAT and PKC pathway changes come before cardiomyopathy.

Limitations: Shows the pathway changes come with isoform loss, not with dominant missense alleles.

Show evidence (1 reference)

PMID:21303826 SUPPORT Model Organism

"At a young age, preceding development of cardiomyopathy, hearts from these mutants exhibited defects in both Z-line ultrastructure and specific aberrations in calcineurin-NFAT and protein kinase C pathways."

Signalling changes come before cardiomyopathy.

S196L transgenic mouse

The only model carrying a CMD1C allele. Mice develop conduction defects and atrioventricular block by 3 months and hemodynamic dysfunction consistent with dilated cardiomyopathy by 10 months. Isolated cardiomyocytes show altered L-type calcium and sodium currents.

Species

Mouse

Genotype

Cardiac-restricted transgenic expression of ZASP S196L on a wild-type background

Publication

PMID:20852297

Pathograph links

Disturbed Cardiomyocyte Ion Currents recapitulates fidelity: moderate observes: cellular Altered calcium and sodium currents in mutant cardiomyocytes.

Limitations: Transgenic overexpression alongside two endogenous wild-type alleles, not a heterozygous knock-in. Human current measurements are not available for comparison.

Divergences from the human mechanism

proxy quantity qualifying

Transgene dosage stands in for the 1:1 mutant to wild-type ratio of a heterozygous patient. Expression level was not matched to human myocardium.

Show evidence (1 reference)

PMID:20852297 SUPPORT Model Organism

"Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca(2+) currents and Na(+) currents were altered."

Current changes in the model.

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate observes: organism Later onset of ventricular dysfunction after the conduction defect.

Limitations: Dosage differs from heterozygous patients; only one allele was modelled.

Divergences from the human mechanism

proxy quantity qualifying

Transgene dosage stands in for the 1:1 mutant to wild-type ratio of a heterozygous patient.

Show evidence (1 reference)

PMID:20852297 SUPPORT Model Organism

"Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block."

Time course of the model phenotype.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1C
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- CMD1C
- dilated cardiomyopathy type 1C
- cardiomyopathy, dilated, 1C, with or without LVNC
- cardiomyopathy, dilated, 1C, with or without left ventricular noncompaction
- cardiomyopathy, hypertrophic, 24
- CMH24
- HCM24
- left ventricular noncompaction 3
- LVNC3
- LDB3-related cardiomyopathy
- ZASP-related cardiomyopathy
description: >-
Dilated cardiomyopathy 1C (CMD1C) is the autosomal dominant cardiomyopathy
attributed to heterozygous missense variants in LDB3, which encodes ZASP
(Cypher), a PDZ-LIM scaffold protein of the sarcomeric Z-disc in cardiac and
skeletal muscle. The MONDO concept (MONDO:0011094; OMIM 601493) spans three
allelic presentations: dilated cardiomyopathy with or without left
ventricular noncompaction (CMD1C), left ventricular noncompaction (LVNC3),
and hypertrophic cardiomyopathy (CMH24). The founding screen found five LDB3
missense variants in six of 100 probands with left ventricular dysfunction.
Later reports added a late-onset familial D626N allele and Z-disc variants in
hypertrophic cardiomyopathy probands. Cell and biochemical studies show that
disease alleles disarrange the cytoskeleton and change ZASP binding to protein
kinase C and phosphoglucomutase 1. A transgenic mouse expressing the S196L
allele develops conduction defects and later ventricular dysfunction. The
evidence base is small: ClinGen classifies the autosomal dominant LDB3-CMD1C
relationship as Limited, rates LDB3 as Disputed for hypertrophic
cardiomyopathy, and one reported allele (D117N) failed to segregate with
disease. Biallelic loss-of-function LDB3 disease (dilated cardiomyopathy 2L)
and LDB3 myofibrillar myopathy (zaspopathy) are separate entities.
disease_term:
preferred_term: dilated cardiomyopathy 1C
term:
id: MONDO:0011094
label: dilated cardiomyopathy 1C
parents:
- Dilated Cardiomyopathy
- Left Ventricular Noncompaction
- Hypertrophic Cardiomyopathy
has_subtypes:
- name: CMD1C
display_name: Dilated cardiomyopathy 1C, with or without left ventricular noncompaction
description: >-
The dilated presentation: left ventricular dilation with systolic
dysfunction, with or without noncompaction. It carries the founding Vatta
alleles and the late-onset Japanese D626N family. It has no separate term
because it is the primary sense of MONDO:0011094, the entry's own disease
term.
genes:
- preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five mutations in six probands (6% of cases) were identified in patients
with familial or sporadic DCM or INLVM.
explanation: >-
The founding screen identified LDB3 variants in probands with dilated
cardiomyopathy or noncompaction. The cached abstract does not split the six
probands between the two presentations.
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A D626N mutation located within the third LIM domain was identified in a
familial case but not found in the unrelated controls.
explanation: >-
A second, independent dilated cardiomyopathy family carrying a
heterozygous LDB3 LIM-domain variant.
- name: LVNC3
display_name: Left ventricular noncompaction 3
description: >-
The noncompaction presentation. The founding screen included probands with
isolated noncompaction, and the D626N allele seen in a Japanese dilated
cardiomyopathy family was also found in two Japanese noncompaction
families. No separate MONDO term exists for this presentation.
genes:
- preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
evidence:
- reference: PMID:16427346
reference_title: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was
identified in LDB3 in four members of two families with LVNC.
explanation: >-
Documents the same LDB3 allele in families with noncompaction, showing that
one allele can produce both the dilated and the noncompaction presentation.
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and
identify a mechanistic basis.
explanation: The founding report includes isolated noncompaction in the LDB3 spectrum.
- name: CMH24
display_name: Cardiomyopathy, familial hypertrophic, 24
description: >-
The hypertrophic presentation. It has no separate disease term because
"cardiomyopathy, hypertrophic, 24" is an exact MONDO synonym of
MONDO:0011094 itself. It rests on rare LDB3 variants in myofilament-negative hypertrophic
cardiomyopathy probands. ClinGen rates LDB3 as Disputed for hypertrophic
cardiomyopathy (see discussions).
genes:
- preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
Z-disc mutations involving residues highly conserved across species and
absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
and VCL (2).
explanation: >-
Six of 239 myofilament-negative hypertrophic cardiomyopathy probands carried
rare LDB3 variants. Segregation was not reported in the abstract.
- reference: CGGV:assertion_1089e729-07ab-4d5b-8fed-1a2ad3f37fd2-2026-01-27T170000.000Z
reference_title: LDB3 / hypertrophic cardiomyopathy (Disputed)
supports: REFUTE
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed"
explanation: >-
ClinGen's hereditary cardiovascular disease panel classifies LDB3 for
hypertrophic cardiomyopathy (MONDO:0005045) as Disputed, which cuts
against LDB3 as a cause of this presentation. It is a different MONDO
term from this entry, so it is not recorded as gene-disease validity.
inheritance:
- name: Autosomal dominant
description: >-
Heterozygous missense alleles are reported in familial and sporadic cases.
Segregation evidence is thin. In the D626N dilated cardiomyopathy family all
affected siblings tested carried the variant. The D117N allele failed to
segregate in two Bedouin families. One healthy heterozygous carrier is
reported: the father of a Barth syndrome proband who also carried a TAZ
variant transmitted the LDB3 T350I allele and is healthy, although he shows
prominent left ventricular trabeculation. No study counts unaffected and
affected carriers of a disease-associated allele, so penetrance is recorded
as UNKNOWN.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: UNKNOWN
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A family study of the patient showed that all affected siblings tested had
the same mutation.
explanation: >-
Co-occurrence of the heterozygous allele with disease in affected sibs is
the strongest segregation datum in the cached record.
- reference: PMID:17394203
reference_title: Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: and one of paternal origin in the LDB3 gene
explanation: >-
The proband's LDB3 variant (T350I) was inherited from his father. The
allele name in square brackets is left out because the validator treats
square brackets as an editorial insertion.
- reference: PMID:17394203
reference_title: Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mother, brother and father are healthy; although the latter two show
prominent left ventricle trabeculation without dysfunction.
explanation: >-
The LDB3-carrying father is healthy, apart from trabeculation without
dysfunction, so at least one heterozygous carrier is unaffected. This
supports incomplete or age-dependent penetrance, but one carrier does not
give a rate.
- reference: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z
reference_title: LDB3 / dilated cardiomyopathy 1C (Limited)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | dilated cardiomyopathy 1C | MONDO:0011094 | AD | Limited"
explanation: >-
ClinGen curated the relationship with an autosomal dominant mode of
inheritance.
prevalence:
- population: Published LDB3 cardiomyopathy reports
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The cited primary reports describe about 16 heterozygous index cases. These
are 6 probands from the founding 100-proband screen, 1 Japanese dilated
cardiomyopathy family (D626N, from 96 patients), 2 Japanese noncompaction
families (D626N, found in four members of two families with LVNC), 6
hypertrophic cardiomyopathy probands from 239 screened, and 1 oligogenic
case that also carried MYH6 and SYNE1 variants. Two further LDB3 carriers
are reported outside these counts: a Barth syndrome proband with a TAZ
variant plus paternal LDB3 T350I, and one ARVC family (c.1051A>G), a
disease ClinGen disputes for LDB3. The D117N allele was later shown not to
segregate. It was first reported in two sporadic cases. The cached
abstracts do not say whether those were among the founding six probands,
so up to 2 of the ~16 index cases may rest on a refuted allele. Whether
the two D626N noncompaction families are related to the D626N dilated
family is not stated. GeneReviews attributes under 1% of dilated
cardiomyopathy to LDB3. No population prevalence has been measured.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "LDB3 AD <1% Limited HCM; myofibrillar myopathy"
explanation: >-
The GeneReviews gene table row for LDB3: autosomal dominant, under 1% of
dilated cardiomyopathy, ClinGen Limited, allelic with hypertrophic
cardiomyopathy and myofibrillar myopathy.
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five mutations in six probands (6% of cases) were identified in patients
with familial or sporadic DCM or INLVM.
explanation: The largest single set of index cases in the literature.
pathophysiology:
- name: LDB3 Heterozygous Missense Variant
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: PROVISIONAL
conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
description: >-
A heterozygous germline missense variant in LDB3 alters ZASP/Cypher, a Z-disc
scaffold that binds alpha-actinin through its PDZ domain and protein kinase C
through its C-terminal LIM domains. Reported alleles cluster in the
cardiac-preferred exons 4 and 10 (S196L/S189L, T213I/T206I, I352M/I345M) or
in the third LIM domain (D626N). Whether these act by gain of function,
dominant interference or partial loss is unresolved, so the functional
impact is recorded as UNKNOWN. Heterozygous loss-of-function carriers in
the recessive families were reported as asymptomatic, which argues against
simple haploinsufficiency.
genes:
- preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
molecular_functions:
- preferred_term: protein kinase C binding
term:
id: GO:0005080
label: protein kinase C binding
modifier: ABNORMAL
- preferred_term: muscle alpha-actinin binding
term:
id: GO:0051371
label: muscle alpha-actinin binding
locations:
- preferred_term: Z disc
term:
id: GO:0030018
label: Z disc
genetic_context:
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: UNKNOWN
allele_type: missense
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and
identify a mechanistic basis.
explanation: The founding report's conclusion that LDB3 variants cause the disease.
- reference: PMID:19377068
reference_title: Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3
and both exons were expressed preferentially in the heart.
explanation: >-
Places the reported dilated cardiomyopathy alleles in cardiac-preferred
exons. This is the paper's framing of earlier human reports.
- reference: PMID:11696561
reference_title: "Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro studies demonstrated that individual domains within Cypher localize
independently to the Z-line via interactions with alpha-actinin or other
Z-line components.
explanation: Grounds the alpha-actinin binding function of the normal protein at the Z-line.
- reference: PMID:36253531
reference_title: Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
suggesting that heterozygous missense variants in the LDB3 gene may be more
deleterious than heterozygous loss-of-function variants in this gene.
explanation: >-
Heterozygous loss-of-function carriers in the recessive families were
asymptomatic (one set of parents declined examination). The authors infer
that dominant disease is not simple haploinsufficiency.
downstream:
- target: Altered ZASP Signalling-Partner Binding
causal_link_type: DIRECT
description: >-
Disease alleles change ZASP binding to protein kinase C (D626N, increased)
and to phosphoglucomutase 1 (exon 4 and 10 alleles, reduced).
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
It was demonstrated by both assays that the D626N mutation of Cypher/ZASP
increased the affinity of the LIM domain for protein kinase C
explanation: Yeast two-hybrid and pull-down assays show the allele changes PKC binding directly.
- reference: PMID:19377068
reference_title: Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another
mutation in exon 10 (Ile345Met) reduced the binding to PGM1.
explanation: Binding assays show three dilated cardiomyopathy alleles reduce PGM1 binding.
- target: Z-Disc Cytoskeletal Disorganization
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cells transfected with mutant ZASP show cytoskeletal disarray. The steps
between the variant and the disarray are not defined.
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
In vitro studies showed cytoskeleton disarray in cells transfected with
mutated Cypher/ZASP.
explanation: >-
Transfection overexpresses the mutant protein in cultured cells, so this
is an inference about the heterozygous heart, not a direct observation in
patient myocardium.
- target: Disturbed Cardiomyocyte Ion Currents
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In a transgenic mouse, cardiac expression of S196L ZASP altered L-type
calcium and sodium currents. ZASP complexes with both channels.
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Electrophysiological analysis on isolated S196L cardiomyocytes
demonstrated that the L-type Ca(2+) currents and Na(+) currents were
altered.
explanation: >-
Cardiomyocytes from transgenic S196L mice show altered currents. The
mutant is expressed on a wild-type background, so this does not
reproduce the human heterozygous dosage.
- target: Left ventricular noncompaction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Heterozygous LDB3 variants are associated with noncompaction, but no study
describes how they disturb ventricular compaction.
evidence:
- reference: PMID:16427346
reference_title: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was
identified in LDB3 in four members of two families with LVNC.
explanation: Genotype-phenotype association in two families; no mechanism is tested.
- target: Hypertrophic cardiomyopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Rare LDB3 variants are reported in hypertrophic cardiomyopathy probands. How
a Z-disc variant would produce hypertrophy is not described. Whether LDB3
causes hypertrophic cardiomyopathy at all is disputed (see the CMH24
subtype and discussions).
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
Z-disc mutations involving residues highly conserved across species and
absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
and VCL (2).
explanation: Case-only association in six LDB3 probands; no mechanism is tested.
- name: Altered ZASP Signalling-Partner Binding
biological_scale: MOLECULAR
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Disease alleles change which partners ZASP holds at the Z-disc. D626N in
the third LIM domain increases binding to protein kinase C. The exon 4
alleles S189L and T206I, and I345M in exon 10, reduce binding to
phosphoglucomutase 1 (PGM1). Under stress, ZASP normally anchors PGM1 at
the Z-disc. All of this comes from binding assays and cultured
cardiomyocytes, not from patient tissue.
genes:
- preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
molecular_functions:
- preferred_term: protein kinase C binding
term:
id: GO:0005080
label: protein kinase C binding
modifier: INCREASED
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
It was demonstrated by both assays that the D626N mutation of Cypher/ZASP
increased the affinity of the LIM domain for protein kinase C
explanation: Yeast two-hybrid and pull-down assays show the allele changes PKC binding directly.
- reference: PMID:19377068
reference_title: Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another
mutation in exon 10 (Ile345Met) reduced the binding to PGM1.
explanation: Binding assays show three dilated cardiomyopathy alleles reduce PGM1 binding.
downstream:
- target: Maladaptive Cardiomyocyte Stress Signalling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed link: changed PKC binding by the LIM domains could disturb PKC
signalling. The only in vivo support is that mice lacking the
LIM-containing long isoforms show PKC pathway changes. That is a deletion
model, not a missense allele.
evidence:
- reference: PMID:21303826
reference_title: Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
At a young age, preceding development of cardiomyopathy, hearts from these
mutants exhibited defects in both Z-line ultrastructure and specific
aberrations in calcineurin-NFAT and protein kinase C pathways.
explanation: >-
Loss of the LIM-domain isoforms disturbs PKC signalling in mouse heart
before cardiomyopathy appears. Extending this to the human D626N
gain-of-affinity allele is an inference.
- target: Left Ventricular Dilation and Systolic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Both binding studies propose that the binding change contributes to
dilated cardiomyopathy. Neither tests it in the heart.
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
suggesting a novel biochemical mechanism of the pathogenesis of dilated
cardiomyopathy
explanation: >-
The PKC-binding study proposes, without testing in heart tissue, that the
affinity change underlies dilated cardiomyopathy.
- reference: PMID:19377068
reference_title: Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The
impaired binding of PGM1 to ZASP/Cypher might be involved in the
pathogenesis of DCM.
explanation: The authors frame the link to dilated cardiomyopathy as a possibility.
- name: Z-Disc Cytoskeletal Disorganization
biological_scale: CELLULAR
role: effector
mechanism_confidence: PROVISIONAL
description: >-
ZASP is not needed to build the Z-disc but keeps it intact during
contraction, acting as a linker-strut. Mutant ZASP disarranges the
cytoskeleton of transfected cells. Loss of Cypher in mice fragments and
disorganizes Z-lines in heart and skeletal muscle. No patient myocardium
with a dominant CMD1C allele has been examined at this level in the cited
sources.
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
locations:
- preferred_term: Z disc
term:
id: GO:0030018
label: Z disc
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
In vitro studies showed cytoskeleton disarray in cells transfected with
mutated Cypher/ZASP.
explanation: >-
Transfection overexpresses the mutant protein in cultured cells, so this
is an inference about the heterozygous heart, not a direct observation in
patient myocardium.
- reference: PMID:11696561
reference_title: "Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Examination of striated muscle from the mutants revealed that Cypher is not
required for sarcomerogenesis or Z-line assembly, but rather is required
for maintenance of the Z-line during muscle function.
explanation: >-
Knockout mice define the normal Z-line maintenance role. They are a null
model, closer to recessive LDB3 disease than to CMD1C.
downstream:
- target: Left Ventricular Dilation and Systolic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In mice, cardiac loss of Cypher disrupts cardiomyocyte ultrastructure and
produces dilated cardiomyopathy. The link from Z-disc failure to chamber
dilation is shown only in loss-of-function models.
evidence:
- reference: PMID:19028670
reference_title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Cardiac-specific Cypher knockout (CKO) mice developed a severe form of DCM
with disrupted cardiomyocyte ultrastructure and decreased cardiac
function, which eventually led to death before 23 weeks of age.
explanation: >-
In mice, cardiomyocyte ultrastructural disruption comes with dilated
cardiomyopathy. INDIRECT because the model deletes the gene rather than
carrying a dominant missense allele.
- reference: PMID:11696561
reference_title: "Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
These results suggest that Cypher functions as a linker-strut to maintain
cytoskeletal structure during contraction.
explanation: The proposed structural reason Z-disc failure impairs contraction.
- target: Maladaptive Cardiomyocyte Stress Signalling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In Cypher-deficient mouse hearts, the Z-line defect comes with changed
ERK, Stat3, calcineurin-NFAT, PKC and actin-MRTFA-SRF signalling.
evidence:
- reference: PMID:21303826
reference_title: Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
At a young age, preceding development of cardiomyopathy, hearts from these
mutants exhibited defects in both Z-line ultrastructure and specific
aberrations in calcineurin-NFAT and protein kinase C pathways.
explanation: >-
Z-line and signalling defects appear together, before cardiomyopathy, in a
mouse deletion model. The order between the two is not established.
- name: Maladaptive Cardiomyocyte Stress Signalling
biological_scale: CELLULAR
role: effector
mechanism_confidence: HYPOTHETICAL
description: >-
Cypher-deficient mouse hearts show several signalling changes: more ERK and
Stat3 activity, abnormal calcineurin-NFAT and PKC signalling when the long
isoforms are lost, and, through F-actin destabilization, less MRTFA-SRF
driven cardiomyocyte maturation. These are all deletion models. Whether a
heterozygous missense allele engages the same pathways in the human heart
has not been tested, so the node is HYPOTHETICAL for CMD1C.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: cardiomyocyte maturation
term:
id: GO:0055007
label: cardiac muscle cell differentiation
modifier: ABNORMAL
evidence:
- reference: PMID:19028670
reference_title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were
augmented.
explanation: Signalling change in cardiac knockout mice.
- reference: PMID:39113806
reference_title: Cypher/ZASP drives cardiomyocyte maturation via actin-mediated MRTFA-SRF signalling.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mechanistically, Cypher deficiency resulted in the destabilization of
F-actin and a notable increase in G-actin levels, thereby impeding the
nuclear localisation of myocardin-related transcription factor A (MRTFA)
explanation: Actin-MRTFA-SRF signalling defect in Cypher-depleted mouse cardiomyocytes.
- reference: PMID:39113806
reference_title: Cypher/ZASP drives cardiomyocyte maturation via actin-mediated MRTFA-SRF signalling.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Cypher deletion led to impaired sarcomere isoform switch and morphological
abnormalities in mitochondria, transverse-tubules, and intercalated discs.
explanation: >-
Grounds the abnormal cardiomyocyte maturation annotation in Cypher-deleted
mouse hearts.
downstream:
- target: Left Ventricular Dilation and Systolic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The knockout studies propose that these pathways help drive progression to
heart failure.
evidence:
- reference: PMID:19028670
reference_title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
specific signaling pathways participate in Cypher mutant-mediated
dysfunction of the heart, and may in concert facilitate the progression
to heart failure.
explanation: The authors propose, without testing, that the signalling changes drive dysfunction.
- name: Disturbed Cardiomyocyte Ion Currents
biological_scale: CELLULAR
role: effector
mechanism_confidence: HYPOTHETICAL
description: >-
ZASP sits in a complex with the L-type calcium channel Cav1.2 and the sodium
channel Nav1.5. In transgenic mice with cardiac expression of S196L,
isolated cardiomyocytes have altered L-type calcium and sodium currents,
and the mice develop conduction defects and atrioventricular block by 3
months. Human electrophysiological data for this mechanism are lacking.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: cardiac conduction
term:
id: GO:0061337
label: cardiac conduction
modifier: ABNORMAL
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The pull-down assay demonstrated that ZASP4 complexes with both calcium
(Ca(v)1.2) and sodium (Na(v)1.5) channels.
explanation: Biochemical evidence that ZASP sits in an ion-channel complex.
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Ten month-old S196L mice developed hemodynamic dysfunction consistent with
DCM, whereas 3-month-old S196L mice presented with cardiac conduction
defects and atrioventricular block.
explanation: In this model the conduction defects come before ventricular dysfunction.
downstream:
- target: Ventricular arrhythmia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The S196L model study proposes that altered channel complexes explain
conduction defects and arrhythmia in LDB3 cardiomyopathy. No human
electrophysiological study tests this.
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
This work represents a novel framework to understand the development of
conduction defects and arrhythmias in subjects with cardiomyopathies,
including DCM.
explanation: A model-based framework, not a demonstration in patients.
- name: Left Ventricular Dilation and Systolic Dysfunction
biological_scale: TISSUE
role: central_effector
mechanism_confidence: ESTABLISHED
conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
description: >-
The defining tissue lesion of the dilated presentation: left ventricular
enlargement with reduced systolic function. Probands were found by screening
patients with left ventricular dysfunction. In the D626N family the disease
came on late.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: heart contraction
term:
id: GO:0060047
label: heart contraction
modifier: DECREASED
locations:
- preferred_term: Left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified and screened 100 probands with left ventricular
dysfunction.
explanation: The founding probands were ascertained for left ventricular dysfunction.
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical information of the affected family members suggested that the
mutation was associated with late onset cardiomyopathy.
explanation: Late-onset dilated cardiomyopathy in a D626N family.
downstream:
- target: Dilated cardiomyopathy
causal_link_type: DIRECT
description: >-
Left ventricular dilation with systolic dysfunction is the clinical
definition of dilated cardiomyopathy.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Systolic dysfunction, a reduction in the myocardial force of
contraction.
explanation: >-
GeneReviews makes systolic dysfunction, together with left ventricular
enlargement, a required criterion for dilated cardiomyopathy. Those are
the two parts of this node.
phenotypes:
- name: Dilated cardiomyopathy
category: Cardiovascular
subtype: CMD1C
diagnostic: true
description: >-
Left ventricular dilation with systolic dysfunction. Onset age is poorly
documented. It was late-onset in the D626N family, and the oligogenic M456R
case had early-onset disease and died at 24.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five mutations in six probands (6% of cases) were identified in patients
with familial or sporadic DCM or INLVM.
explanation: Dilated cardiomyopathy in LDB3 variant carriers.
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical information of the affected family members suggested that the
mutation was associated with late onset cardiomyopathy.
explanation: Late-onset dilated cardiomyopathy in a D626N family.
sequelae:
- target: Congestive heart failure
causal_link_type: DIRECT
description: Progressive systolic dysfunction leads to clinical heart failure.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: >-
Persons with DCM may be asymptomatic for a number of years.
Manifestations usually occur late in the disease course with one or more
of the following findings:
explanation: >-
GeneReviews describes heart failure as a late manifestation of dilated
cardiomyopathy in general. It is not specific to LDB3.
- name: Left ventricular noncompaction
category: Cardiovascular
subtype: LVNC3
description: >-
Excessive trabeculation with deep intertrabecular recesses, alone or with
left ventricular dilation. It was seen in founding probands and in two
D626N families.
phenotype_term:
preferred_term: Left ventricular noncompaction
term:
id: HP:0030682
label: Left ventricular noncompaction
evidence:
- reference: PMID:16427346
reference_title: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was
identified in LDB3 in four members of two families with LVNC.
explanation: Noncompaction in four D626N carriers from two families.
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and
identify a mechanistic basis.
explanation: The founding report includes isolated noncompaction in the LDB3 spectrum.
- name: Hypertrophic cardiomyopathy
category: Cardiovascular
subtype: CMH24
description: >-
Hypertrophic cardiomyopathy in myofilament-negative probands carrying rare
LDB3 variants. ClinGen rates LDB3 as Disputed for hypertrophic
cardiomyopathy.
phenotype_term:
preferred_term: Hypertrophic cardiomyopathy
term:
id: HP:0001639
label: Hypertrophic cardiomyopathy
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
Z-disc mutations involving residues highly conserved across species and
absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
and VCL (2).
explanation: Six LDB3 variant carriers among 239 hypertrophic cardiomyopathy probands.
sequelae:
- target: Ventricular septal hypertrophy
causal_link_type: DIRECT
description: >-
In Z-disc hypertrophic cardiomyopathy the hypertrophy mostly takes a
sigmoidal septal form.
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
For this subset with Z-disc-associated HCM, the septal contour was
sigmoidal in 11 (85%) and apical in 2 (15%).
explanation: >-
INDIRECT because the figures cover all 13 Z-disc probands, of whom 6
carried LDB3 variants. The morphology is not broken down by gene.
- name: Ventricular septal hypertrophy
category: Cardiovascular
subtype: CMH24
description: >-
Sigmoidal septal contour was the main hypertrophy pattern in the Z-disc
hypertrophic cardiomyopathy group that included the LDB3 probands.
phenotype_term:
preferred_term: Ventricular septal hypertrophy
term:
id: HP:0005144
label: Ventricular septal hypertrophy
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially
with sigmoidal morphology.
explanation: >-
Group-level finding for Z-disc hypertrophic cardiomyopathy. It is not
broken down for LDB3 carriers alone.
- name: Congestive heart failure
category: Cardiovascular
description: >-
Heart failure with congestion or low output in advanced dilated disease. No
LDB3-specific frequency is reported.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: >-
Heart failure. Symptoms include those of congestion (edema, orthopnea,
paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue,
dyspnea on exertion).
explanation: >-
General dilated cardiomyopathy synthesis from GeneReviews. No LDB3-specific
heart failure series exists.
- name: Ventricular arrhythmia
category: Cardiovascular
description: >-
Ventricular tachycardia and fibrillation are reported, but only in an
oligogenic case that also carried MYH6 and SYNE1 variants. The role of LDB3
alone in arrhythmia is not established.
phenotype_term:
preferred_term: Ventricular arrhythmia
term:
id: HP:0004308
label: Ventricular arrhythmia
evidence:
- reference: PMID:33949037
reference_title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a Chinese Han family, the patient of 24 years old occurred with
early-onset and DCM and died of SCD associated with ICD storms induced by
repetitive ventricular tachycardia/fibrillation (VT/F).
explanation: >-
Ventricular tachycardia and fibrillation in a carrier of LDB3 p.M456R
together with MYH6 and SYNE1 variants. It cannot be assigned to LDB3
alone.
sequelae:
- target: Sudden cardiac death
causal_link_type: DIRECT
description: Recurrent ventricular tachycardia and fibrillation ended in sudden death.
evidence:
- reference: PMID:33949037
reference_title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a Chinese Han family, the patient of 24 years old occurred with
early-onset and DCM and died of SCD associated with ICD storms induced by
repetitive ventricular tachycardia/fibrillation (VT/F).
explanation: Sudden death from recurrent ventricular arrhythmia in this case.
- name: Sudden cardiac death
category: Cardiovascular
description: >-
Sudden cardiac death occurred in the S196L family from the founding screen
and in the oligogenic case. Its frequency in CMD1C is unknown.
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP
in a family with DCM and sudden cardiac death.
explanation: >-
The mouse paper's background recalls the human S196L family with sudden
death. "LBD3" is the source's typo for LDB3.
- reference: PMID:33949037
reference_title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The multiple heterozygous mutations of SYNE1, LDB3, and MYH6 may be
associated with young and early-onset of DCM and SCD.
explanation: Oligogenic case; LDB3 is one of three candidate contributors.
progression:
- phase: Adult-onset, progressive dilated disease
subtype: CMD1C
age_range: Mostly adult; late onset in the D626N family, age 24 at death in one oligogenic case
notes: >-
No LDB3-specific natural-history series exists. The D626N family had late
onset. The oligogenic M456R case was 24 at sudden death. In general dilated
cardiomyopathy, carriers may be asymptomatic for years before heart failure
or arrhythmia.
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical information of the affected family members suggested that the
mutation was associated with late onset cardiomyopathy.
explanation: Late onset in the D626N family.
- reference: PMID:36253531
reference_title: Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the
PDZ-LIM domain-binding factor, have been linked to a late onset phenotype
of cardiomyopathy and myofibrillar myopathy in humans.
explanation: Background summary of the dominant LDB3 phenotype as late-onset.
diagnosis:
- name: Cardiac imaging
diagnosis_term:
preferred_term: Echocardiography Test
term:
id: NCIT:C16525
label: Echocardiography Test
description: >-
Echocardiography or cardiac MRI measures left ventricular size and systolic
function, shows noncompaction, and grades septal hypertrophy and contour.
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and
physical examination.
explanation: Clinical workup used in the founding cohort.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Enlargement is most commonly assessed in adults by either echocardiography
or cardiac MRI.
explanation: General GeneReviews guidance on imaging in dilated cardiomyopathy.
- name: Electrocardiography
diagnosis_term:
preferred_term: Electrocardiography
term:
id: NCIT:C38053
label: Electrocardiography
description: >-
Resting ECG, and Holter monitoring where indicated, to detect conduction
disease and ventricular arrhythmia. The arrhythmia risk is suggested by the
S196L family and the mouse model, but is not quantified in humans.
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and
physical examination.
explanation: ECG was part of the founding cohort's workup.
- name: Creatine kinase screening for skeletal muscle involvement
diagnosis_term:
preferred_term: Creatine Kinase Measurement
term:
id: NCIT:C64489
label: Creatine Kinase Measurement
description: >-
Muscle creatine kinase was measured in the founding cohort to look for
skeletal muscle involvement, since LDB3 is also a myofibrillar myopathy
gene. The cached abstract does not report the result.
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, levels of the muscular isoform of creatine kinase were
measured to evaluate for skeletal muscle involvement.
explanation: CK screening was part of the founding protocol.
- name: Multigene cardiomyopathy panel or exome sequencing
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
LDB3 is tested on cardiomyopathy panels and exomes. Because ClinGen rates the
dominant relationship as Limited, and one previously reported allele (D117N)
did not segregate, report a heterozygous LDB3 missense variant with caution
and test segregation in the family.
evidence:
- reference: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z
reference_title: LDB3 / dilated cardiomyopathy 1C (Limited)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | dilated cardiomyopathy 1C | MONDO:0011094 | AD | Limited"
explanation: The Limited tier is why a single LDB3 variant is weak diagnostic evidence.
- reference: PMID:26419279
reference_title: D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, p.(D117N) did not segregate as the causative mutation in these
families, i.e. it was not present in some patients and was found in
several individuals who had no clinical manifestations.
explanation: A reported LDB3 allele failed segregation, so segregation testing is needed.
- name: Cascade screening of relatives
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Clinical cardiac screening of first-degree relatives, with genetic testing
when the familial variant is actionable. This is general dilated
cardiomyopathy guidance, not LDB3-specific.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Cardiovascular screening of asymptomatic first-degree family members of an
individual with DCM can allow early detection of DCM, prompt initiation of
treatment, and improvement in long-term outcome
explanation: General GeneReviews guidance for families with dilated cardiomyopathy.
differential_diagnoses:
- name: Dilated cardiomyopathy 2L
disease_term:
preferred_term: cardiomyopathy, dilated, 2l
term:
id: MONDO:0979236
label: cardiomyopathy, dilated, 2l
description: >-
The recessive LDB3 disease: biallelic loss-of-function variants cause
severe dilated cardiomyopathy in infancy, childhood or the fetus, sometimes
with noncompaction and myopathy. ClinGen rates it Strong (AR). It is a
separate concept and not part of this entry.
distinguishing_features:
- Biallelic truncating LDB3 variants rather than a single missense allele
- Early-onset, often lethal pediatric disease
evidence:
- reference: PMID:36253531
reference_title: Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings demonstrate that recessive LDB3 variants can lead to an
early-onset severe human phenotype of cardiomyopathy and myopathy,
reminiscent of the knockout mouse phenotype, and supporting a loss of
function mechanism.
explanation: Defines the recessive LDB3 phenotype that this entry excludes.
- reference: CGGV:assertion_c9d89b2d-2761-47d5-a773-e592f8e6d1df-2026-03-04T170000.000Z
reference_title: LDB3 / cardiomyopathy, dilated, 2l (Strong)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | cardiomyopathy, dilated, 2l | MONDO:0979236 | AR | Strong"
explanation: ClinGen classifies the recessive concept separately, as Strong.
- name: Myofibrillar myopathy 4
disease_term:
preferred_term: myofibrillar myopathy 4
term:
id: MONDO:0012277
label: myofibrillar myopathy 4
description: >-
Dominant LDB3 zaspopathy is a late-onset skeletal myofibrillar myopathy,
curated under Myofibrillar_Myopathy. Cardiac involvement occurs in a
minority, so a patient with cardiomyopathy and distal weakness may belong to
this allelic disorder.
distinguishing_features:
- Skeletal myopathy with distal-predominant weakness and myofibrillar pathology on biopsy
- Alleles mostly in exon 6 (A147T, A165V) rather than the cardiac-preferred exons
evidence:
- reference: PMID:15668942
reference_title: Mutations in ZASP define a novel form of muscular dystrophy in humans.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dominant inheritance was apparent in seven patients, cardiac involvement in
three, and signs of peripheral neuropathy in five.
explanation: Cardiac involvement in 3 of 11 LDB3 myofibrillar myopathy patients.
- name: Barth syndrome
disease_term:
preferred_term: Barth syndrome
term:
id: MONDO:0010543
label: Barth syndrome
description: >-
X-linked TAZ disease presenting with dilated cardiomyopathy and
noncompaction in boys. One reported proband carried a TAZ variant together
with an inherited LDB3 variant.
distinguishing_features:
- X-linked inheritance with neutropenia, skeletal myopathy and 3-methylglutaconic aciduria
evidence:
- reference: PMID:17394203
reference_title: Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Barth syndrome is an X-linked recessive disorder caused by the tafazzin
(TAZ) gene mutations and includes dilated cardiomyopathy (DCM) with left
ventricular non-compaction, neutropenia, skeletal myopathy, abnormal
mitochondria and 3-methylglutaconic aciduria.
explanation: Overlapping cardiac phenotype with distinguishing systemic features.
- name: Arrhythmogenic right ventricular cardiomyopathy
disease_term:
preferred_term: arrhythmogenic right ventricular cardiomyopathy
term:
id: MONDO:0016587
label: arrhythmogenic right ventricular cardiomyopathy
description: >-
Left-dominant arrhythmogenic cardiomyopathy can present as dilated
cardiomyopathy. An LDB3 variant was also reported in one ARVC family. ClinGen
classifies LDB3 for ARVC as Disputed.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant
left ventricular involvement may present as DCM
explanation: GeneReviews names ARVC as a dilated cardiomyopathy mimic.
- reference: CGGV:assertion_8ebdc3e8-2e0a-4a5e-8906-8e616d14008b-2019-09-12T160000.000Z
reference_title: LDB3 / arrhythmogenic right ventricular cardiomyopathy (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | arrhythmogenic right ventricular cardiomyopathy | MONDO:0016587 | AD | Disputed"
explanation: ClinGen's ARVC panel disputes LDB3 as an ARVC gene.
- reference: PMID:25041374
reference_title: A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A heterozygous missense mutation in LDB3 c.1051A>G was identified.
explanation: The single ARVC family report involving LDB3.
genetic:
- name: LDB3
gene_term:
preferred_term: LDB3
term:
id: hgnc:15710
label: LDB3
variant_origin: GERMLINE
association: >-
Heterozygous missense variants; ClinGen Limited (autosomal dominant) for
dilated cardiomyopathy 1C
frequency: Under 1% of dilated cardiomyopathy (GeneReviews)
case_fractions:
- population: Probands with left ventricular dysfunction (founding screen)
case_fraction_percent: 6.0
cohort_size: 100
notes: >-
Five variants in six probands with familial or sporadic dilated
cardiomyopathy or isolated noncompaction. Not replicated at this yield.
evidence:
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five mutations in six probands (6% of cases) were identified in patients
with familial or sporadic DCM or INLVM.
explanation: Gives the yield in the founding cohort.
- population: Myofilament-negative hypertrophic cardiomyopathy probands
case_fraction_percent: 2.5
cohort_size: 239
notes: Six LDB3 carriers out of 239 (calculated from the published counts).
evidence:
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
Z-disc mutations involving residues highly conserved across species and
absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
and VCL (2).
explanation: Gives the LDB3 count in this cohort.
- population: Japanese dilated cardiomyopathy patients
case_fraction_percent: 1.0
cohort_size: 96
notes: One familial D626N case out of 96 unrelated patients (1.04%, rounded).
evidence:
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, we searched for sequence variations in Cypher/ZASP in 96
unrelated Japanese patients with dilated cardiomyopathy.
explanation: Gives the cohort size; the abstract reports one familial D626N case.
notes: >-
Gene-disease validity. The current ClinGen record for exactly this concept
(MONDO:0011094, AD, Limited, Dilated Cardiomyopathy GCEP, 2026-03-04) is
copied below. It matches the row in the committed ClinGen ingest table
(kb/genes/ingest/clingen_gene_validity.tsv), so it was not withdrawn (issue
#13576). The same holds for the other three LDB3 records cited here:
hypertrophic cardiomyopathy (2026-01-27), dilated cardiomyopathy 2L
(2026-03-04) and ARVC (2019-09-12). Those dates match the cache-file stamps.
The 2026-03-04 record supersedes a 2025-03-21 version of the same
assertion, which mapped to generic dilated cardiomyopathy
(MONDO:0005021). relationship_type is left unset because the
schema reserves CAUSATIVE for Definitive or Strong. Other ClinGen LDB3
records: hypertrophic cardiomyopathy AD Disputed (MONDO:0005045),
arrhythmogenic right ventricular cardiomyopathy AD Disputed (MONDO:0016587),
and dilated cardiomyopathy 2L AR Strong (MONDO:0979236). The 2026 ClinGen
reassessment states LDB3 AD-Limited, AR-Strong. Variant numbering
differs between OMIM and RefSeq (S196L is S189L, T213I is T206I, I352M is
I345M on the transcript used in the PGM1 study).
gene_disease_validity:
- validity_classification: LIMITED
classified_by: CLINGEN
external_id: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z
evidence:
- reference: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z
reference_title: LDB3 / dilated cardiomyopathy 1C (Limited)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | dilated cardiomyopathy 1C | MONDO:0011094 | AD | Limited"
explanation: ClinGen Limited classification for autosomal dominant LDB3 and this exact MONDO concept.
evidence:
- reference: PMID:42708185
reference_title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
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).
explanation: The ClinGen expert panel's published summary of the split LDB3 classifications.
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five mutations in six probands (6% of cases) were identified in patients
with familial or sporadic DCM or INLVM.
explanation: Founding human genetic evidence.
treatments:
- name: Guideline-directed heart failure pharmacotherapy
description: >-
Standard heart failure therapy for symptomatic or asymptomatic left
ventricular systolic dysfunction. No LDB3-specific trial or case series
exists.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Congestive heart failure
description: Treats heart failure; does not address the Z-disc lesion.
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: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: >-
The 2022 heart failure guideline provides recommendations based on
contemporary evidence for the treatment of these patients.
explanation: General heart failure guideline, applied by extrapolation.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: >-
permit initiation of medical therapy aimed at preventing/delaying the
morbidity of late-stage symptomatic disease
explanation: GeneReviews supports early medical therapy in genetic dilated cardiomyopathy generally.
- name: Implantable cardioverter-defibrillator
description: >-
Considered for sudden death prevention under general cardiomyopathy
criteria.
notes: >-
No source gives LDB3-specific evidence for ICD benefit or for
risk-stratification thresholds. It is listed because sudden cardiac death
is reported in the S196L family and the oligogenic case. In the oligogenic
M456R case an ICD was in place and the patient still died during
recurrent ICD storms. Indication follows general guidelines.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: Implantable Cardioverter-Defibrillator Placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
target_mechanisms:
- target: Sudden cardiac death
description: Prevents arrhythmic death; does not modify the cardiomyopathy.
evidence:
- reference: PMID:33949037
reference_title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
In a Chinese Han family, the patient of 24 years old occurred with
early-onset and DCM and died of SCD associated with ICD storms induced by
repetitive ventricular tachycardia/fibrillation (VT/F).
explanation: >-
Context only: an ICD was implanted in an LDB3 variant carrier with
malignant arrhythmia. It did not prevent death, and the case is
oligogenic, so it gives no LDB3-specific evidence of benefit.
- name: Heart transplantation
description: Option for end-stage heart failure under general criteria.
notes: >-
No source reports transplantation outcomes in LDB3 cardiomyopathy. Listed as
standard end-stage care without LDB3-specific evidence.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Heart Transplantation
term:
id: NCIT:C15246
label: Heart Transplantation
target_mechanisms:
- target: Congestive heart failure
description: Replaces the failing heart.
- name: Genetic counseling
description: >-
Counsel families on autosomal dominant inheritance, the Limited
gene-disease classification, and the uncertainty of any one LDB3 missense
variant. Offer cardiac surveillance of at-risk relatives.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
It is appropriate to clarify the clinical and genetic status of
asymptomatic family members at risk for DCM prior to the onset of
manifestations
explanation: General GeneReviews family guidance for dilated cardiomyopathy.
animal_models:
- name: Global Cypher knockout mouse
species: Mouse
genotype: Ldb3 (Cypher) null, homozygous
publication: PMID:11696561
description: >-
Homozygous loss of both Cypher isoforms causes a severe congenital myopathy
with fragmented, disorganized Z-lines in skeletal and cardiac muscle, and
death soon after birth.
modeled_mechanisms:
- target: Z-Disc Cytoskeletal Disorganization
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: CELLULAR
description: Z-line maintenance fails without Cypher.
limitations: >-
A homozygous null allele models recessive LDB3 disease, not a dominant
missense allele, and the lethal skeletal myopathy dominates.
divergences:
- divergence_type: CAUSE_UNREPRESENTED
materiality: QUALIFYING
description: >-
The human cause is one heterozygous missense allele. The model removes
both copies, so it cannot show any gain-of-function or dominant effect
of the variant protein.
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Neonatal mouse striated muscle shows the defect. Adult human myocardium
with a dominant allele has not been studied at the same level.
evidence:
- reference: PMID:11696561
reference_title: "Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Cypher knockout mice display a severe form of congenital myopathy and die
postnatally from functional failure in multiple striated muscles.
explanation: Shows the severity and skeletal predominance of the null phenotype.
- name: Cardiac-specific Cypher knockout mouse
species: Mouse
genotype: Cardiomyocyte-restricted and adult-inducible Ldb3 deletion
publication: PMID:19028670
description: >-
Cardiac deletion, in development or in adult myocardium, causes severe
dilated cardiomyopathy with ultrastructural disruption and death before 23
weeks. ERK and Stat3 activity is increased.
modeled_mechanisms:
- target: Left Ventricular Dilation and Systolic Dysfunction
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: Cardiac loss of Cypher is enough to cause dilated cardiomyopathy.
limitations: >-
Loss of function on both alleles. It is much more severe and earlier than
the late-onset dominant human disease.
divergences:
- divergence_type: CAUSE_UNREPRESENTED
materiality: QUALIFYING
description: >-
The deletion removes the protein, but CMD1C alleles are missense
variants that keep the protein and change its binding.
evidence:
- reference: PMID:19028670
reference_title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A similar phenotype was observed in inducible cardiac-specific CKO mice in
which Cypher was specifically ablated in adult myocardium.
explanation: Adult deletion also causes the dilated phenotype, so it is not only developmental.
- target: Maladaptive Cardiomyocyte Stress Signalling
relationship: MEASURES
fidelity: LOW
model_scale: CELLULAR
description: ERK and Stat3 signalling increase.
limitations: Signalling was measured in deletion hearts, not in hearts with a missense allele.
evidence:
- reference: PMID:19028670
reference_title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were
augmented.
explanation: Signalling readout in the model.
- name: Cypher long-isoform knockout mouse
species: Mouse
genotype: Selective deletion of LIM-domain-containing Cypher long isoforms
publication: PMID:21303826
description: >-
Losing only the long isoforms causes late-onset dilated cardiomyopathy with
fibrosis and calcification. It is preceded by Z-line defects and changed
calcineurin-NFAT and PKC signalling. Losing only the short isoforms has no
effect.
modeled_mechanisms:
- target: Left Ventricular Dilation and Systolic Dysfunction
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: Late-onset course resembles the dominant human disease better than full deletion.
limitations: Isoform deletion, not a missense allele; the mice also have growth retardation and partial neonatal lethality.
divergences:
- divergence_type: CAUSE_UNREPRESENTED
materiality: QUALIFYING
description: >-
The model removes the LIM-domain isoforms. The human D626N allele keeps
them and increases their PKC affinity.
evidence:
- reference: PMID:21303826
reference_title: Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Surviving mutants exhibited growth retardation and late-onset dilated
cardiomyopathy, which was associated with cardiac fibrosis and
calcification, leading to premature adult mortality.
explanation: Late-onset dilated phenotype in the isoform model.
- target: Maladaptive Cardiomyocyte Stress Signalling
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: CELLULAR
description: Calcineurin-NFAT and PKC pathway changes come before cardiomyopathy.
limitations: Shows the pathway changes come with isoform loss, not with dominant missense alleles.
evidence:
- reference: PMID:21303826
reference_title: Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
At a young age, preceding development of cardiomyopathy, hearts from these
mutants exhibited defects in both Z-line ultrastructure and specific
aberrations in calcineurin-NFAT and protein kinase C pathways.
explanation: Signalling changes come before cardiomyopathy.
- name: S196L transgenic mouse
species: Mouse
genotype: Cardiac-restricted transgenic expression of ZASP S196L on a wild-type background
publication: PMID:20852297
description: >-
The only model carrying a CMD1C allele. Mice develop conduction defects and
atrioventricular block by 3 months and hemodynamic dysfunction consistent
with dilated cardiomyopathy by 10 months. Isolated cardiomyocytes show
altered L-type calcium and sodium currents.
modeled_mechanisms:
- target: Disturbed Cardiomyocyte Ion Currents
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Altered calcium and sodium currents in mutant cardiomyocytes.
limitations: >-
Transgenic overexpression alongside two endogenous wild-type alleles, not
a heterozygous knock-in. Human current measurements are not available for
comparison.
divergences:
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >-
Transgene dosage stands in for the 1:1 mutant to wild-type ratio of a
heterozygous patient. Expression level was not matched to human
myocardium.
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electrophysiological analysis on isolated S196L cardiomyocytes
demonstrated that the L-type Ca(2+) currents and Na(+) currents were
altered.
explanation: Current changes in the model.
- target: Left Ventricular Dilation and Systolic Dysfunction
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: Later onset of ventricular dysfunction after the conduction defect.
limitations: Dosage differs from heterozygous patients; only one allele was modelled.
divergences:
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >-
Transgene dosage stands in for the 1:1 mutant to wild-type ratio of a
heterozygous patient.
evidence:
- reference: PMID:20852297
reference_title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Ten month-old S196L mice developed hemodynamic dysfunction consistent with
DCM, whereas 3-month-old S196L mice presented with cardiac conduction
defects and atrioventricular block.
explanation: Time course of the model phenotype.
discussions:
- discussion_id: dominant_mechanism_unresolved
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Do dominant LDB3 missense alleles act through the same pathways that
knockout mice reveal?
attaches_to:
- pathophysiology#Maladaptive Cardiomyocyte Stress Signalling
- pathophysiology#Z-Disc Cytoskeletal Disorganization
- animal_models#Global Cypher knockout mouse
- animal_models#Cardiac-specific Cypher knockout mouse
rationale: >-
Nearly all mechanistic mouse work deletes Cypher or its isoforms. That
matches recessive LDB3 disease. Heterozygous loss-of-function carriers in
the recessive families were reported as asymptomatic. The one human allele
tested biochemically for PKC binding (D626N) increases binding rather than
removing it. The only allele-specific mouse is a transgenic overexpressor.
So the signalling and Z-disc nodes are carried over from loss-of-function
models, and no heterozygous knock-in or patient iPSC model tests them.
evidence:
- reference: PMID:36253531
reference_title: Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
suggesting that heterozygous missense variants in the LDB3 gene may be more
deleterious than heterozygous loss-of-function variants in this gene.
explanation: >-
Heterozygous loss-of-function carriers in the recessive families were
asymptomatic (one set of parents declined examination). The authors infer
that dominant disease is not simple haploinsufficiency.
- reference: PMID:14660611
reference_title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
It was demonstrated by both assays that the D626N mutation of Cypher/ZASP
increased the affinity of the LIM domain for protein kinase C
explanation: Yeast two-hybrid and pull-down assays show the allele changes PKC binding directly.
- discussion_id: hcm_presentation_disputed
kind: CONTROVERSY
status: OPEN
prompt: >-
Should the CMH24 hypertrophic presentation remain inside this concept when
ClinGen disputes LDB3 for hypertrophic cardiomyopathy?
attaches_to:
- has_subtypes#CMH24
- phenotypes#Hypertrophic cardiomyopathy
rationale: >-
MONDO lists cardiomyopathy, hypertrophic, 24 as an exact synonym of
MONDO:0011094, so the entry keeps it. The supporting data are case-only:
six LDB3 carriers among 239 myofilament-negative probands, with no
segregation in the abstract. ClinGen's hereditary cardiovascular panel
classified LDB3 for hypertrophic cardiomyopathy as Disputed in January 2026.
evidence:
- reference: CGGV:assertion_1089e729-07ab-4d5b-8fed-1a2ad3f37fd2-2026-01-27T170000.000Z
reference_title: LDB3 / hypertrophic cardiomyopathy (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: "LDB3 | HGNC:15710 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed"
explanation: The current ClinGen tier for LDB3 in hypertrophic cardiomyopathy.
- reference: PMID:17097056
reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
Z-disc mutations involving residues highly conserved across species and
absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
and VCL (2).
explanation: The case-only evidence behind CMH24.
- discussion_id: variant_level_doubt
kind: CONTROVERSY
status: OPEN
prompt: Which reported dominant LDB3 alleles are truly pathogenic?
attaches_to:
- genetic#LDB3
rationale: >-
The D117N allele was first reported in two sporadic cases. It did not
segregate in two Bedouin families. It was found on 11 of 210 Bedouin
chromosomes (5.2%, an allele frequency, all heterozygous).
The M456R case also carried MYH6 and SYNE1 variants. Most LDB3 missense
variants on clinical panels are of uncertain significance, which fits the
Limited classification.
evidence:
- reference: PMID:26419279
reference_title: D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, p.(D117N) did not segregate as the causative mutation in these
families, i.e. it was not present in some patients and was found in
several individuals who had no clinical manifestations.
explanation: Direct segregation evidence against one allele.
- reference: PMID:26419279
reference_title: D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eleven out of 210 chromosomes (5.2%) were found to carry p.(D117N) (all in
heterozygous state).
explanation: The variant is too common in the source population to cause a rare dominant disease.
- reference: PMID:33949037
reference_title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The multiple heterozygous mutations of SYNE1, LDB3, and MYH6 may be
associated with young and early-onset of DCM and SCD.
explanation: The LDB3 contribution cannot be separated from co-occurring variants.
- discussion_id: cardiac_skeletal_overlap
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Do CMD1C patients have subclinical skeletal myopathy, and how many zaspopathy
patients develop cardiomyopathy?
attaches_to:
- genetic#LDB3
- differential_diagnoses#Myofibrillar myopathy 4
rationale: >-
LDB3 causes both this cardiomyopathy and a dominant myofibrillar myopathy,
curated separately in Myofibrillar_Myopathy. Cardiac involvement was found
in 3 of 11 myopathy patients. The founding cardiac cohort measured muscle
creatine kinase, but the cached abstract does not report the result. No
cited study examined skeletal muscle systematically in cardiac probands.
The two entries therefore overlap at the gene level without a measured
shared-phenotype rate.
evidence:
- reference: PMID:15668942
reference_title: Mutations in ZASP define a novel form of muscular dystrophy in humans.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We therefore searched for mutations in ZASP in 54 MFM patients and detected
3 heterozygous missense mutations in 11.
explanation: Denominator for the myopathy cohort (11 carriers, 3 with cardiac involvement).
- reference: PMID:14662268
reference_title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, levels of the muscular isoform of creatine kinase were
measured to evaluate for skeletal muscle involvement.
explanation: CK was measured in the cardiac cohort, but the result is not in the abstract.
- discussion_id: lvnc_mechanism_unknown
kind: KNOWLEDGE_GAP
status: OPEN
prompt: How do heterozygous LDB3 variants produce noncompaction rather than, or as well as, dilation?
attaches_to:
- phenotypes#Left ventricular noncompaction
rationale: >-
The same D626N allele was reported with late-onset dilated cardiomyopathy in
one family and with noncompaction in two others. No study explains how the
variant affects trabecular compaction, so the edge to noncompaction is
recorded with unknown intermediates.
evidence:
- reference: PMID:16427346
reference_title: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was
identified in LDB3 in four members of two families with LVNC.
explanation: Same allele, different presentation.
references:
- reference: PMID:14662268
title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
- reference: PMID:14660611
title: A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.
- reference: PMID:16427346
title: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.
- reference: PMID:17097056
title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
- reference: PMID:19377068
title: Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.
- reference: PMID:20852297
title: "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy."
- reference: PMID:11696561
title: "Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy."
- reference: PMID:19028670
title: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.
- reference: PMID:21303826
title: Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy.
- reference: PMID:39113806
title: Cypher/ZASP drives cardiomyocyte maturation via actin-mediated MRTFA-SRF signalling.
- reference: PMID:36253531
title: Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
- reference: PMID:26419279
title: D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.
- reference: PMID:33949037
title: "Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations."
- reference: PMID:15668942
title: Mutations in ZASP define a novel form of muscular dystrophy in humans.
- reference: PMID:17394203
title: Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes.
- reference: PMID:25041374
title: A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.
- reference: PMID:42708185
title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
- 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: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2026-03-04T170000.000Z
title: LDB3 / dilated cardiomyopathy 1C (Limited)
- reference: CGGV:assertion_1089e729-07ab-4d5b-8fed-1a2ad3f37fd2-2026-01-27T170000.000Z
title: LDB3 / hypertrophic cardiomyopathy (Disputed)
- reference: CGGV:assertion_c9d89b2d-2761-47d5-a773-e592f8e6d1df-2026-03-04T170000.000Z
title: LDB3 / cardiomyopathy, dilated, 2l (Strong)
- reference: CGGV:assertion_8ebdc3e8-2e0a-4a5e-8906-8e616d14008b-2019-09-12T160000.000Z
title: LDB3 / arrhythmogenic right ventricular cardiomyopathy (Disputed)
- reference: PMID:20301486
title: Dilated Cardiomyopathy Overview.
tags:
- GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
tags:
- GeneReviews
notes: >-
Scope. MONDO:0011094 (OMIM 601493) covers three allelic presentations of
heterozygous LDB3 disease: dilated cardiomyopathy with or without
noncompaction, noncompaction (LVNC3), and hypertrophic cardiomyopathy (CMH24).
They are recorded as has_subtypes rows without separate disease terms, because
MONDO has none. Recessive LDB3 disease (dilated cardiomyopathy 2L,
MONDO:0979236) is excluded and appears only as a differential. LDB3
myofibrillar myopathy (zaspopathy, MFM4) is curated in Myofibrillar_Myopathy
and is cross-referenced here, not duplicated. The Hypertrophic_Cardiomyopathy_15,
Hypertrophic_Cardiomyopathy_25 and Left_Ventricular_Noncompaction entries cite
the same Z-disc cohort (PMID:17097056) but do not claim this concept. Their
six-LDB3-carrier count matches the count used here. GeneReviews: `just
check-genereviews --online` reports the Dilated Cardiomyopathy Overview
(PMID:20301486, NBK1309) as TAGGED, matched by identity, and StatPearls as
NO_CHAPTER. No LDB3-specific chapter exists. The cited
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
is the full text of that same chapter, whose PubMed record is abstract-only.
It supplies the LDB3 gene-table row, the DCM definition and the general
family-screening guidance quoted here. The deep-research report
said one mechanism study (PMID:39113806) used human stem-cell
cardiomyocytes. The cached text describes Cypher-depleted mice, and it is
curated that way here.

📚

References & Deep Research

References

PMID:14662268

Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.