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Classifications

Harrison's Part

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Inheritance

2

Autosomal dominant HP:0000006

Most reported CSRP3 HCM alleles are heterozygous missense variants that cosegregate with disease in families, which is the autosomal dominant pattern recorded by OMIM. Penetrance is incomplete and strongly age-dependent: in the p.Cys150Tyr families, carriers were diagnosed at a mean of 55 years and wild-type relatives were unaffected. Expressivity is variable.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (3 references)

PMID:12642359 SUPPORT PRIMARY RESULT Human Clinical

"Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP."

Heterozygous LIM1 missense variants cosegregate with HCM in families, the dominant transmission pattern.

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families."

Segregation of CSRP3 missense variants with HCM in further families.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The variant showed highly age-dependent penetrance."

Penetrance of the heterozygous p.Cys150Tyr allele depends strongly on age.

Semidominant HP:0032113

ClinGen curated CSRP3 for hypertrophic cardiomyopathy as semidominant: heterozygous variants cause disease, and biallelic variants cause disease that is at least as penetrant and, for p.Cys150Tyr, more severe. Homozygous truncating CSRP3 alleles (complete loss of MLP) have been reported in several adult HCM probands, and CSRP3 variants are found in the homozygous state unusually often in a highly consanguineous Egyptian HCM cohort. One group argued from the first homozygous truncating cases that CSRP3 HCM may be recessive rather than dominant; the semidominant classification covers both observations.

Semidominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (7 references)

CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z SUPPORT Other

ClinGen records the mode of inheritance for CSRP3 in hypertrophic cardiomyopathy as SD (semidominant). The assertion is for the generic HCM term; see the genetic notes.

PMID:39971408 SUPPORT REVIEW SYNTHESIS Other

"CSRP3 was curated for a semidominant mode of inheritance (definitive)."

The expert-panel reappraisal that assigned the semidominant mode.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype."

Gene-dose effect for one allele, the hallmark of semidominance.

+ 4 more references

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Discussions and Knowledge Gaps

3

Is CSRP3 HCM dominant, recessive or semidominant, and how penetrant are heterozygous alleles?

CONTROVERSY OPEN cmh12_inheritance_mode

Attached to

genetic#CSRP3 inheritance#Semidominant

OMIM records CMH12 as autosomal dominant, and most published alleles are heterozygous missense variants that cosegregate with disease. After the first homozygous truncating cases, one group argued for recessive inheritance and noted that only C58G met ACMG likely pathogenic criteria. Later data showed both: heterozygous p.Cys150Tyr causes late-onset disease, the homozygote is more severe, and homozygous variants are enriched where consanguinity is common. ClinGen settled on semidominant. The open part is penetrance of heterozygous missense and truncating alleles, which needs age-stratified family data.

Show evidence (4 references)

PMID:30012424 SUPPORT PRIMARY RESULT Human Clinical

"By combining meta-analysis results and identification of two unrelated HCM patients with homozygous CSRP3 truncating variants, we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal..."

The recessive-inheritance position.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers."

Heterozygous disease, against a purely recessive model.

PMID:37431535 SUPPORT PRIMARY RESULT Human Clinical

"variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity."

Reduced heterozygous penetrance inferred from homozygosity enrichment.

+ 1 more reference

Does loss of MLP increase or decrease calcineurin-NFAT signalling in the heart?

CONTROVERSY OPEN cmh12_calcineurin_direction

Attached to

pathophysiology#Disinhibited Calcineurin-NFAT Hypertrophic Signalling

In human iPSC cardiomyocytes (MLP lost secondarily to a sarcomeric variant) and in homozygous C58G knock-in hearts, reduced MLP is followed by more calcineurin-NFAT activity and hypertrophy. In heterozygous MLP-null mice after myocardial infarction, halving MLP displaced calcineurin from the Z-disc and blunted NFAT activation, and the hearts dilated. The settings differ (high sarcomeric force or near-complete MLP loss with a hypertrophic outcome, versus an ischaemic stressor with a dilated outcome). The authors of the human study, who cite the mouse anchoring work, propose that MLP both restrains calcineurin-NFAT at rest and is needed to localize it, so the net effect of MLP loss may depend on context. This entry follows the human cardiomyocyte data for the hypertrophic phenotype; the allelic dilated entry (Dilated Cardiomyopathy 1M) follows the mouse data for the dilated phenotype. Neither direction has been measured in cells carrying a primary pathogenic CSRP3 allele at heterozygous dose.

Show evidence (3 references)

PMID:35384713 SUPPORT PRIMARY RESULT In Vitro

"Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."

Reduced MLP increases calcineurin-NFAT activity.

PMID:35384713 SUPPORT PRIMARY RESULT In Vitro

"It is possible that MLP has both inhibitory and facilitative effects on calcineurin activity."

The human-study authors' proposed reconciliation of the two directions: MLP may both restrain and facilitate Z-disc calcineurin. Stated as a possibility in their discussion.

PMID:15665106 REFUTE PRIMARY RESULT Model Organism

"Activation of the stress-responsive, prohypertrophic calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP+/- mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP+/-/NFAT-luciferase reporter gene transgenic mice."

Contradicts the increased-signalling direction: halving MLP reduced calcineurin-NFAT activation after infarction in mice.

Why do heterozygous CSRP3 patient alleles cause HCM in humans when heterozygous knock-in mice stay normal, and why does the MLP-null mouse dilate while human CSRP3 knockouts hypertrophy?

HUMAN MODEL MISMATCH OPEN cmh12_heterozygous_model_gap

Attached to

animal_models#Csrp3 C58G knock-in mouse animal_models#Csrp3 (Mlp) knockout mouse pathophysiology#Maladaptive Hypertrophic Remodeling

The C58G knock-in halves MLP in heterozygotes without a cardiac phenotype, even with aging or pressure overload, while heterozygous humans develop late-onset HCM. Complete MLP loss gives dilated cardiomyopathy with hypertrophy in mice but adult HCM in humans. The differences may reflect lifespan (human disease appears in mid-life), species differences in load or myosin isoforms, or the mouse strain. Human stem-cell cardiomyocytes lacking MLP do take on hypertrophic features. A heterozygous patient-allele isogenic iPSC model, studied under load, would test whether partial MLP loss is enough in human cells.

Show evidence (3 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Heterozygous KI/+ mice did not develop an overt cardiac phenotype even upon aging up to 12 months (data not shown)."

The heterozygous mouse has no phenotype.

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."

The null mouse is dilated.

PMID:31406109 SUPPORT PRIMARY RESULT In Vitro

"MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."

Human MLP-null cells take on hypertrophic features.

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Pathophysiology

9

CSRP3 Germline Variant

Mechanism confidence: Established

The initiating lesion is a germline CSRP3 variant. Heterozygous HCM alleles are mostly missense changes at conserved residues of the first LIM domain (for example p.Leu44Pro, p.Ser54Arg/Glu55Gly and p.Cys58Gly), which binds alpha-actinin, plus the LIM2 allele p.Cys150Tyr. Biallelic truncating alleles remove the protein. The zinc-coordinating cysteine substitution p.Cys58Gly prevents zinc binding and folding of the first LIM domain.

Cardiomyocyte CL:0000746

CSRP3 hgnc:2472

Muscle alpha-actinin binding GO:0051371 ↓ DECREASED Zinc ion binding GO:0008270 ↓ DECREASED

Downstream

Reduced MLP Binding to Alpha-Actinin and N-RAP HCM missense alleles weaken MLP binding to its Z-disc and myofibrillar partners.

MLP Protein Destabilization and Depletion Misfolded LIM-domain mutants are unstable and degraded; truncating alleles produce no functional protein.

Show evidence (5 references)

PMID:12642359 SUPPORT PRIMARY RESULT Human Clinical

"We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls."

The founding report of CSRP3 missense variants in familial HCM.

PMID:12642359 SUPPORT PRIMARY RESULT Human Clinical

"All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with alpha-actinin and with certain muscle-specific transcription factors."

Places the HCM alleles in the alpha-actinin-binding LIM1 domain.

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene."

Linkage evidence establishing CSRP3 as an HCM gene.

+ 2 more references

Reduced MLP Binding to Alpha-Actinin and N-RAP

Mechanism confidence: Provisional

MLP forms a ternary complex with alpha-actinin, the main Z-disc actin cross-linker, and with N-RAP through separate binding sites. HCM missense alleles weaken both interactions. The authors of the C58G binding study proposed that the altered balance of this complex, and a compensatory rise in N-RAP when MLP falls, could lead to myocyte disarray. That step is a proposal and has not been tested.

Cardiomyocyte CL:0000746

Muscle alpha-actinin binding GO:0051371 ↓ DECREASED

Z disc GO:0030018

Downstream

Sarcomere Disorganization and Myocyte Disarray Proposed: an altered MLP-N-RAP-alpha-actinin equilibrium and compensatory N-RAP upregulation lead to myocyte disarray. Untested.

Show evidence (2 references)

PMID:15205937 SUPPORT PRIMARY RESULT In Vitro

"We show that MLP can form a ternary complex with two of its previously documented myofibrillar ligand proteins, N-RAP and alpha-actinin, which indicates the presence of distinct, non-overlapping binding sites."

Defines the complex whose binding the HCM alleles weaken.

PMID:15205937 SUPPORT PRIMARY RESULT In Vitro

"Our data also show that, in comparison to wild-type MLP, the capacity of the mutated MLP protein to bind both N-RAP and alpha-actinin is significantly decreased."

Reduced binding of C58G MLP to both partners.

MLP Protein Destabilization and Depletion

Mechanism confidence: Provisional

Unstable mutant MLP is degraded by the ubiquitin-proteasome system. In C58G knock-in mice, myocardial MLP falls to about 50% of normal in heterozygotes and about 20% in homozygotes, and two further HCM alleles are depleted in cultured cells. A C58G patient myocardium also showed reduced MLP, although MLP levels vary widely in failing and non-failing hearts. Biallelic truncating alleles give complete loss. Reduced functional MLP is therefore the common molecular end-point of the known pathogenic alleles; this has been shown in mice and cells, with one human tissue observation.

Cardiomyocyte CL:0000746

Proteasome-mediated degradation of mutant MLP GO:0043161 ↑ INCREASED

Animal models

Csrp3 C58G knock-in mouse Mouse recapitulates Carries the human allele and reproduces dose-dependent proteasomal MLP depletion.

Mlp W4R knock-in mouse Mouse recapitulates Reduced MLP mRNA and protein in knock-in hearts.

Downstream

Proteotoxic Stress Response Mutant C58G MLP engages BAG3 and induces a heat-shock chaperone response in homozygous knock-in hearts.

Disinhibited Calcineurin-NFAT Hypertrophic Signalling Lower MLP at the Z-disc releases calcineurin-NFAT signalling. Shown where MLP was depleted secondarily (MYH7 hypercontractility plus W4R) in human iPSC cardiomyocytes, and as calcineurin pathway activation in homozygous C58G knock-in hearts (about 20% of normal MLP); heterozygous knock-in hearts, with about 50% of normal MLP, showed no hypertrophic phenotype.

Abnormal Cardiomyocyte Calcium Handling MLP-null human stem-cell cardiomyocytes develop impaired calcium handling.

Sarcomere Disorganization and Myocyte Disarray Without MLP, human stem-cell cardiomyocytes develop disorganized sarcomeric ultrastructure, and strained rat myocytes lacking nuclear MLP develop disarrayed sarcomeres.

Skeletal myopathy MLP is also expressed in skeletal muscle. Its loss produces only mild skeletal muscle abnormalities in mice, consistent with the mild skeletal muscle disease described in CSRP3 HCM carriers. The intermediate steps are not known.

Show evidence (4 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%."

Gene-dose-dependent MLP depletion in C58G knock-in mouse hearts.

PMID:30048712 SUPPORT PRIMARY RESULT In Vitro

"We show that MLP depletion is caused by proteasome action."

The depletion is proteasomal.

PMID:30048712 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations."

The authors' conclusion that reduced functional MLP is a shared mechanism. The misspelling "CSPR3" is in the source.

+ 1 more reference

Proteotoxic Stress Response

Mechanism confidence: Hypothetical

In homozygous C58G knock-in hearts, the mutant protein binds the co-chaperone BAG3, heat shock proteins are induced, and a ubiquitin-proteasome reporter accumulates, indicating proteasomal overload. Whether this response contributes to hypertrophy, and whether it occurs at the lower mutant dose of heterozygous patients, is not known; the node has no downstream edge for that reason.

Cardiomyocyte CL:0000746

Response to unfolded protein GO:0006986 ↑ INCREASED

Show evidence (2 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins."

Proteotoxic chaperone response in homozygous knock-in hearts.

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"While the ubiquitin-GFP reporter protein was only detectable at low levels in WT and KI/+ mice, it clearly accumulated in KI/KI mice"

Proteasomal overload is detectable in homozygous but not heterozygous knock-in hearts, which is why the node is HYPOTHETICAL for heterozygous human disease.

Disinhibited Calcineurin-NFAT Hypertrophic Signalling

Mechanism confidence: Provisional

Reduced MLP at the Z-disc stretch-sensing complex is followed by increased calcineurin-NFAT activity and hypertrophic gene expression in human iPSC-derived cardiomyocytes, and homozygous C58G knock-in hearts induce calcineurin-responsive Rcan1.4. MLP also anchors calcineurin at the Z-disc, and a mouse study after myocardial infarction found the opposite direction (halving MLP blunted calcineurin-NFAT activation and the hearts dilated). The authors of the human study propose that MLP both restrains and facilitates Z-disc calcineurin, so the net direction may depend on the setting; the allelic dilated entry (Dilated Cardiomyopathy 1M) models the reduced direction. See the discussion on this node.

Cardiomyocyte CL:0000746

Calcineurin-NFAT signaling cascade GO:0033173 ↑ INCREASED

Z disc GO:0030018

Experimental models

Patient iPSC-derived cardiomyocytes and engineered heart tissue (MYH7 p.Arg723Cys with MLP W4R) IPSC DERIVED MODEL MLP reduction followed by calcineurin-NFAT disinhibition and hypertrophy.

Downstream

Maladaptive Hypertrophic Remodeling Calcineurin-NFAT activity drives the hypertrophic growth programme.

Show evidence (2 references)

PMID:35384713 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."

Calcineurin-NFAT disinhibition follows MLP reduction in human cardiomyocytes. INDIRECT because MLP loss there was secondary to a sarcomeric MYH7 variant plus W4R.

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Induction of proteins implicated in hypertrophic signalling, such as Fhl1, Ankrd1/cardiac ankyrin repeat protein (Carp) and calcineurin responsive Rcan1.4 was confirmed by Western blotting in KI/KI mice"

Calcineurin-responsive Rcan1.4 is induced in homozygous C58G knock-in hearts.

Abnormal Cardiomyocyte Calcium Handling

Mechanism confidence: Hypothetical

MLP-null human embryonic stem-cell cardiomyocytes develop impaired calcium handling with raised intracellular calcium, and restoring calcium homeostasis with verapamil prevents the hypertrophic and heart-failure phenotypes in culture. This has been shown only in a complete knockout cell model; it has not been measured in patient cells or tissue.

Cardiomyocyte CL:0000746

Intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL

Experimental models

MLP-knockout hESC-derived cardiomyocytes OTHER Impaired calcium handling that drives the hypertrophic phenotype.

Downstream

Maladaptive Hypertrophic Remodeling Raised intracellular calcium is required for the hypertrophic phenotype of MLP-null human cardiomyocytes.

Show evidence (1 reference)

PMID:31406109 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Cellular phenotypes of MLP-deficient hESC-CMs subsequently progressed to mimic heart failure (HF) by 30 days post differentiation, including exhibiting mitochondrial damage, increased ROS generation, and impaired Ca2+ handling."

Impaired calcium handling in MLP-null human cardiomyocytes. INDIRECT because the cells are a complete knockout, not a heterozygous patient allele.

Sarcomere Disorganization and Myocyte Disarray

Mechanism confidence: Provisional

Disorganized sarcomeric ultrastructure appears early in MLP-null human cardiomyocytes, and myocyte disarray is the characteristic histology of HCM. No CSRP3-specific human histology study was found, and no source states how cellular disarray feeds into tissue remodeling, so the node has no downstream edge.

Cardiomyocyte CL:0000746

Sarcomere organization GO:0045214 ⚠ ABNORMAL

Experimental models

MLP-knockout hESC-derived cardiomyocytes OTHER Disorganized sarcomeric ultrastructure.

Show evidence (1 reference)

PMID:31406109 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."

Sarcomere disorganization in MLP-null human cardiomyocytes. INDIRECT because the cells are a complete knockout, not a heterozygous patient allele.

Maladaptive Hypertrophic Remodeling

Mechanism confidence: Provisional

Cardiomyocyte hypertrophy with a fetal and hypertrophic gene programme produces the asymmetric, septum-predominant left ventricular wall thickening of clinical disease. In the C58G knock-in mouse, homozygotes develop increased heart weight with diastolic and systolic dysfunction and mild fibrosis, while heterozygotes show at most a small rise in anterior wall thickness. In patients, wall thickening is typically moderate (mean maximal wall thickness 18 mm in p.Cys150Tyr carriers).

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy in response to stress GO:0014898 ↑ INCREASED

Interventricular septum UBERON:0002094 Left ventricle UBERON:0002084

Animal models

Csrp3 C58G knock-in mouse Mouse partially recapitulates Homozygotes develop cardiomyopathy with increased heart weight.

Csrp3 (Mlp) knockout mouse Mouse partially recapitulates Hypertrophy is present but is accompanied by dilation and heart failure.

Downstream

Hypertrophic cardiomyopathy The remodelled, thickened left ventricle is clinical hypertrophic cardiomyopathy.

Asymmetric septal hypertrophy The hypertrophy is septum-predominant.

Myocardial Fibrotic Remodeling Profibrotic signalling and mild interstitial fibrosis accompany remodeling in homozygous knock-in hearts.

Show evidence (3 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements."

Ventricular remodeling in the patient-allele knock-in mouse.

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts."

Fetal gene and hypertrophic programmes in knock-in hearts.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm."

The degree of wall thickening in human heterozygous carriers.

Myocardial Fibrotic Remodeling

Mechanism confidence: Hypothetical

Profibrotic transcripts and mild interstitial fibrosis in homozygous C58G knock-in hearts. Heterozygous knock-in hearts show no fibrosis, and no CSRP3-specific human late gadolinium enhancement or histology series was found, so myocardial fibrosis is not curated as a patient phenotype.

Cardiac fibroblast CL:0002548

Show evidence (2 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Histological analysis showed no differences between WT and KI/+ mice, with no evidence of fibrosis"

Heterozygous knock-in hearts have no fibrosis, which limits the node to the homozygous model.

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"RNAseq findings and qPCR show concordant results with upregulation of key genes involved in hypertrophy and fibrosis such as Acta1, Myh7, Tgfb, Nppa, Nppb, Ankrd1/2."

Profibrotic gene expression in homozygous knock-in hearts.

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Pathograph

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Phenotypes

3

Cardiovascular 2

Hypertrophic cardiomyopathy HP:0001639

No frequency band is assigned. HCM is the ascertainment criterion for every reported case.

Show evidence (4 references)

PMID:12642359 SUPPORT PRIMARY RESULT Human Clinical

"We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls."

HCM in the founding CSRP3 families.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers."

Late-onset HCM in heterozygous p.Cys150Tyr carriers.

PMID:34558151 SUPPORT PRIMARY RESULT Human Clinical

"Through histopathological and imaging examinations, an obvious left ventricular hypertrophy was found in the proband."

Left ventricular hypertrophy in a Chinese family with a CSRP3 nonsense variant.

+ 1 more reference

Asymmetric septal hypertrophy HP:0001670

No frequency band is assigned; the only CSRP3-specific denominator is three probands.

Show evidence (2 references)

PMID:12642359 SUPPORT PRIMARY RESULT Human Clinical

"All 3 index patients were characterized by typical asymmetrical septal hypertrophy."

Asymmetric septal hypertrophy in all three founding probands.

PMID:17097056 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%)."

Septal morphology in Z-disc-gene HCM. INDIRECT because only one of the 13 carriers had a CSRP3 variant.

Musculoskeletal 1

Skeletal myopathy HP:0003756

Severity: MILD

Show evidence (1 reference)

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"We also present evidence for mild skeletal muscle disease in affected persons."

Mild skeletal muscle disease in CSRP3 HCM carriers.

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Genetic Associations

2

CSRP3 (Pathogenic CSRP3 variants: heterozygous LIM-domain missense variants and biallelic truncating variants. ClinGen classifies CSRP3 as Definitive for hypertrophic cardiomyopathy with semidominant inheritance.)

Gene: CSRP3 hgnc:2472 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (9 references)

CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z SUPPORT Other

ClinGen Definitive classification for CSRP3 in hypertrophic cardiomyopathy (generic HCM term), semidominant.

PMID:39971408 SUPPORT REVIEW SYNTHESIS Other

"CSRP3 was curated for a semidominant mode of inheritance (definitive)."

The 2025 ClinGen HCM gene reappraisal.

PMID:30681346 SUPPORT REVIEW SYNTHESIS Other

"Moderate level gene classifications included TNNC1, JPH2, and CSRP3, with evidence typically including either segregation evidence or reported de novo variants and some experimental evidence (Table 2)."

The earlier (2019) ClinGen classification, Moderate, since superseded.

+ 6 more references

Variants (6)

CSRP3 p.Cys58Gly (C58G)

LIM1 zinc-finger cysteine substitution. Cosegregates with HCM in a large four-generation family with genome-wide linkage. Abolishes zinc coordination, destabilizes MLP and reduces binding to alpha-actinin and N-RAP; the knock-in mouse loses about half of myocardial MLP as a heterozygote. A 2018 ACMG meta-analysis rated it the only likely pathogenic CSRP3 variant among those then reported.

CSRP3 p.Leu44Pro (L44P)

LIM1 missense allele reported in HCM; depleted by the proteasome in cultured cells.

CSRP3 p.Ser54Arg/Glu55Gly (S54R/E55G)

Double LIM1 missense allele reported in HCM; depleted by the proteasome in cultured cells.

CSRP3 p.Cys150Tyr (C150Y)

LIM2 missense allele found in 11 of 6,456 Spanish HCM index cases and absent from other cardiomyopathy and control groups. Heterozygotes develop late-onset, low-risk HCM with highly age-dependent penetrance; the single homozygote was more severely affected.

CSRP3 p.Arg122Ter (c.364C>T)

Nonsense allele (NM_003476.5:c.364C>T). Found homozygous in a Polish HCM patient, and cosegregating with HCM in a three-generation Chinese family (zygosity not stated in the cited abstract).

Homozygous CSRP3 truncating alleles

Two unrelated French HCM probands were the first reported human CSRP3 knockouts. A 2024 meta-analysis counted six reported adult HCM cases with biallelic CSRP3 truncating variants.

CSRP3 p.Trp4Arg (W4R) modifier allele (The common N-terminal W4R allele (up to 1% of people of European ancestry) is not a cause of HCM on its own but worsens the expression of sarcomeric (MYH7 and MYBPC3) HCM. It is recorded here so that a W4R result on CSRP3 testing is read as a modifier rather than as a CMH12 diagnosis; the HCM it modifies is sarcomeric, not CSRP3-caused.)

Gene: CSRP3 hgnc:2472 gene page relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (4 references)

PMID:35384713 SUPPORT PRIMARY RESULT In Vitro

"We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation."

W4R modifies sarcomeric HCM and is not sufficient alone.

PMID:35384713 SUPPORT PRIMARY RESULT In Vitro

"Further, while ectopic expression of MLP-W4R in healthy control iPSC-CMs did not cause any abnormalities, it significantly worsened the HCM defects in iPSC-CMs derived from five HCM patients bearing different MYH7 and MYBPC3 mutations"

The modifier effect is reproduced across several sarcomeric backgrounds.

PMID:16352453 SUPPORT PRIMARY RESULT Human Clinical

"Four of the seven patients with W4R-MLP in the present study also have a published HCM-associated myofilament mutation."

W4R often co-occurs with a sarcomeric variant in HCM patients.

+ 1 more reference

💊

Medical Actions

5

Cascade Screening and Cardiac Surveillance of At-Risk Relatives

Action: cascade genetic and cardiac screening of at-risk relatives Ontology label: Cardiac Disease Screening NCIT:C168126

Platform: Other

Predictive testing of first-degree relatives for the familial CSRP3 variant, then serial cardiac evaluation of carriers. In the p.Cys150Tyr families, relatives without the variant showed no disease, so the genotype is informative. Because penetrance is late, an unaffected young carrier stays under surveillance.

Show evidence (1 reference)

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease."

Family screening identifies carriers, and non-carriers are unaffected.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counseling should cover dominant transmission with late, incomplete penetrance, the more severe disease of homozygotes and the recessive-like presentation of biallelic truncating alleles (relevant in consanguineous families), and the modifier rather than causal status of W4R.

Show evidence (2 references)

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype."

Dose-dependent severity that counseling must convey.

PMID:31919335 SUPPORT PRIMARY RESULT Human Clinical

"This report expands the mutational spectrum and the inheritance pattern of HCM."

Biallelic inheritance is part of the CSRP3 spectrum.

Pharmacotherapy for Symptomatic Hypertrophic Cardiomyopathy

Action: Pharmacotherapy NCIT:C15986

Agent: metoprolol CHEBI:6904 verapamil CHEBI:9948 disopyramide CHEBI:4657

Platform: Small molecule

Standard HCM pharmacotherapy (beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide) for symptoms and outflow obstruction. No CSRP3-specific clinical study exists. In MLP-null human stem-cell cardiomyocytes, verapamil restored calcium homeostasis and prevented the hypertrophic phenotype, a preclinical observation that fits the calcium node but has not been tested in patients.

Mechanism Target:

INHIBITS Abnormal Cardiomyocyte Calcium Handling — Verapamil corrects the raised intracellular calcium of MLP-null cardiomyocytes in vitro.

Show evidence (1 reference)

PMID:31406109 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."

Preclinical rescue by verapamil. INDIRECT because it is a knockout cell model, not patients.

Cardiac Myosin Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten CHEBI:756998

Platform: Small molecule

Mavacamten improves exercise capacity and outflow obstruction in symptomatic obstructive HCM. The pivotal trial was not stratified by genotype and reports no CSRP3 carriers. In patient iPSC cardiomyocytes in which MLP was depleted secondarily to a sarcomeric variant combined with W4R, mavacamten raised MLP levels and suppressed calcineurin-NFAT signalling; whether it helps primary CSRP3 disease, in which MLP loss is caused by the CSRP3 variant itself, is untested.

Mechanism Target:

INHIBITS Disinhibited Calcineurin-NFAT Hypertrophic Signalling — Reducing crossbridge force restores MLP and lowers NFAT activity in secondary MLP depletion.

Show evidence (1 reference)

PMID:35384713 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Notably, administration of mavacamten resulted in a reproducible upregulation of MLP (Figure 5M and 5N) as well as downregulation of nuclear NFATc4 (Figure 5J and 5O), its target gene MCIP1, and NFAT-luciferase activities (Figure S5Y’ and 5Z’) in the proband CMs."

Mavacamten reverses MLP loss and NFAT activation in MYH7/W4R proband cardiomyocytes. INDIRECT because MLP loss there is secondary to a sarcomeric variant.

Show evidence (1 reference)

PMID:32871100 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."

Efficacy in obstructive HCM generally; applying it to CSRP3 carriers is an inference.

Implantable Cardioverter-Defibrillator

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

Platform: Device

Primary or secondary prevention of sudden death on standard HCM risk criteria. Risk models have not been validated for CSRP3, and heterozygous p.Cys150Tyr carriers had no adverse events over a mean of 11 years.

🔬

Diagnosis

3

Echocardiography

Imaging for unexplained left ventricular wall thickening, usually asymmetric septal hypertrophy, with grading of the septal contour. Serial imaging of carriers is needed because penetrance is late and age-dependent.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:17097056 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography."

Transthoracic echocardiography defines the septal morphology of Z-disc HCM, including the CSRP3 carrier in this series. INDIRECT because the series is not CSRP3-specific.

Clinical Evaluation for Nonsyndromic Hypertrophic Cardiomyopathy

The phenotype is established clinically, with phenocopies (storage, infiltrative and syndromic causes of left ventricular hypertrophy) excluded, following the general evaluation of a proband with nonsyndromic HCM. Nothing on imaging separates CSRP3 HCM from sarcomeric HCM.

Show evidence (1 reference)

PMID:20301725 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Provide an evaluation strategy to identify (when possible) the genetic cause of nonsyndromic HCM in a proband"

The GeneReviews overview sets out the evaluation of an HCM proband. INDIRECT because it covers HCM in general.

Multigene HCM Panel Testing Including CSRP3

CSRP3 is included on standard HCM gene panels. Interpretation should not treat W4R alone as a diagnosis, should look for a second CSRP3 allele (biallelic disease) and for a sarcomeric co-variant, and should take account of late, age-dependent penetrance when testing relatives.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:30012424 SUPPORT BACKGROUND Human Clinical

"Among them, CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing (NGS)."

CSRP3 is a standard panel gene.

PMID:16352453 SUPPORT PRIMARY RESULT Human Clinical

"The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation."

Reason for caution in interpreting W4R.

📈

Progression

2

Genotype-positive carrier before clinical expression

Heterozygous carriers can remain unaffected into late adulthood. In the p.Cys150Tyr families penetrance was highly age-dependent and the mean age at diagnosis was 55 years, so a normal echocardiogram in a young carrier does not exclude later disease.

Show evidence (2 references)

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The variant showed highly age-dependent penetrance."

Late, age-dependent penetrance.

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm."

Late mean age at diagnosis.

Established hypertrophic cardiomyopathy

For heterozygous p.Cys150Tyr carriers the course was benign, with no adverse events over a mean of 11 years. Biallelic disease is reported to be more severe. Outcome data for other CSRP3 alleles are too sparse to summarize.

Show evidence (1 reference)

PMID:33035702 SUPPORT PRIMARY RESULT Human Clinical

"After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients."

Low event rate in heterozygous carriers of one allele.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 12:

Dilated Cardiomyopathy 1M MONDO:0011840

Overlapping Features The allelic CSRP3 dilated designation (CMD1M), rated Limited by ClinGen and built mainly on the W4R and K69R alleles. A CSRP3 carrier with a dilated, poorly contracting ventricle should have end-stage HCM considered as well as CMD1M.

Distinguishing Features

Primary left ventricular dilation with systolic dysfunction rather than unexplained hypertrophy.

Show evidence (1 reference)

PMID:18505755 SUPPORT BACKGROUND Human Clinical

"Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations."

CSRP3 variants have been reported in both dilated and hypertrophic disease.

Sarcomeric Hypertrophic Cardiomyopathy MONDO:0005045

Overlapping Features HCM caused by variants in sarcomere genes such as MYBPC3 and MYH7, which explain most genotype-positive HCM. The clinical picture is the same, so only genetic testing separates them. A sarcomeric variant and a CSRP3 variant can occur together, including in families where double heterozygotes are more severely affected.

Distinguishing Features

A pathogenic variant in a sarcomere gene, with no pathogenic CSRP3 variant.

Show evidence (2 references)

PMID:16352453 SUPPORT PRIMARY RESULT Human Clinical

"Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."

CSRP3 and sarcomeric HCM are clinically alike.

PMID:20087448 SUPPORT PRIMARY RESULT Human Clinical

"Here we describe a family with double heterozygosity for pathogenic mutations in cysteine and glycine-rich protein 3 (CSRP3) and MYH7."

A CSRP3 variant and a sarcomeric variant can segregate in the same family.

🧫

Experimental Models

2

MLP-knockout hESC-derived cardiomyocytes OTHER

CRISPR/Cas9 CSRP3-null human embryonic stem cell line (H9) differentiated to cardiomyocytes. The cells develop hypertrophic features early and heart-failure features by 30 days, with impaired calcium handling; verapamil prevents the phenotype. Models complete loss of MLP, comparable to biallelic truncation.

Organism

human NCBITaxon:9606

Publication

PMID:31406109

Pathograph links

Abnormal Cardiomyocyte Calcium Handling recapitulates fidelity: moderate observes: cellular Impaired calcium handling that drives the hypertrophic phenotype.

Limitations: Complete knockout in immature stem-cell cardiomyocytes, not a heterozygous patient allele.

Show evidence (1 reference)

PMID:31406109 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."

Calcium dependence of the phenotype in the model.

Sarcomere Disorganization and Myocyte Disarray recapitulates fidelity: moderate observes: cellular Disorganized sarcomeric ultrastructure.

Limitations: Immature cardiomyocytes and a null genotype.

Show evidence (1 reference)

PMID:31406109 SUPPORT PRIMARY RESULT In Vitro

"MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."

Sarcomere disorganization in the model.

Patient iPSC-derived cardiomyocytes and engineered heart tissue (MYH7 p.Arg723Cys with MLP W4R) IPSC_DERIVED_MODEL

Cardiomyocytes and engineered heart tissue from an HCM proband carrying MYH7 p.Arg723Cys and MLP W4R, with gene-edited corrections. Increased force destabilizes the Z-disc MLP complex, MLP falls and calcineurin-NFAT is disinhibited; correcting either variant, or mavacamten, rescues the phenotype. Here MLP depletion is secondary to a sarcomeric variant, so the model informs the downstream steps of CMH12 rather than its initiating lesion.

Organism

human NCBITaxon:9606

Publication

PMID:35384713

Pathograph links

Disinhibited Calcineurin-NFAT Hypertrophic Signalling recapitulates fidelity: moderate observes: cellular MLP reduction followed by calcineurin-NFAT disinhibition and hypertrophy.

Limitations: MLP loss is secondary to MYH7 hypercontractility plus W4R, not to a pathogenic CSRP3 allele.

Divergences from the human mechanism

cause unrepresented qualifying

The initiating lesion is a sarcomeric MYH7 variant; no primary CSRP3 HCM allele is present, so only the steps after MLP loss are modelled.

Show evidence (1 reference)

PMID:35384713 SUPPORT PRIMARY RESULT In Vitro

"Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."

The signalling step in the model.

🐁

Animal Models

3

Csrp3 C58G knock-in mouse

The first knock-in of a clearly pathogenic CSRP3 HCM allele. Homozygotes develop cardiomyopathy with diastolic and systolic dysfunction, increased heart weight, fetal and hypertrophic gene programmes, calcineurin pathway activation, mild fibrosis and a proteotoxic response. Heterozygotes lose about half of myocardial MLP but have no overt phenotype at baseline, with aging to 12 months, or after pressure overload.

Species

Mouse

Genotype

Csrp3 p.C58G knock-in, heterozygous (KI/+) and homozygous (KI/KI)

Publication

PMID:30048712

Pathograph links

MLP Protein Destabilization and Depletion recapitulates fidelity: high observes: molecular Carries the human allele and reproduces dose-dependent proteasomal MLP depletion.

Limitations: Mouse myocardium; whether human heterozygous myocardium loses the same fraction of MLP has been examined only in one patient sample.

Show evidence (1 reference)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%."

MLP depletion in the model.

Maladaptive Hypertrophic Remodeling partially recapitulates fidelity: moderate observes: organism Homozygotes develop cardiomyopathy with increased heart weight.

Limitations: Only homozygotes are affected, whereas most patients are heterozygous; the phenotype combines diastolic and systolic dysfunction rather than isolated septal hypertrophy.

Divergences from the human mechanism

species mismatch qualifying

Heterozygous knock-in mice, the genotype of most patients, have no overt cardiac phenotype, whereas heterozygous humans develop (late-onset) HCM.

Show evidence (2 references)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements."

The homozygous phenotype.

+ 1 more reference

Show evidence (1 reference)

PMID:30048712 SUPPORT PRIMARY RESULT Model Organism

"In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP."

The authors' statement of the model's purpose.

Mlp W4R knock-in mouse

Knock-in of the common W4R allele. Heterozygous and homozygous mice develop age- and dose-dependent hypertrophic cardiomyopathy and heart failure with reduced MLP and weaker telethonin binding. Human carriers of W4R alone are usually unaffected, so the model overstates the allele's effect in humans.

Species

Mouse

Genotype

Mlp(W4R/+) and Mlp(W4R/W4R) knock-in

Publication

PMID:20044516

Pathograph links

MLP Protein Destabilization and Depletion recapitulates fidelity: moderate observes: molecular Reduced MLP mRNA and protein in knock-in hearts.

Limitations: W4R is a modifier in humans; the reduction here is caused by an allele that does not cause HCM on its own in people.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals."

MLP reduction in the model.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under..."

The knock-in phenotype is hypertrophic cardiomyopathy.

Csrp3 (Mlp) knockout mouse

The classic MLP-null mouse. Hearts are soft at birth with disrupted cytoarchitecture, and the mice develop dilated cardiomyopathy with hypertrophy and heart failure. Human complete loss of CSRP3 (biallelic truncation) gives adult HCM instead.

Species

Mouse

Genotype

Csrp3-/- (MLP-/-), homozygous null

Publication

PMID:9039266

Pathograph links

Maladaptive Hypertrophic Remodeling partially recapitulates fidelity: low observes: organism Hypertrophy is present but is accompanied by dilation and heart failure.

Limitations: The dominant remodeling phenotype in the mouse is dilated, not hypertrophic.

Divergences from the human mechanism

species mismatch qualifying

Complete MLP loss gives dilated cardiomyopathy with hypertrophy in the mouse but hypertrophic cardiomyopathy in humans with biallelic truncating CSRP3 variants.

Show evidence (1 reference)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."

Mixed dilated and hypertrophic phenotype of the null mouse.

Show evidence (1 reference)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture."

The structural lesion of complete MLP loss.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 12
creation_date: "2026-10-13T00:00:00Z"
category: Mendelian
synonyms:
- CMH12
- cardiomyopathy, familial hypertrophic, 12
- cardiomyopathy, hypertrophic, 12
- hypertrophic cardiomyopathy type 12
- CSRP3-related hypertrophic cardiomyopathy
- muscle LIM protein-related hypertrophic cardiomyopathy
description: >-
  Hypertrophic cardiomyopathy 12 (CMH12) is familial hypertrophic cardiomyopathy caused by
  germline variants in CSRP3, which encodes muscle LIM protein (MLP). MLP is a small
  striated-muscle protein with two zinc-finger LIM domains. It is found at the Z-disc and
  costamere, in the cytosol and in the nucleus, and is not an integral part of the sarcomere,
  so CSRP3 is one of the few established non-sarcomeric HCM genes.

  The first CSRP3 HCM variants were missense changes in the first LIM domain that cosegregated
  with disease and weakened MLP binding to alpha-actinin (2003). Linkage in a large German
  family and segregation in four more families confirmed the gene in 2008. Later reports added
  homozygous truncating alleles (human CSRP3 knockouts) with adult-onset HCM, and a LIM2
  missense allele, p.Cys150Tyr, that causes late-onset, low-risk HCM in heterozygotes and a more
  severe phenotype in a homozygote. ClinGen now classifies CSRP3 as Definitive for hypertrophic
  cardiomyopathy with semidominant inheritance. Patients with CSRP3-associated HCM resemble
  patients with sarcomeric HCM clinically; asymmetric septal hypertrophy is the usual pattern,
  and mild skeletal muscle involvement has been described.

  The best-supported mechanism is loss of functional MLP. Pathogenic LIM-domain missense
  proteins misfold and are cleared by the proteasome, so heterozygous knock-in mouse hearts keep
  about half the normal MLP, and biallelic truncation removes it. Loss of MLP is linked to
  disinhibited calcineurin-NFAT hypertrophic signalling, disturbed calcium handling and
  sarcomere disorganisation in human stem-cell-derived cardiomyocytes. The common N-terminal
  allele p.Trp4Arg (W4R) is carried by up to 1% of Europeans and is curated here as a modifier,
  not a cause. The allelic dilated phenotype is a separate entry (Dilated Cardiomyopathy 1M).
disease_term:
  preferred_term: hypertrophic cardiomyopathy 12
  term:
    id: MONDO:0012804
    label: hypertrophic cardiomyopathy 12
parents:
- Hypertrophic Cardiomyopathy
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant
  description: >-
    Most reported CSRP3 HCM alleles are heterozygous missense variants that cosegregate with
    disease in families, which is the autosomal dominant pattern recorded by OMIM. Penetrance is
    incomplete and strongly age-dependent: in the p.Cys150Tyr families, carriers were diagnosed
    at a mean of 55 years and wild-type relatives were unaffected. Expressivity is variable.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP."
    explanation: >-
      Heterozygous LIM1 missense variants cosegregate with HCM in families, the dominant
      transmission pattern.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families."
    explanation: Segregation of CSRP3 missense variants with HCM in further families.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The variant showed highly age-dependent penetrance."
    explanation: Penetrance of the heterozygous p.Cys150Tyr allele depends strongly on age.
- name: Semidominant
  description: >-
    ClinGen curated CSRP3 for hypertrophic cardiomyopathy as semidominant: heterozygous variants
    cause disease, and biallelic variants cause disease that is at least as penetrant and, for
    p.Cys150Tyr, more severe. Homozygous truncating CSRP3 alleles (complete loss of MLP) have
    been reported in several adult HCM probands, and CSRP3 variants are found in the homozygous
    state unusually often in a highly consanguineous Egyptian HCM cohort. One group argued from
    the first homozygous truncating cases that CSRP3 HCM may be recessive rather than dominant;
    the semidominant classification covers both observations.
  inheritance_term:
    preferred_term: Semidominant inheritance
    term:
      id: HP:0032113
      label: Semidominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z
    reference_title: "CSRP3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | hypertrophic cardiomyopathy | MONDO:0005045 | SD | Definitive"
    explanation: >-
      ClinGen records the mode of inheritance for CSRP3 in hypertrophic cardiomyopathy as SD
      (semidominant). The assertion is for the generic HCM term; see the genetic notes.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CSRP3 was curated for a semidominant mode of inheritance (definitive)."
    explanation: The expert-panel reappraisal that assigned the semidominant mode.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype."
    explanation: Gene-dose effect for one allele, the hallmark of semidominance.
  - reference: PMID:30012424
    reference_title: "First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "More surprisingly, our molecular study led also to detect, for the first time, homozygous CSRP3 truncating variants in two unrelated HCM probands."
    explanation: Biallelic loss-of-function alleles cause HCM.
  - reference: PMID:31919335
    reference_title: "Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity."
    explanation: A further homozygous truncating CSRP3 HCM case.
  - reference: PMID:38666070
    reference_title: "Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Conversely, biallelic PTVs in CSRP3 are seemingly associated with HCM in adults (based on six reported cases), with ages at onset not dissimilar to standard autosomal dominant HCM, even though most reported pathogenic variants in this gene are associated with dominant inheritance (for both missense variants and PTVs)"
    explanation: >-
      Meta-analysis of published biallelic cases: biallelic truncation gives adult HCM, while
      most pathogenic CSRP3 variants act dominantly.
  - reference: PMID:37431535
    reference_title: "Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Homozygous variants were particularly enriched in three minor HCM genes—CSRP3 and the MLC genes MYL2 and MYL318 (Table 3)."
    explanation: >-
      Homozygous CSRP3 variants are enriched in a consanguineous Egyptian HCM cohort. The "18"
      after MYL3 is a reference number in the source.
pathophysiology:
- name: CSRP3 Germline Variant
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion is a germline CSRP3 variant. Heterozygous HCM alleles are mostly
    missense changes at conserved residues of the first LIM domain (for example p.Leu44Pro,
    p.Ser54Arg/Glu55Gly and p.Cys58Gly), which binds alpha-actinin, plus the LIM2 allele
    p.Cys150Tyr. Biallelic truncating alleles remove the protein. The zinc-coordinating
    cysteine substitution p.Cys58Gly prevents zinc binding and folding of the first LIM domain.
  genes:
  - preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  molecular_functions:
  - preferred_term: Muscle alpha-actinin binding
    term:
      id: GO:0051371
      label: muscle alpha-actinin binding
    modifier: DECREASED
  - preferred_term: Zinc ion binding
    term:
      id: GO:0008270
      label: zinc ion binding
    modifier: DECREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls."
    explanation: The founding report of CSRP3 missense variants in familial HCM.
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with alpha-actinin and with certain muscle-specific transcription factors."
    explanation: Places the HCM alleles in the alpha-actinin-binding LIM1 domain.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene."
    explanation: Linkage evidence establishing CSRP3 as an HCM gene.
  - reference: PMID:15205937
    reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "In addition, this single point mutation prevents zinc coordination and proper folding of the second zinc-finger in the first LIM domain, which consequently renders the protein less stable and more susceptible to proteolysis."
    explanation: >-
      The C58G substitution abolishes zinc coordination by the LIM1 domain, which supports the
      decreased zinc-binding annotation for this allele.
  - reference: PMID:30012424
    reference_title: "First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "More surprisingly, our molecular study led also to detect, for the first time, homozygous CSRP3 truncating variants in two unrelated HCM probands."
    explanation: Biallelic truncating alleles are a second class of initiating lesion.
  downstream:
  - target: Reduced MLP Binding to Alpha-Actinin and N-RAP
    causal_link_type: DIRECT
    description: >-
      HCM missense alleles weaken MLP binding to its Z-disc and myofibrillar partners.
    evidence:
    - reference: PMID:12642359
      reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to alpha-actinin."
      explanation: The variant-to-binding step, measured in protein-binding assays.
    - reference: PMID:15205937
      reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Our data also show that, in comparison to wild-type MLP, the capacity of the mutated MLP protein to bind both N-RAP and alpha-actinin is significantly decreased."
      explanation: C58G MLP binds both partners less well.
  - target: MLP Protein Destabilization and Depletion
    causal_link_type: DIRECT
    description: >-
      Misfolded LIM-domain mutants are unstable and degraded; truncating alleles produce no
      functional protein.
    evidence:
    - reference: PMID:15205937
      reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "In addition, this single point mutation prevents zinc coordination and proper folding of the second zinc-finger in the first LIM domain, which consequently renders the protein less stable and more susceptible to proteolysis."
      explanation: Misfolding of the LIM1 zinc finger makes the C58G protein unstable.
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G)."
      explanation: Depletion is not unique to C58G; two more HCM alleles are depleted in cells.
- name: Reduced MLP Binding to Alpha-Actinin and N-RAP
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    MLP forms a ternary complex with alpha-actinin, the main Z-disc actin cross-linker, and with
    N-RAP through separate binding sites. HCM missense alleles weaken both interactions. The
    authors of the C58G binding study proposed that the altered balance of this complex, and a
    compensatory rise in N-RAP when MLP falls, could lead to myocyte disarray. That step is a
    proposal and has not been tested.
  molecular_functions:
  - preferred_term: Muscle alpha-actinin binding
    term:
      id: GO:0051371
      label: muscle alpha-actinin binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:15205937
    reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We show that MLP can form a ternary complex with two of its previously documented myofibrillar ligand proteins, N-RAP and alpha-actinin, which indicates the presence of distinct, non-overlapping binding sites."
    explanation: Defines the complex whose binding the HCM alleles weaken.
  - reference: PMID:15205937
    reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Our data also show that, in comparison to wild-type MLP, the capacity of the mutated MLP protein to bind both N-RAP and alpha-actinin is significantly decreased."
    explanation: Reduced binding of C58G MLP to both partners.
  downstream:
  - target: Sarcomere Disorganization and Myocyte Disarray
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed: an altered MLP-N-RAP-alpha-actinin equilibrium and compensatory N-RAP
      upregulation lead to myocyte disarray. Untested.
    evidence:
    - reference: PMID:15205937
      reference_title: "Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "This assumption is supported by the previous observation that in the pathological situation accompanied by MLP down regulation, cardiomyocytes try to compensate for the decreased stability of MLP protein by increasing the expression of its ligand N-RAP, which might finally result in the development of myocyte disarray that is characteristic of this disease."
      explanation: >-
        The authors' hypothesis linking the binding defect to disarray. INDIRECT because it is
        stated as a possibility, not shown.
- name: MLP Protein Destabilization and Depletion
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Unstable mutant MLP is degraded by the ubiquitin-proteasome system. In C58G knock-in mice,
    myocardial MLP falls to about 50% of normal in heterozygotes and about 20% in homozygotes,
    and two further HCM alleles are depleted in cultured cells. A C58G patient myocardium also
    showed reduced MLP, although MLP levels vary widely in failing and non-failing hearts.
    Biallelic truncating alleles give complete loss. Reduced functional MLP is therefore the
    common molecular end-point of the known pathogenic alleles; this has been shown in mice and
    cells, with one human tissue observation.
  biological_processes:
  - preferred_term: Proteasome-mediated degradation of mutant MLP
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%."
    explanation: Gene-dose-dependent MLP depletion in C58G knock-in mouse hearts.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We show that MLP depletion is caused by proteasome action."
    explanation: The depletion is proteasomal.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations."
    explanation: >-
      The authors' conclusion that reduced functional MLP is a shared mechanism. The misspelling
      "CSPR3" is in the source.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation."
    explanation: Human myocardial evidence that a mutant MLP is destabilized.
  downstream:
  - target: Proteotoxic Stress Response
    causal_link_type: DIRECT
    description: >-
      Mutant C58G MLP engages BAG3 and induces a heat-shock chaperone response in homozygous
      knock-in hearts.
    evidence:
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins."
      explanation: The mutant protein triggers a proteotoxic response.
  - target: Disinhibited Calcineurin-NFAT Hypertrophic Signalling
    causal_link_type: DIRECT
    description: >-
      Lower MLP at the Z-disc releases calcineurin-NFAT signalling. Shown where MLP was depleted
      secondarily (MYH7 hypercontractility plus W4R) in human iPSC cardiomyocytes, and as
      calcineurin pathway activation in homozygous C58G knock-in hearts (about 20% of normal
      MLP); heterozygous knock-in hearts, with about 50% of normal MLP, showed no hypertrophic
      phenotype.
    evidence:
    - reference: PMID:35384713
      reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."
      explanation: >-
        Reduced MLP disinhibits calcineurin-NFAT in human cardiomyocytes. INDIRECT because MLP
        loss there was secondary to a sarcomeric MYH7 variant, not to a primary CSRP3 lesion.
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "At the molecular level, unbiased transcriptome profiling combined with analyses of specific gene and protein candidates provided clear evidence of cardiac remodelling and activation of hypertrophic signalling pathways, including calcineurin signalling, in KI homozygotes."
      explanation: Calcineurin signalling is activated in MLP-depleted C58G knock-in hearts.
  - target: Abnormal Cardiomyocyte Calcium Handling
    causal_link_type: DIRECT
    description: >-
      MLP-null human stem-cell cardiomyocytes develop impaired calcium handling.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Cellular phenotypes of MLP-deficient hESC-CMs subsequently progressed to mimic heart failure (HF) by 30 days post differentiation, including exhibiting mitochondrial damage, increased ROS generation, and impaired Ca2+ handling."
      explanation: >-
        Loss of MLP disturbs calcium handling in human cardiomyocytes. INDIRECT because the cells
        are a complete knockout, comparable to biallelic truncation rather than to a
        heterozygous missense allele.
  - target: Sarcomere Disorganization and Myocyte Disarray
    causal_link_type: DIRECT
    description: >-
      Without MLP, human stem-cell cardiomyocytes develop disorganized sarcomeric ultrastructure,
      and strained rat myocytes lacking nuclear MLP develop disarrayed sarcomeres.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."
      explanation: >-
        Loss of MLP disorganizes the sarcomere in human cardiomyocytes. INDIRECT because the cells
        are a complete knockout, not a heterozygous patient allele.
    - reference: PMID:19376126
      reference_title: "Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, cyclic strain of myocytes after prior NLS treatment to remove nuclear MLP resulted in disarrayed sarcomeres."
      explanation: >-
        Removing nuclear MLP from rat neonatal myocytes under strain disarrays the sarcomeres.
        INDIRECT because this is a pharmacological block of MLP shuttling, not a CSRP3 variant.
  - target: Skeletal myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      MLP is also expressed in skeletal muscle. Its loss produces only mild skeletal muscle
      abnormalities in mice, consistent with the mild skeletal muscle disease described in
      CSRP3 HCM carriers. The intermediate steps are not known.
    evidence:
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: "Of equal importance is probably the observation that loss of MLP is associated with a severe spontaneous cardiac phenotype but only very mild skeletal muscle abnormality"
      explanation: >-
        Loss of MLP in mice gives mild skeletal muscle abnormality. INDIRECT because it is mouse
        data summarized in a review.
- name: Proteotoxic Stress Response
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In homozygous C58G knock-in hearts, the mutant protein binds the co-chaperone BAG3, heat
    shock proteins are induced, and a ubiquitin-proteasome reporter accumulates, indicating
    proteasomal overload. Whether this response contributes to hypertrophy, and whether it
    occurs at the lower mutant dose of heterozygous patients, is not known; the node has no
    downstream edge for that reason.
  biological_processes:
  - preferred_term: Response to unfolded protein
    term:
      id: GO:0006986
      label: response to unfolded protein
    modifier: INCREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins."
    explanation: Proteotoxic chaperone response in homozygous knock-in hearts.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "While the ubiquitin-GFP reporter protein was only detectable at low levels in WT and KI/+ mice, it clearly accumulated in KI/KI mice"
    explanation: >-
      Proteasomal overload is detectable in homozygous but not heterozygous knock-in hearts,
      which is why the node is HYPOTHETICAL for heterozygous human disease.
- name: Disinhibited Calcineurin-NFAT Hypertrophic Signalling
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Reduced MLP at the Z-disc stretch-sensing complex is followed by increased calcineurin-NFAT
    activity and hypertrophic gene expression in human iPSC-derived cardiomyocytes, and
    homozygous C58G knock-in hearts induce calcineurin-responsive Rcan1.4. MLP also anchors
    calcineurin at the Z-disc, and a mouse study after myocardial infarction found the opposite
    direction (halving MLP blunted calcineurin-NFAT activation and the hearts dilated). The
    authors of the human study propose that MLP both restrains and facilitates Z-disc
    calcineurin, so the net direction may depend on the setting; the allelic dilated entry
    (Dilated Cardiomyopathy 1M) models the reduced direction. See the discussion on this node.
  biological_processes:
  - preferred_term: Calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: INCREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35384713
    reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."
    explanation: >-
      Calcineurin-NFAT disinhibition follows MLP reduction in human cardiomyocytes. INDIRECT
      because MLP loss there was secondary to a sarcomeric MYH7 variant plus W4R.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Induction of proteins implicated in hypertrophic signalling, such as Fhl1, Ankrd1/cardiac ankyrin repeat protein (Carp) and calcineurin responsive Rcan1.4 was confirmed by Western blotting in KI/KI mice"
    explanation: Calcineurin-responsive Rcan1.4 is induced in homozygous C58G knock-in hearts.
  downstream:
  - target: Maladaptive Hypertrophic Remodeling
    causal_link_type: DIRECT
    description: >-
      Calcineurin-NFAT activity drives the hypertrophic growth programme.
    evidence:
    - reference: PMID:35384713
      reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."
      explanation: >-
        The same sentence states that the signalling promoted hypertrophy. INDIRECT because the
        cells carry a sarcomeric MYH7 variant, not a primary CSRP3 allele.
- name: Abnormal Cardiomyocyte Calcium Handling
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    MLP-null human embryonic stem-cell cardiomyocytes develop impaired calcium handling with
    raised intracellular calcium, and restoring calcium homeostasis with verapamil prevents the
    hypertrophic and heart-failure phenotypes in culture. This has been shown only in a complete
    knockout cell model; it has not been measured in patient cells or tissue.
  biological_processes:
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31406109
    reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Cellular phenotypes of MLP-deficient hESC-CMs subsequently progressed to mimic heart failure (HF) by 30 days post differentiation, including exhibiting mitochondrial damage, increased ROS generation, and impaired Ca2+ handling."
    explanation: >-
      Impaired calcium handling in MLP-null human cardiomyocytes. INDIRECT because the cells are
      a complete knockout, not a heterozygous patient allele.
  downstream:
  - target: Maladaptive Hypertrophic Remodeling
    causal_link_type: DIRECT
    description: >-
      Raised intracellular calcium is required for the hypertrophic phenotype of MLP-null human
      cardiomyocytes.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."
      explanation: >-
        Correcting calcium homeostasis prevents the hypertrophic phenotype. INDIRECT because this
        is a knockout cell model in culture.
- name: Sarcomere Disorganization and Myocyte Disarray
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Disorganized sarcomeric ultrastructure appears early in MLP-null human cardiomyocytes, and
    myocyte disarray is the characteristic histology of HCM. No CSRP3-specific human histology
    study was found, and no source states how cellular disarray feeds into tissue remodeling,
    so the node has no downstream edge.
  biological_processes:
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31406109
    reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."
    explanation: >-
      Sarcomere disorganization in MLP-null human cardiomyocytes. INDIRECT because the cells are
      a complete knockout, not a heterozygous patient allele.
- name: Maladaptive Hypertrophic Remodeling
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  mechanism_confidence: PROVISIONAL
  description: >-
    Cardiomyocyte hypertrophy with a fetal and hypertrophic gene programme produces the
    asymmetric, septum-predominant left ventricular wall thickening of clinical disease. In the
    C58G knock-in mouse, homozygotes develop increased heart weight with diastolic and systolic
    dysfunction and mild fibrosis, while heterozygotes show at most a small rise in anterior wall
    thickness. In patients, wall thickening is typically moderate (mean maximal wall thickness
    18 mm in p.Cys150Tyr carriers).
  locations:
  - preferred_term: Interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy in response to stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements."
    explanation: Ventricular remodeling in the patient-allele knock-in mouse.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts."
    explanation: Fetal gene and hypertrophic programmes in knock-in hearts.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm."
    explanation: The degree of wall thickening in human heterozygous carriers.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: The remodelled, thickened left ventricle is clinical hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:16352453
      reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation."
      explanation: >-
        CSRP3-associated disease has the clinical HCM phenotype of sarcomeric disease. INDIRECT
        because the cohort pools MLP and TCAP carriers and includes W4R carriers.
  - target: Asymmetric septal hypertrophy
    causal_link_type: DIRECT
    description: The hypertrophy is septum-predominant.
    evidence:
    - reference: PMID:12642359
      reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "All 3 index patients were characterized by typical asymmetrical septal hypertrophy."
      explanation: Septal-predominant hypertrophy in the founding CSRP3 probands.
  - target: Myocardial Fibrotic Remodeling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Profibrotic signalling and mild interstitial fibrosis accompany remodeling in homozygous
      knock-in hearts.
    evidence:
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In contrast, KI/KI mice showed signs of fibrosis, albeit mild, on Sirius Red staining"
      explanation: Mild fibrosis in remodelled homozygous knock-in hearts.
- name: Myocardial Fibrotic Remodeling
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Profibrotic transcripts and mild interstitial fibrosis in homozygous C58G knock-in hearts.
    Heterozygous knock-in hearts show no fibrosis, and no CSRP3-specific human late gadolinium
    enhancement or histology series was found, so myocardial fibrosis is not curated as a
    patient phenotype.
  cell_types:
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Histological analysis showed no differences between WT and KI/+ mice, with no evidence of fibrosis"
    explanation: Heterozygous knock-in hearts have no fibrosis, which limits the node to the homozygous model.
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "RNAseq findings and qPCR show concordant results with upregulation of key genes involved in hypertrophy and fibrosis such as Acta1, Myh7, Tgfb, Nppa, Nppb, Ankrd1/2."
    explanation: Profibrotic gene expression in homozygous knock-in hearts.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  description: >-
    The defining diagnosis. Disease in heterozygous carriers is usually adult-onset; in the
    p.Cys150Tyr families the mean age at diagnosis was 55 years. CSRP3-associated HCM clinically
    resembles sarcomeric HCM.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  diagnostic: true
  evidence:
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls."
    explanation: HCM in the founding CSRP3 families.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers."
    explanation: Late-onset HCM in heterozygous p.Cys150Tyr carriers.
  - reference: PMID:34558151
    reference_title: "CSRP3, p.Arg122*, is responsible for hypertrophic cardiomyopathy in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Through histopathological and imaging examinations, an obvious left ventricular hypertrophy was found in the proband."
    explanation: Left ventricular hypertrophy in a Chinese family with a CSRP3 nonsense variant.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."
    explanation: The clinical picture matches sarcomeric HCM (cohort pools MLP and TCAP carriers).
  notes: >-
    No frequency band is assigned. HCM is the ascertainment criterion for every reported case.
- category: Cardiovascular
  name: Asymmetric septal hypertrophy
  description: >-
    The usual morphology. All three founding probands had asymmetric septal hypertrophy. In a
    Mayo Clinic series of Z-disc-gene HCM (one CSRP3 carrier among 13), the septal contour was
    sigmoidal in 85%, which the authors contrast with myofilament HCM.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  evidence:
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All 3 index patients were characterized by typical asymmetrical septal hypertrophy."
    explanation: Asymmetric septal hypertrophy in all three founding probands.
  - reference: PMID:17097056
    reference_title: "Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%)."
    explanation: >-
      Septal morphology in Z-disc-gene HCM. INDIRECT because only one of the 13 carriers had a
      CSRP3 variant.
  notes: >-
    No frequency band is assigned; the only CSRP3-specific denominator is three probands.
- category: Musculoskeletal
  name: Skeletal myopathy
  description: >-
    Mild skeletal muscle disease was described in affected persons with CSRP3 missense variants
    in the 2008 linkage and segregation study. MLP is expressed in skeletal as well as cardiac
    muscle. The type and frequency of the skeletal findings are not given in the cited abstract,
    so no frequency is assigned.
  phenotype_term:
    preferred_term: Mild skeletal myopathy
    term:
      id: HP:0003756
      label: Skeletal myopathy
    severity: MILD
  evidence:
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We also present evidence for mild skeletal muscle disease in affected persons."
    explanation: Mild skeletal muscle disease in CSRP3 HCM carriers.
genetic:
- name: CSRP3
  gene_term:
    preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Pathogenic CSRP3 variants: heterozygous LIM-domain missense variants and biallelic
    truncating variants. ClinGen classifies CSRP3 as Definitive for hypertrophic cardiomyopathy
    with semidominant inheritance.
  notes: >-
    Gene-disease validity. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
    classifies CSRP3 as Definitive for hypertrophic cardiomyopathy, semidominant (SD), SOP9,
    dated 2023-08-09 (CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z).
    That assertion is filed against the generic term hypertrophic cardiomyopathy
    (MONDO:0005045), not against MONDO:0012804, so it is cited as ordinary evidence and not
    copied into gene_disease_validity. relationship_type CAUSATIVE follows the Definitive tier,
    as for the sibling FHOD3 entry (Hypertrophic Cardiomyopathy 28). The classification has
    risen over time: the 2019 ClinGen HCM curation placed CSRP3 in the Moderate group, and the
    2025 reappraisal made it Definitive with a semidominant mode. A 2026 multi-biobank analysis
    found a positive effect size for CSRP3 that was nominally significant but did not survive
    Bonferroni correction, as for other uncommon Definitive genes. The CSRP3 dilated
    cardiomyopathy assertion (Limited, AD, MONDO:0011840) belongs to the allelic entry Dilated
    Cardiomyopathy 1M.

    Case fraction. No reliable CSRP3 share of HCM exists. A Mayo Clinic series found CSRP3
    variants in 12 of 389 HCM probands, but seven of the twelve were the common W4R allele and
    several carriers also had a sarcomeric variant. The p.Cys150Tyr allele alone was found in 11
    of 6,456 HCM index cases in a Spanish multicentre series.
  evidence:
  - reference: CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z
    reference_title: "CSRP3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | hypertrophic cardiomyopathy | MONDO:0005045 | SD | Definitive"
    explanation: >-
      ClinGen Definitive classification for CSRP3 in hypertrophic cardiomyopathy (generic HCM
      term), semidominant.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CSRP3 was curated for a semidominant mode of inheritance (definitive)."
    explanation: The 2025 ClinGen HCM gene reappraisal.
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Moderate level gene classifications included TNNC1, JPH2, and CSRP3, with evidence typically including either segregation evidence or reported de novo variants and some experimental evidence (Table 2)."
    explanation: The earlier (2019) ClinGen classification, Moderate, since superseded.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene."
    explanation: Linkage evidence for causation.
  - reference: PMID:12642359
    reference_title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP."
    explanation: Cosegregation in the founding families.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001)."
    explanation: Case-control enrichment of one CSRP3 allele in HCM.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "CSRP3 2167 60647 0.00081 1.28 (0.63–2.60) 0.22 (0.00–0.61) 0.00102 3.82 (1.14–12.7) 0.74 (0.00–0.92)"
    explanation: >-
      The CSRP3 row in the hypertrophic cardiomyopathy section of Table 1 (2,167 cases against
      60,647 ExAC samples). Truncating variants are enriched in cases (OR 3.82, 95% CI
      1.14-12.7), while the non-truncating odds ratio (1.28) is not significant.
  - reference: PMID:37431535
    reference_title: "Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Regarding minor nonsarcomeric HCM genes, rare variants in both CSRP3 (truncating and nontruncating) and JPH2 (nontruncating) are more prevalent in the Egypt HCM cohort, as seen in both the case excess (Figure 1B) and proportion of genotype-positive case comparisons (Figure 1C and Table 2)."
    explanation: Excess of rare CSRP3 variants in Egyptian HCM cases.
  - reference: PMID:41893039
    reference_title: "Leveraging Large and Diverse Biobanks to Evaluate Gene-Disease Associations in Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Three definitive HCM genes (CSRP3, MYL3, and ACTC1) were nominally significant but did not reach significance after Bonferroni correction."
    explanation: >-
      Population-scale biobank association for CSRP3 is positive but weak, as expected for a
      gene that explains few cases.
  variants:
  - name: CSRP3 p.Cys58Gly (C58G)
    description: >-
      LIM1 zinc-finger cysteine substitution. Cosegregates with HCM in a large four-generation
      family with genome-wide linkage. Abolishes zinc coordination, destabilizes MLP and reduces
      binding to alpha-actinin and N-RAP; the knock-in mouse loses about half of myocardial MLP
      as a heterozygote. A 2018 ACMG meta-analysis rated it the only likely pathogenic CSRP3
      variant among those then reported.
  - name: CSRP3 p.Leu44Pro (L44P)
    description: LIM1 missense allele reported in HCM; depleted by the proteasome in cultured cells.
  - name: CSRP3 p.Ser54Arg/Glu55Gly (S54R/E55G)
    description: >-
      Double LIM1 missense allele reported in HCM; depleted by the proteasome in cultured
      cells.
  - name: CSRP3 p.Cys150Tyr (C150Y)
    description: >-
      LIM2 missense allele found in 11 of 6,456 Spanish HCM index cases and absent from other
      cardiomyopathy and control groups. Heterozygotes develop late-onset, low-risk HCM with
      highly age-dependent penetrance; the single homozygote was more severely affected.
  - name: CSRP3 p.Arg122Ter (c.364C>T)
    description: >-
      Nonsense allele (NM_003476.5:c.364C>T). Found homozygous in a Polish HCM patient, and
      cosegregating with HCM in a three-generation Chinese family (zygosity not stated in the
      cited abstract).
  - name: Homozygous CSRP3 truncating alleles
    description: >-
      Two unrelated French HCM probands were the first reported human CSRP3 knockouts. A 2024
      meta-analysis counted six reported adult HCM cases with biallelic CSRP3 truncating
      variants.
- name: CSRP3 p.Trp4Arg (W4R) modifier allele
  gene_term:
    preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  association: >-
    The common N-terminal W4R allele (up to 1% of people of European ancestry) is not a cause of
    HCM on its own but worsens the expression of sarcomeric (MYH7 and MYBPC3) HCM. It is
    recorded here so that a W4R result on CSRP3 testing is read as a modifier rather than as a
    CMH12 diagnosis; the HCM it modifies is sarcomeric, not CSRP3-caused.
  notes: >-
    W4R was first reported in dilated cardiomyopathy and weakens MLP binding to telethonin. It
    was found in seven of 389 HCM probands in a Mayo Clinic series, four of whom also carried a
    sarcomeric variant, and in one healthy control. In patient iPSC cardiomyocytes, W4R alone
    caused no abnormality, whereas combined with MYH7 p.Arg723Cys it depleted MLP and worsened
    hypertrophy; correcting either variant rescued the phenotype. The W4R knock-in mouse develops
    age- and dose-dependent hypertrophic cardiomyopathy, which is one reason the human role was
    long debated.
  evidence:
  - reference: PMID:35384713
    reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation."
    explanation: W4R modifies sarcomeric HCM and is not sufficient alone.
  - reference: PMID:35384713
    reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Further, while ectopic expression of MLP-W4R in healthy control iPSC-CMs did not cause any abnormalities, it significantly worsened the HCM defects in iPSC-CMs derived from five HCM patients bearing different MYH7 and MYBPC3 mutations"
    explanation: The modifier effect is reproduced across several sarcomeric backgrounds.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Four of the seven patients with W4R-MLP in the present study also have a published HCM-associated myofilament mutation."
    explanation: W4R often co-occurs with a sarcomeric variant in HCM patients.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "W4R-MLP was also noted in a single white control subject."
    explanation: W4R is present in controls.
diagnosis:
- name: Echocardiography
  description: >-
    Imaging for unexplained left ventricular wall thickening, usually asymmetric septal
    hypertrophy, with grading of the septal contour. Serial imaging of carriers is needed
    because penetrance is late and age-dependent.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:17097056
    reference_title: "Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography."
    explanation: >-
      Transthoracic echocardiography defines the septal morphology of Z-disc HCM, including the
      CSRP3 carrier in this series. INDIRECT because the series is not CSRP3-specific.
- name: Clinical Evaluation for Nonsyndromic Hypertrophic Cardiomyopathy
  description: >-
    The phenotype is established clinically, with phenocopies (storage, infiltrative and
    syndromic causes of left ventricular hypertrophy) excluded, following the general evaluation
    of a proband with nonsyndromic HCM. Nothing on imaging separates CSRP3 HCM from sarcomeric
    HCM.
  evidence:
  - reference: PMID:20301725
    reference_title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Provide an evaluation strategy to identify (when possible) the genetic cause of nonsyndromic HCM in a proband"
    explanation: >-
      The GeneReviews overview sets out the evaluation of an HCM proband. INDIRECT because it
      covers HCM in general.
- name: Multigene HCM Panel Testing Including CSRP3
  description: >-
    CSRP3 is included on standard HCM gene panels. Interpretation should not treat W4R alone as
    a diagnosis, should look for a second CSRP3 allele (biallelic disease) and for a sarcomeric
    co-variant, and should take account of late, age-dependent penetrance when testing
    relatives.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30012424
    reference_title: "First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Among them, CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing (NGS)."
    explanation: CSRP3 is a standard panel gene.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation."
    explanation: Reason for caution in interpreting W4R.
progression:
- phase: Genotype-positive carrier before clinical expression
  notes: >-
    Heterozygous carriers can remain unaffected into late adulthood. In the p.Cys150Tyr families
    penetrance was highly age-dependent and the mean age at diagnosis was 55 years, so a normal
    echocardiogram in a young carrier does not exclude later disease.
  evidence:
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The variant showed highly age-dependent penetrance."
    explanation: Late, age-dependent penetrance.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm."
    explanation: Late mean age at diagnosis.
- phase: Established hypertrophic cardiomyopathy
  notes: >-
    For heterozygous p.Cys150Tyr carriers the course was benign, with no adverse events over a
    mean of 11 years. Biallelic disease is reported to be more severe. Outcome data for other
    CSRP3 alleles are too sparse to summarize.
  evidence:
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients."
    explanation: Low event rate in heterozygous carriers of one allele.
differential_diagnoses:
- name: Dilated Cardiomyopathy 1M
  disease_term:
    preferred_term: dilated cardiomyopathy 1M
    term:
      id: MONDO:0011840
      label: dilated cardiomyopathy 1M
  description: >-
    The allelic CSRP3 dilated designation (CMD1M), rated Limited by ClinGen and built mainly on
    the W4R and K69R alleles. A CSRP3 carrier with a dilated, poorly contracting ventricle should
    have end-stage HCM considered as well as CMD1M.
  distinguishing_features:
  - >-
    Primary left ventricular dilation with systolic dysfunction rather than unexplained
    hypertrophy.
  evidence:
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations."
    explanation: CSRP3 variants have been reported in both dilated and hypertrophic disease.
- name: Sarcomeric Hypertrophic Cardiomyopathy
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  description: >-
    HCM caused by variants in sarcomere genes such as MYBPC3 and MYH7, which explain most
    genotype-positive HCM. The clinical picture is the same, so only genetic testing separates
    them. A sarcomeric variant and a CSRP3 variant can occur together, including in families
    where double heterozygotes are more severely affected.
  distinguishing_features:
  - A pathogenic variant in a sarcomere gene, with no pathogenic CSRP3 variant.
  evidence:
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."
    explanation: CSRP3 and sarcomeric HCM are clinically alike.
  - reference: PMID:20087448
    reference_title: "Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here we describe a family with double heterozygosity for pathogenic mutations in cysteine and glycine-rich protein 3 (CSRP3) and MYH7."
    explanation: A CSRP3 variant and a sarcomeric variant can segregate in the same family.
treatments:
- name: Cascade Screening and Cardiac Surveillance of At-Risk Relatives
  description: >-
    Predictive testing of first-degree relatives for the familial CSRP3 variant, then serial
    cardiac evaluation of carriers. In the p.Cys150Tyr families, relatives without the variant
    showed no disease, so the genotype is informative. Because penetrance is late, an unaffected
    young carrier stays under surveillance.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cascade genetic and cardiac screening of at-risk relatives
    term:
      id: NCIT:C168126
      label: Cardiac Disease Screening
  evidence:
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease."
    explanation: Family screening identifies carriers, and non-carriers are unaffected.
- name: Genetic Counseling
  description: >-
    Counseling should cover dominant transmission with late, incomplete penetrance, the more
    severe disease of homozygotes and the recessive-like presentation of biallelic truncating
    alleles (relevant in consanguineous families), and the modifier rather than causal status of
    W4R.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype."
    explanation: Dose-dependent severity that counseling must convey.
  - reference: PMID:31919335
    reference_title: "Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This report expands the mutational spectrum and the inheritance pattern of HCM."
    explanation: Biallelic inheritance is part of the CSRP3 spectrum.
- name: Pharmacotherapy for Symptomatic Hypertrophic Cardiomyopathy
  description: >-
    Standard HCM pharmacotherapy (beta-blockers, non-dihydropyridine calcium channel blockers,
    disopyramide) for symptoms and outflow obstruction. No CSRP3-specific clinical study exists.
    In MLP-null human stem-cell cardiomyocytes, verapamil restored calcium homeostasis and
    prevented the hypertrophic phenotype, a preclinical observation that fits the calcium node
    but has not been tested in patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
    - preferred_term: verapamil
      term:
        id: CHEBI:9948
        label: verapamil
    - preferred_term: disopyramide
      term:
        id: CHEBI:4657
        label: disopyramide
  target_mechanisms:
  - target: Abnormal Cardiomyocyte Calcium Handling
    treatment_effect: INHIBITS
    description: >-
      Verapamil corrects the raised intracellular calcium of MLP-null cardiomyocytes in vitro.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."
      explanation: >-
        Preclinical rescue by verapamil. INDIRECT because it is a knockout cell model, not
        patients.
- name: Cardiac Myosin Inhibitor Therapy
  description: >-
    Mavacamten improves exercise capacity and outflow obstruction in symptomatic obstructive
    HCM. The pivotal trial was not stratified by genotype and reports no CSRP3 carriers. In
    patient iPSC cardiomyocytes in which MLP was depleted secondarily to a sarcomeric variant
    combined with W4R, mavacamten raised MLP levels and suppressed calcineurin-NFAT signalling;
    whether it helps primary CSRP3 disease, in which MLP loss is caused by the CSRP3 variant
    itself, is untested.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
  target_mechanisms:
  - target: Disinhibited Calcineurin-NFAT Hypertrophic Signalling
    treatment_effect: INHIBITS
    description: >-
      Reducing crossbridge force restores MLP and lowers NFAT activity in secondary MLP
      depletion.
    evidence:
    - reference: PMID:35384713
      reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Notably, administration of mavacamten resulted in a reproducible upregulation of MLP (Figure 5M and 5N) as well as downregulation of nuclear NFATc4 (Figure 5J and 5O), its target gene MCIP1, and NFAT-luciferase activities (Figure S5Y’ and 5Z’) in the proband CMs."
      explanation: >-
        Mavacamten reverses MLP loss and NFAT activation in MYH7/W4R proband cardiomyocytes.
        INDIRECT because MLP loss there is secondary to a sarcomeric variant.
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."
    explanation: Efficacy in obstructive HCM generally; applying it to CSRP3 carriers is an inference.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Primary or secondary prevention of sudden death on standard HCM risk criteria. Risk models
    have not been validated for CSRP3, and heterozygous p.Cys150Tyr carriers had no adverse
    events over a mean of 11 years.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  notes: >-
    Deliberately carries no evidence item. No CSRP3-specific device outcome data exist;
    indications are guideline-generic.
animal_models:
- name: Csrp3 C58G knock-in mouse
  species: Mouse
  genotype: Csrp3 p.C58G knock-in, heterozygous (KI/+) and homozygous (KI/KI)
  publication: PMID:30048712
  description: >-
    The first knock-in of a clearly pathogenic CSRP3 HCM allele. Homozygotes develop
    cardiomyopathy with diastolic and systolic dysfunction, increased heart weight, fetal and
    hypertrophic gene programmes, calcineurin pathway activation, mild fibrosis and a
    proteotoxic response. Heterozygotes lose about half of myocardial MLP but have no overt
    phenotype at baseline, with aging to 12 months, or after pressure overload.
  modeled_mechanisms:
  - target: MLP Protein Destabilization and Depletion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Carries the human allele and reproduces dose-dependent proteasomal MLP depletion.
    limitations: >-
      Mouse myocardium; whether human heterozygous myocardium loses the same fraction of MLP has
      been examined only in one patient sample.
    evidence:
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%."
      explanation: MLP depletion in the model.
  - target: Maladaptive Hypertrophic Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Homozygotes develop cardiomyopathy with increased heart weight.
    limitations: >-
      Only homozygotes are affected, whereas most patients are heterozygous; the phenotype
      combines diastolic and systolic dysfunction rather than isolated septal hypertrophy.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Heterozygous knock-in mice, the genotype of most patients, have no overt cardiac
        phenotype, whereas heterozygous humans develop (late-onset) HCM.
    evidence:
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements."
      explanation: The homozygous phenotype.
    - reference: PMID:30048712
      reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Heterozygous KI/+ mice did not develop an overt cardiac phenotype even upon aging up to 12 months (data not shown)."
      explanation: The heterozygous limitation.
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP."
    explanation: The authors' statement of the model's purpose.
- name: Mlp W4R knock-in mouse
  species: Mouse
  genotype: Mlp(W4R/+) and Mlp(W4R/W4R) knock-in
  publication: PMID:20044516
  description: >-
    Knock-in of the common W4R allele. Heterozygous and homozygous mice develop age- and
    dose-dependent hypertrophic cardiomyopathy and heart failure with reduced MLP and weaker
    telethonin binding. Human carriers of W4R alone are usually unaffected, so the model
    overstates the allele's effect in humans.
  modeled_mechanisms:
  - target: MLP Protein Destabilization and Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Reduced MLP mRNA and protein in knock-in hearts.
    limitations: >-
      W4R is a modifier in humans; the reduction here is caused by an allele that does not cause
      HCM on its own in people.
    evidence:
    - reference: PMID:20044516
      reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals."
      explanation: MLP reduction in the model.
  evidence:
  - reference: PMID:20044516
    reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress."
    explanation: The knock-in phenotype is hypertrophic cardiomyopathy.
- name: Csrp3 (Mlp) knockout mouse
  species: Mouse
  genotype: Csrp3-/- (MLP-/-), homozygous null
  publication: PMID:9039266
  description: >-
    The classic MLP-null mouse. Hearts are soft at birth with disrupted cytoarchitecture, and
    the mice develop dilated cardiomyopathy with hypertrophy and heart failure. Human complete
    loss of CSRP3 (biallelic truncation) gives adult HCM instead.
  modeled_mechanisms:
  - target: Maladaptive Hypertrophic Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Hypertrophy is present but is accompanied by dilation and heart failure.
    limitations: >-
      The dominant remodeling phenotype in the mouse is dilated, not hypertrophic.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Complete MLP loss gives dilated cardiomyopathy with hypertrophy in the mouse but
        hypertrophic cardiomyopathy in humans with biallelic truncating CSRP3 variants.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."
      explanation: Mixed dilated and hypertrophic phenotype of the null mouse.
  evidence:
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture."
    explanation: The structural lesion of complete MLP loss.
experimental_models:
- name: MLP-knockout hESC-derived cardiomyocytes
  description: >-
    CRISPR/Cas9 CSRP3-null human embryonic stem cell line (H9) differentiated to cardiomyocytes.
    The cells develop hypertrophic features early and heart-failure features by 30 days, with
    impaired calcium handling; verapamil prevents the phenotype. Models complete loss of MLP,
    comparable to biallelic truncation.
  experimental_model_type: OTHER
  publication: PMID:31406109
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Abnormal Cardiomyocyte Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Impaired calcium handling that drives the hypertrophic phenotype.
    limitations: Complete knockout in immature stem-cell cardiomyocytes, not a heterozygous patient allele.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."
      explanation: Calcium dependence of the phenotype in the model.
  - target: Sarcomere Disorganization and Myocyte Disarray
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Disorganized sarcomeric ultrastructure.
    limitations: Immature cardiomyocytes and a null genotype.
    evidence:
    - reference: PMID:31406109
      reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."
      explanation: Sarcomere disorganization in the model.
- name: Patient iPSC-derived cardiomyocytes and engineered heart tissue (MYH7 p.Arg723Cys with MLP W4R)
  description: >-
    Cardiomyocytes and engineered heart tissue from an HCM proband carrying MYH7 p.Arg723Cys and
    MLP W4R, with gene-edited corrections. Increased force destabilizes the Z-disc MLP complex,
    MLP falls and calcineurin-NFAT is disinhibited; correcting either variant, or mavacamten,
    rescues the phenotype. Here MLP depletion is secondary to a sarcomeric variant, so the model
    informs the downstream steps of CMH12 rather than its initiating lesion.
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:35384713
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Disinhibited Calcineurin-NFAT Hypertrophic Signalling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: MLP reduction followed by calcineurin-NFAT disinhibition and hypertrophy.
    limitations: >-
      MLP loss is secondary to MYH7 hypercontractility plus W4R, not to a pathogenic CSRP3
      allele.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The initiating lesion is a sarcomeric MYH7 variant; no primary CSRP3 HCM allele is
        present, so only the steps after MLP loss are modelled.
    evidence:
    - reference: PMID:35384713
      reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."
      explanation: The signalling step in the model.
discussions:
- discussion_id: cmh12_inheritance_mode
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is CSRP3 HCM dominant, recessive or semidominant, and how penetrant are heterozygous
    alleles?
  attaches_to:
  - genetic#CSRP3
  - inheritance#Semidominant
  rationale: >-
    OMIM records CMH12 as autosomal dominant, and most published alleles are heterozygous
    missense variants that cosegregate with disease. After the first homozygous truncating
    cases, one group argued for recessive inheritance and noted that only C58G met ACMG likely
    pathogenic criteria. Later data showed both: heterozygous p.Cys150Tyr causes late-onset
    disease, the homozygote is more severe, and homozygous variants are enriched where
    consanguinity is common. ClinGen settled on semidominant. The open part is penetrance of
    heterozygous missense and truncating alleles, which needs age-stratified family data.
  evidence:
  - reference: PMID:30012424
    reference_title: "First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "By combining meta-analysis results and identification of two unrelated HCM patients with homozygous CSRP3 truncating variants, we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM (OMIM 612124)."
    explanation: The recessive-inheritance position.
  - reference: PMID:33035702
    reference_title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers."
    explanation: Heterozygous disease, against a purely recessive model.
  - reference: PMID:37431535
    reference_title: "Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity."
    explanation: Reduced heterozygous penetrance inferred from homozygosity enrichment.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CSRP3 was curated for a semidominant mode of inheritance (definitive)."
    explanation: The expert-panel resolution.
- discussion_id: cmh12_calcineurin_direction
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does loss of MLP increase or decrease calcineurin-NFAT signalling in the heart?
  attaches_to:
  - pathophysiology#Disinhibited Calcineurin-NFAT Hypertrophic Signalling
  rationale: >-
    In human iPSC cardiomyocytes (MLP lost secondarily to a sarcomeric variant) and in homozygous
    C58G knock-in hearts, reduced MLP is followed by more calcineurin-NFAT activity and
    hypertrophy. In heterozygous MLP-null mice after myocardial infarction, halving MLP displaced
    calcineurin from the Z-disc and blunted NFAT activation, and the hearts dilated. The settings
    differ (high sarcomeric force or near-complete MLP loss with a hypertrophic outcome, versus
    an ischaemic stressor with a dilated outcome). The authors of the human study, who cite the
    mouse anchoring work, propose that MLP both restrains calcineurin-NFAT at rest and is needed
    to localize it, so the net effect of MLP loss may depend on context. This entry follows the
    human cardiomyocyte data for the hypertrophic phenotype; the allelic dilated entry (Dilated
    Cardiomyopathy 1M) follows the mouse data for the dilated phenotype. Neither direction has
    been measured in cells carrying a primary pathogenic CSRP3 allele at heterozygous dose.
  evidence:
  - reference: PMID:35384713
    reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy."
    explanation: Reduced MLP increases calcineurin-NFAT activity.
  - reference: PMID:35384713
    reference_title: "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "It is possible that MLP has both inhibitory and facilitative effects on calcineurin activity."
    explanation: >-
      The human-study authors' proposed reconciliation of the two directions: MLP may both
      restrain and facilitate Z-disc calcineurin. Stated as a possibility in their discussion.
  - reference: PMID:15665106
    reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Activation of the stress-responsive, prohypertrophic calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP+/- mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP+/-/NFAT-luciferase reporter gene transgenic mice."
    explanation: >-
      Contradicts the increased-signalling direction: halving MLP reduced calcineurin-NFAT
      activation after infarction in mice.
- discussion_id: cmh12_heterozygous_model_gap
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why do heterozygous CSRP3 patient alleles cause HCM in humans when heterozygous knock-in mice
    stay normal, and why does the MLP-null mouse dilate while human CSRP3 knockouts hypertrophy?
  attaches_to:
  - animal_models#Csrp3 C58G knock-in mouse
  - animal_models#Csrp3 (Mlp) knockout mouse
  - pathophysiology#Maladaptive Hypertrophic Remodeling
  rationale: >-
    The C58G knock-in halves MLP in heterozygotes without a cardiac phenotype, even with aging
    or pressure overload, while heterozygous humans develop late-onset HCM. Complete MLP loss
    gives dilated cardiomyopathy with hypertrophy in mice but adult HCM in humans. The
    differences may reflect lifespan (human disease appears in mid-life), species differences in
    load or myosin isoforms, or the mouse strain. Human stem-cell cardiomyocytes lacking MLP do
    take on hypertrophic features. A heterozygous patient-allele isogenic iPSC model, studied
    under load, would test whether partial MLP loss is enough in human cells.
  evidence:
  - reference: PMID:30048712
    reference_title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Heterozygous KI/+ mice did not develop an overt cardiac phenotype even upon aging up to 12 months (data not shown)."
    explanation: The heterozygous mouse has no phenotype.
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."
    explanation: The null mouse is dilated.
  - reference: PMID:31406109
    reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."
    explanation: Human MLP-null cells take on hypertrophic features.
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z
  title: "CSRP3 / hypertrophic cardiomyopathy (Definitive)"
- reference: PMID:39971408
  title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
- reference: PMID:12642359
  title: "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy."
- reference: PMID:18505755
  title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
- reference: PMID:30048712
  title: "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion."
- reference: PMID:33035702
  title: "The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals."
notes: >-
  Scope. This entry covers CSRP3 hypertrophic cardiomyopathy (CMH12, MONDO:0012804, OMIM
  612124). The allelic dilated designation CMD1M (MONDO:0011840) has its own entry and is listed
  as a differential. The umbrella Hypertrophic_Cardiomyopathy entry lists CSRP3 among its genes.

  Gene-disease validity. The ClinGen Definitive, semidominant CSRP3 assertion is for generic
  hypertrophic cardiomyopathy (MONDO:0005045), so it is cited as evidence and not recorded in
  gene_disease_validity, which is reserved for assertions on this entry's own MONDO term.

  GeneReviews. There is no CSRP3- or CMH12-specific GeneReviews chapter. The Nonsyndromic
  Hypertrophic Cardiomyopathy Overview (PMID:20301725) is tagged; its cached record holds only
  the purpose statement, so no phenotype baseline could be taken from it.

  Phenotypes. Only HCM, asymmetric septal hypertrophy and mild skeletal myopathy are curated,
  because those are the features reported specifically for CSRP3 carriers. General HCM
  features (outflow obstruction, arrhythmia, sudden death, heart failure, myocardial fibrosis)
  were not found with CSRP3-specific data and are left out rather than inferred from HCM in
  general; heterozygous p.Cys150Tyr carriers had no adverse events over 11 years. Septal
  reduction therapy is not listed because no CSRP3-specific outflow-obstruction data exist.

  Mechanism. The chain is: CSRP3 variant, then reduced partner binding and proteasomal MLP
  depletion, then disinhibited calcineurin-NFAT signalling, abnormal calcium handling and
  sarcomere disorganization, then ventricular hypertrophic remodeling. The depletion step is
  shown with a patient allele in mice and cells. The steps after it come from MLP-null human
  stem-cell cardiomyocytes and from iPSC cardiomyocytes in which MLP loss is secondary to a
  sarcomeric variant, and are marked PROVISIONAL or HYPOTHETICAL accordingly. The direction of
  the calcineurin-NFAT step differs between human cardiomyocyte and post-infarction mouse data;
  the allelic dilated entry models the reduced direction (see the calcineurin discussion).

📚

References & Deep Research

References

7

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z

CSRP3 / hypertrophic cardiomyopathy (Definitive)

No top-level findings curated for this source.

PMID:39971408

Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.

No top-level findings curated for this source.

PMID:12642359

Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.

No top-level findings curated for this source.

PMID:18505755

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy.

No top-level findings curated for this source.

PMID:30048712

Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion.

No top-level findings curated for this source.

PMID:33035702

The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Hypertrophic_Cardiomyopathy_12 · 2026-10-13T18:20:59Z · View source

Created the CMH12 (CSRP3, MONDO:0012804) entry and deleted stubs/Hypertrophic_Cardiomyopathy_12.yaml. Deep research: research/Hypertrophic_Cardiomyopathy_12-deep-research-claude_code.md (claude_code provider; 18/18 references resolved, 2/2 quotes valid; term validation flagged only a paraphrased MONDO:0005045 label; just preflight-dr PASS, CSRP3 mentioned 40 times). The report was used as leads; it marked Bos 2006, Geier 2008, Knoll 2002 and Theis 2006 as uncached, but all four were already in references_cache and were read directly. It also stated that no skeletal myopathy is documented for CMH12, which the Geier 2008 abstract (PMID:18505755) contradicts; the entry follows the abstract. PMID:15781201 (W4R letter) has no abstract text and is not cited. Key sources: Geier 2003 PMID:12642359 and Geier 2008 PMID:18505755 (cosegregation, linkage, mild skeletal muscle disease), Gehmlich 2004 PMID:15205937 (C58G binding and folding), Ehsan 2018 PMID:30048712 (C58G knock-in, proteasomal MLP depletion), Salazar-Mendiguchia 2020 PMID:33035702 (C150Y, late-onset, age-dependent penetrance), homozygous truncating cases PMID:30012424, 31919335, 38666070, Egypt cohort PMID:37431535, biobank PMID:41893039, Walsh 2017 PMID:27532257 HCM table row, Bos 2006 PMID:16352453, Li 2019 hESC knockout PMID:31406109, Riaz 2022 iPSC/W4R modifier PMID:35384713, ClinGen reappraisal PMID:39971408 and the CGGV Definitive SD assertion. Judgement calls: relationship_type CAUSATIVE follows the ClinGen Definitive tier (CMH28 precedent); the CGGV assertion is for generic HCM (MONDO:0005045), so it is cited as evidence and not copied into gene_disease_validity (list-gene-validity reports other_disease, as expected). Two inheritance blocks (autosomal dominant and semidominant HP:0032113). W4R is a separate genetic row with relationship_type MODIFIER. The calcineurin-NFAT node follows the human iPSC data (increased signalling) and a CONTROVERSY discussion records the opposite direction in MLP+/- mice after infarction (PMID:15665106). General HCM features without CSRP3-specific data (arrhythmia, SCD, outflow obstruction, fibrosis in patients) were left out rather than inferred. Re-fetching a few already-tracked caches during the run rewrote them (PMID:17097056, 30681346, 12507422, 16352453, 18505755, 34526680); those rewrites were reverted to the committed versions, and snippets were verified against the committed text. Validation: just validate, validate-terms, count-verified-snippets 105/105, check-causal-targets, check-entity-refs, check-duplicate-keys, check-gene-validity, check-snippet-grading, check-gene-activity-grounding --against-ref origin/main, check-genereviews (GeneReviews TAGGED, PMID:20301725), list-disconnected-phenotypes 3/3 connected, and validate-disorders as the final gate.

Claude Code ▸

Research report: Hypertrophic Cardiomyopathy 12 (CMH12, CSRP3-related HCM)

claude-haiku-5-5, claude-opus-5-5 17 citations 2026-10-13T14:06:37.251955

Research report: Hypertrophic Cardiomyopathy 12 (CMH12, CSRP3-related HCM)

Target: MONDO:0012804 · Mendelian · prepared 2026-10-13

How to read the evidence. Quotes marked [cached] are exact text from abstracts already in this worktree's references_cache/, so they can be used as snippets as they stand. References marked [not cached] were found by web search. They need just fetch-reference before anything from them is used as evidence, and I have not quoted them verbatim. Ontology CURIEs marked ✔ were checked against the committed cache/*/terms.csv. CURIEs without ✔ are leads and must be looked up before they are bound.

1. Disease information

Overview. CMH12 is familial hypertrophic cardiomyopathy caused by variants in CSRP3 (11p15.1). CSRP3 encodes muscle LIM protein (MLP), a small protein with two LIM domains. MLP sits at the Z-disc and costamere and also moves into the nucleus. Unlike most HCM genes, CSRP3 is non-sarcomeric. Its role is mechanosensing and signalling, not generating force.

"MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes." — PMID:30048712 [cached]

Identifiers | System | ID | |---|---| | MONDO | MONDO:0012804 hypertrophic cardiomyopathy 12 (already in the draft entry) | | OMIM (phenotype) | 612124 (CMH12; listed as AD) | | OMIM (gene) | 600824 CSRP3 | | HGNC | hgnc:2472 CSRP3 (taken from the ClinGen rows below; not yet checked in cache/hgnc) | | MedGen | 393755 | | LOVD disease | 03091 | | Orphanet | No CMH12-specific entry was found. The umbrella entry is "Familial isolated hypertrophic cardiomyopathy" (ORPHA:217569, not verified*; check with just fetch-reference ORPHA:…) | | ICD-10 / ICD-11 | Only the general HCM codes apply (I42.1 obstructive / I42.2 other HCM; ICD-11 BC43.1). Neither has been checked against the ICD10CM cache |

Synonyms: CMH12; cardiomyopathy, familial hypertrophic, 12; CSRP3-related hypertrophic cardiomyopathy; MLP-related HCM. Allelic disorder: dilated cardiomyopathy 1M (CMD1M, MONDO:0011840).

Data provenance: All of the data are disease-level aggregates (family cosegregation studies, case–control cohorts, and the ClinGen and OMIM curations). No EHR-derived data were found.

2. Etiology

Primary cause: Germline CSRP3 variants. Three kinds are reported: - Heterozygous missense variants in the LIM1 domain. Examples are C58G, L44P, S54R/E55G, K42Q and C150Y. - Homozygous or biallelic variants, including truncating variants that effectively knock the gene out. Examples are p.Arg122Ter and other truncations. - The W4R variant (p.Trp4Arg). It is common (about 1% in Europeans) and now looks like a modifier rather than a cause of disease on its own.

"We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain" — PMID:12642359 [cached]

Gene-disease validity: the classification moved between curations, and the mode of inheritance is disputed - ClinGen 2019 (Ingles et al., Circ Genom Precis Med) put CSRP3 in the Moderate group, together with TNNC1 and JPH2 [not cached; ClinGen HCM gene curation]. - The current ClinGen record is Definitive, with MOI recorded as SD (semidominant), from the Hereditary Cardiovascular Disease GCEP, dated 2023-08-09:

"CSRP3 | HGNC:2472 | hypertrophic cardiomyopathy | MONDO:0005045 | SD | Definitive" — CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z [cached] - Curation caveat: this ClinGen assertion is for the general HCM term MONDO:0005045, not MONDO:0012804. Under the CLAUDE.md rule ("The assertion must be for this entry's disease"), it is copied onto CMH12's gene_disease_validity only if CMH12 maps to that term with exactMatch. Otherwise it is an other_disease lead. - For the allelic DCM phenotype: "CSRP3 | HGNC:2472 | dilated cardiomyopathy 1M | MONDO:0011840 | AD | Limited" — CGGV:assertion_beaafc90-…-2026-03-04 [cached]. - Recessive inheritance was argued early on: "we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM (OMIM 612124)." — PMID:30012424 [cached] - Population-scale association (2026): "Several definitive genes which are much less commonly affected in HCM (CSRP3, MYL3, ACTC1, TPM1, FHOD3, MYL2, and TNNC1) did not pass our Bonferroni corrected-significance threshold, but all had positively associated effect sizes with HCM." — PMID:41893039 [cached]

Risk factors - Genetic: Biallelic state, which consanguinity makes more likely (see section 9). Co-inheritance of a sarcomeric variant, which W4R makes worse (see Modifiers). - Age: Penetrance depends strongly on age (C150Y; PMID:33035702). - Environmental: No CSRP3-specific environmental risk factor has been reported. General HCM modifiers such as hypertension and obesity are plausible but unstudied for CMH12.

Protective factors: None reported. Mechanistically, lowering sarcomeric crossbridge load protects iPSC tissue (PMID:35384713, see section 6), but this is a treatment effect and not a protective factor in a population.

Gene–environment interactions: No human data. MLP's subcellular location responds to load and contractility (PMID:19376126). This suggests mechanical load is a plausible G×E axis, but that is an inference.

3. Phenotypes

All of the HP CURIEs below are ✔ in cache/hp/terms.csv.

Phenotype	HP term	Frequency / characteristics	Evidence
Asymmetric septal hypertrophy	HP:0001670 ✔	Typical pattern; all 3 original index cases	"All 3 index patients were characterized by typical asymmetrical septal hypertrophy." PMID:12642359 [cached]
Hypertrophic cardiomyopathy / LV hypertrophy	HP:0001639 ✔ / HP:0001712 ✔	Defining. Mean maximal LV wall 18 ± 3 mm in C150Y carriers	PMID:33035702 [cached]; PMID:34558151 "an obvious left ventricular hypertrophy was found in the proband" [cached]
Late (adult) onset	onset descriptor	Mean age at diagnosis 55 ± 13 y (C150Y); "highly age-dependent penetrance"	PMID:33035702 [cached]
Sigmoid septal contour	none checked; candidate Sigmoid septum (look up)	85% of Z-disc-variant HCM in one cohort (mixed genes)	Theis 2006, PMID:17097056 [not cached]
LV diastolic dysfunction	HP:0025168 ✔	General HCM feature; seen in the KI mouse	PMID:30048712 (mouse) [cached]
LV systolic dysfunction / progression to dilation	HP:0025169 ✔ / HP:0001644 ✔	Reported for biallelic or severe cases and the allelic CMD1M. Uncommon in heterozygous CMH12	PMID:30048712 (mouse); ClinGen DCM Limited
LVOT obstruction	HP:0032092 ✔	No CSRP3-specific frequency found	general HCM
Exertional dyspnea, chest pain, palpitations, syncope	HP:0002875 ✔, HP:0100749 ✔, HP:0001962 ✔, HP:0001279 ✔	Usual HCM symptom set; no CMH12-specific frequencies	general HCM
Atrial fibrillation, ventricular tachycardia	HP:0005110 ✔, HP:0004756 ✔	Not quantified for CMH12	—
Sudden cardiac death	HP:0001645 ✔	Low risk in heterozygous C150Y. "After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients."	PMID:33035702 [cached]
Myocardial fibrosis	HP:0001685 ✔	Profibrotic signalling in the KI mouse; human LGE data not found	PMID:30048712 [cached]
Myocyte disarray (histology)	candidate HP term (look up)	Proposed mechanism	PMID:15205937 [cached]

Severity: Varies with dose. The phenotype is mild, late-onset and low-risk in heterozygotes, and more severe in homozygotes:

"Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype." — PMID:33035702 [cached]

Quality of life: No CMH12-specific QoL data were found. General HCM data (e.g. KCCQ in the mavacamten trials) apply only by inference.

4. Genetic / molecular information

Gene: CSRP3 (hgnc:2472; OMIM *600824; NCBI Gene 8048), 11p15.1, 194-aa protein with two LIM domains (LIM1 and LIM2), a nuclear localization signal, and a glycine-rich region.
Reference sequences: NM_003476.5 / NP_003467.1 (used in PMID:34558151).

Key variants | Variant | Type | Zygosity | Status / notes | Source | |---|---|---|---|---| | p.Cys58Gly (C58G) | missense, LIM1 zinc finger | het (familial) | The only variant rated likely pathogenic in the 2018 ACMG meta-analysis. Abolishes zinc coordination | PMID:12642359, 15205937, 30012424, 30048712 [cached] | | p.Leu44Pro, p.Ser54Arg/Glu55Gly | missense, LIM1 | het | Cause protein depletion in cells | PMID:30048712 [cached] | | p.Cys150Tyr | missense, LIM2 | het (10) / hom (1) | 11/6456 HCM probands vs 0 in other cardiomyopathy and control groups (p<0.0001). Late-onset, low risk | PMID:33035702 [cached] | | p.Arg122Ter (c.364C>T) | nonsense | hom (Polish), het (Chinese family, cosegregating) | Homozygous null; the heterozygous Chinese family conflicts with recessive-only models | PMID:31919335, 34558151 [cached] | | Homozygous truncating (2 probands) | nonsense/frameshift | hom | First homozygous CSRP3 knockouts in HCM | PMID:30012424 [cached] | | p.Trp4Arg (W4R; rs45550635, look up) | missense, N-terminal | het, ~1% of Europeans | Modifier, not causal on its own | PMID:35384713 [cached]; Geier 2008 PMID:18505755 [not cached] |

"We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation." — PMID:35384713 [cached]

Functional consequence: The pathogenic missense variants cause loss of function through protein destabilization and proteasomal depletion, which amounts to haploinsufficiency or hypomorphism. They do not act as gain of function (functional_impact_category: LOSS_OF_FUNCTION or PARTIAL_LOSS_OF_FUNCTION):

"Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action." — PMID:30048712 [cached]

Yield and frequency: About 3% of HCM probands carry a CSRP3 variant (12/389 in the Mayo cohort; Bos 2006, PMID:16352453 [not cached]). This share should be read as an upper bound, because pathogenicity is unresolved for many of those variants. Geier 2008 reported a large linkage family plus 4 more families with segregating missense variants (PMID:18505755 [not cached]).

Modifiers: W4R (above). Sarcomeric co-variants such as MYH7 interact with MLP depletion (PMID:35384713).

Epigenetic changes / chromosomal abnormalities: None reported. CNVs involving 11p15.1 are not known as a CMH12 mechanism.

Somatic origin: Not applicable (germline).

5. Environmental information

There are no known environmental, lifestyle or infectious causes. Mechanical load and contractility regulate where MLP sits in the cell (PMID:19376126), which makes exercise and pressure load plausible modulators. This is an inference, not an observation in patients. Following CLAUDE.md, an environmental entry should either be left out or carry a "Left deliberately uncited." waiver.

6. Mechanism / pathophysiology

Ordered causal chain

Germline CSRP3 variant (LIM1/LIM2 missense, or biallelic truncation) leads to misfolding of a zinc-finger LIM domain:

"this single point mutation prevents zinc coordination and proper folding of the second zinc-finger in the first LIM domain, which consequently renders the protein less stable and more susceptible to proteolysis." — PMID:15205937 [cached; IN_VITRO]
Unstable MLP is degraded by the proteasome, which results in MLP depletion (about 50% in heterozygous and about 80% in homozygous knock-in mice; PMID:30048712 [cached; MODEL_ORGANISM]). Truncating biallelic alleles reach the same end state, a null, directly.
Branch 2b (proteotoxic): Mutant MLP C58G binds BAG3, which triggers a proteotoxic, heat-shock-protein stress response (PMID:30048712).
Loss of MLP binding partners at the Z-disc: binding to α-actinin, N-RAP and telethonin (T-cap) drops:

"Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to alpha-actinin." — PMID:12642359 [cached] W4R specifically disrupts the interaction with telethonin and its localization (Knöll 2002, Cell 111:943, PMID:12507422 [not cached]).
The Z-disc stretch-sensing complex fails, which leads to a mechanosensing defect, disinhibition of calcineurin–NFAT signalling, and hypertrophic gene expression. This step was shown in human iPSC engineered heart tissue, where MLP depletion was secondary to MYH7 load. Applying it to primary CSRP3 depletion is a mechanistic inference:

"Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy." — PMID:35384713 [cached; IN_VITRO]
Disrupted nucleocytoplasmic shuttling of MLP impairs myofilament remodelling and stress gene expression (sarcomere disarray, BNP). This was demonstrated in rat neonatal myocytes:

"cyclic strain of myocytes after prior NLS treatment to remove nuclear MLP resulted in disarrayed sarcomeres" — PMID:19376126 [cached; IN_VITRO]
Cardiomyocyte hypertrophy and myocyte disarray, plus compensatory N-RAP upregulation (proposed in PMID:15205937), lead to asymmetric septal LV hypertrophy.
Fetal gene programme, profibrotic signalling and interstitial fibrosis result in diastolic dysfunction, and with biallelic or severe loss, systolic dysfunction with progression towards DCM:

"Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts." — PMID:30048712 [cached]
Clinical expression (dyspnea, arrhythmia, rarely SCD) depends on gene dose and age. Heterozygous carriers have a late-onset, low-risk course (PMID:33035702).

Upstream vs downstream: Steps 1–3 are molecular (MOLECULAR scale). Steps 4–5 are cellular signalling (CELLULAR). Steps 6–7 are tissue and organ (TISSUE). Step 8 is organism-level (ORGANISM).

Suggested terms (✔ = in cache) - GO BP: response to muscle stretch GO:0035994 ✔; calcineurin-NFAT signaling cascade GO:0033173 ✔ (modifier INCREASED); cardiac muscle hypertrophy GO:0003300 ✔; sarcomere organization GO:0045214 ✔; cardiac myofibril assembly GO:0055003 ✔; proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 ✔ (MLP depletion) - GO CC: Z disc GO:0030018 ✔; costamere GO:0043173 ✔; nucleus GO:0005634 ✔ - CL: cardiac muscle cell CL:0000746 ✔; fibroblast of cardiac tissue CL:0002548 ✔ (fibrosis node) - Module conformance candidates: run just list-modules cardiomyopathy and just list-modules fibro. cardiomyopathy_maladaptive_remodeling and fibrotic_response are named in CLAUDE.md; check them before conforming.

Molecular profiling: The only omics dataset found is the bulk RNA-seq of C58G knock-in mouse hearts (PMID:30048712; locate the GEO accession using just discover-datasets). No human single-cell, proteomic or metabolomic data specific to CSRP3 were found.

7. Anatomical structures

Organ: heart UBERON:0000948 ✔; cardiovascular system.
Site: interventricular septum UBERON:0002094 ✔ (asymmetric). The left ventricle term was not found in the cache; look it up.
Tissue: cardiac muscle tissue UBERON:0001133 ✔.
Cells: cardiomyocytes (CL:0000746 ✔); cardiac fibroblasts (secondary).
Subcellular: Z-disc, costamere, nucleus and nucleolus (PMID:19376126: "The NLS of MLP also localizes to the nucleolus.").
Secondary organs: None. MLP is also expressed in skeletal muscle, but no skeletal myopathy is documented in CMH12.

8. Temporal development

Onset: Usually adulthood (mean 55 ± 13 y for C150Y). Biallelic cases can present in adolescence or young adulthood (PMID:30012424 MeSH lists adolescent and adult; check the full text for exact ages).
Pattern: Insidious. Hypertrophy develops progressively with age-dependent penetrance.
Course: Chronic and lifelong. Heterozygotes appear to have a stable, low-event course (no events over a mean 11 y follow-up). Homozygous and knockout states are more severe and can progress to systolic dysfunction.
Remission: None.
Critical period: Not defined. Serial screening of carriers into later life is warranted because of late penetrance (an inference from PMID:33035702).

9. Inheritance and population

Inheritance: OMIM lists AD and ClinGen lists semidominant. The literature supports gene-dose effects: heterozygous variants have low penetrance, and homozygous variants give a more severe phenotype.
Suggested inheritance blocks: Autosomal dominant (HP:0000006) and Autosomal recessive (HP:0000007). Neither is in the cache list I checked, so look both up. Name semidominance in description. Look up whether HPO has a "Semidominant inheritance" term (possibly HP:0032113, unverified).
Penetrance: Incomplete and age-dependent (PMID:33035702).
Expressivity: Variable; modified by W4R and sarcomeric co-variants.
Consanguinity: Biallelic variants are enriched:

"variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity." — PMID:37431535 [cached; Egyptian cohort n=514]
Founder effects: Not established. C150Y was found in a Spanish/European multicentre cohort, and R122Ter recurs in Polish and Chinese families.
Prevalence: HCM overall affects about 1/500 ("estimated prevalence of 1/500", PMID:30012424 [cached]). CSRP3 accounts for a small minority of genotyped HCM: 11/6456 probands (about 0.17%) for C150Y alone, and about 3% of the Mayo cohort carried any CSRP3 variant. No CMH12-specific prevalence exists. Record it as measure_type: UNKNOWN / prevalence_class: RARE rather than deriving a number.
Sex ratio and geography: Not reported for CMH12 specifically.
Germline mosaicism / anticipation: Not reported.

10. Diagnostics

Imaging: Echocardiography and cardiac MRI showing LV wall ≥15 mm (≥13 mm in relatives) without another explanation, which is the general ESC/AHA HCM criterion. MRI LGE can assess fibrosis.
ECG: LVH and repolarization changes; Holter monitoring for AF and NSVT.
Biomarkers: NT-proBNP and BNP (non-specific). BNP expression depends on MLP in the myocyte models (PMID:19376126).
Histopathology: Myocyte hypertrophy, disarray and fibrosis (the proband biopsy in PMID:34558151).
Genetic testing: A multigene HCM panel or exome. CSRP3 is on the ClinGen-curated HCM panel and is typically included (PMID:30012424: "CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing"). Points for interpreting results:
Rule out W4R as the sole explanation.
Look for a second allele or a sarcomeric co-variant.
Use ancestry-matched controls (PMID:37431535).
CMA, karyotype, FISH, mtDNA and repeat expansion testing are not indicated.
Differential diagnosis: Sarcomeric HCM (MYBPC3 and MYH7, which account for most genotype-positive cases). Phenocopies: Fabry disease, PRKAG2, Danon disease (LAMP2), TTR amyloidosis, RASopathies, mitochondrial disease. Also athlete's heart and hypertensive LVH. TRIM63 is another recessive non-sarcomeric HCM gene.
Screening: Cascade genetic testing and serial imaging of first-degree relatives. This matters particularly because of late penetrance.

11. Outcome / prognosis

Heterozygous C150Y: favourable. "The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hype[rtrophic cardiomyopathy]" (PMID:33035702; the cached abstract is cut off there, so quote only up to the truncation).
Homozygous / null: more severe, with risk of systolic dysfunction (human case reports plus the KI/KI mouse). There are too few cases to estimate survival.
No CMH12-specific survival, mortality or QoL statistics exist. Prognostic factors follow general HCM SCD risk models (ESC HCM Risk-SCD), which have not been validated for CSRP3.

12. Treatment

No CSRP3-specific therapy exists. Management follows the general HCM guidelines (2024 AHA/ACC; 2023 ESC).

Treatment	NCIT action term	Agent (look up CHEBI/NCIT)	Notes
Beta-blockers, non-dihydropyridine CCBs (verapamil, diltiazem), disopyramide	Pharmacotherapy NCIT:C15986 ✔	e.g. metoprolol, verapamil	First line for symptoms. Note that verapamil reduces nuclear MLP in vitro (PMID:19376126), which is a mechanistic curiosity with no clinical correlate
Cardiac myosin inhibitors (mavacamten, aficamten)	NCIT:C15986 ✔	mavacamten	Approved for obstructive HCM. Lowering crossbridge load rescued Z-disc/MLP stress in iPSC tissue: "By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations." (PMID:35384713 [cached]). Efficacy in primary CSRP3 HCM has not been tested
Septal myectomy / alcohol septal ablation	Surgical Procedure NCIT:C15329 ✔	—	For drug-refractory LVOT obstruction
ICD implantation	NCIT:C15329 ✔ + device qualifier pattern	—	Per SCD risk; probably rarely needed for heterozygous C150Y
Heart-failure therapy / transplant	NCIT:C15986 / transplantation	—	For the dilated/end-stage evolution
Genetic counseling	NCIT:C15240 ✔	—	Cascade testing; recessive and dose-dependent risk in consanguineous families

Gene therapy, ASO, siRNA: None for CSRP3. A loss-of-function mechanism points towards replacement or stabilization strategies, but this is speculative. PMID:35384713 frames "mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex."
Trials: No CSRP3-specific trials were found on ClinicalTrials.gov. General HCM trials (EXPLORER-HCM NCT03470545, SEQUOIA-HCM) included unselected genotypes. Verify the NCT IDs with just fetch-reference before citing them.
Pharmacogenomics: None specific.

13. Prevention

Primary: Not possible. Preimplantation or prenatal testing is an option in families with known biallelic alleles.
Secondary: Cascade genotyping. Long-term echo surveillance of heterozygous carriers, given late-onset penetrance.
Tertiary: SCD risk stratification, AF anticoagulation, and activity counselling per the HCM guidelines.
Immunization / public health: Not applicable.

14. Other species / natural disease

No naturally occurring CSRP3-related disease is recorded in OMIA (I did not search directly; verify). Feline HCM is mainly MYBPC3/ALMS1, not CSRP3.
Orthologs: mouse Csrp3 (MGI). Look up the NCBI Gene ID; zebrafish csrp3.
MLP's Z-disc mechanosensing role is conserved across vertebrates.

15. Model organisms

Model	Phenotype recapitulation	Limitations	Source
Csrp3 C58G knock-in mouse (KI/KI, KI/+)	KI/KI: "robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction", increased heart weight, fetal genes, fibrosis. Protein depletion in KI/+	Severe phenotype mainly when homozygous. The mixed systolic/diastolic phenotype overlaps DCM. Mouse MHC isoform differences	PMID:30048712 [cached; `RECAPITULATES`/`PARTIALLY_RECAPITULATES` LV dysfunction; `MEASURES` MLP depletion]
MLP-null (Csrp3−/−) mouse	DCM with hypertrophy and heart failure; disrupted cytoarchitecture; soft hearts at birth	Models DCM, not HCM, so a `FAILS_TO_RECAPITULATE`/`PARTIALLY_RECAPITULATES` candidate for the septal-HCM node	Arber et al., Cell 1997;88:393 (doi:10.1016/s0092-8674(00)81878-4; PMID not confirmed) [not cached]
MLP-null mouse, stretch-sensing analysis; W4R telethonin binding	Stretch-response defect	Knockout ≠ missense allele	Knöll 2002, PMID:12507422 [not cached]
Neonatal rat cardiomyocytes (NLS peptide blockade)	Shows that MLP shuttling is needed for hypertrophic remodelling	Rat, neonatal, pharmacological	PMID:19376126 [cached; IN_VITRO]
Patient iPSC-CM engineered heart tissue (MYH7 + MLP-W4R)	MLP destabilization, calcineurin–NFAT, hypertrophy; rescued by gene editing or myosin inhibition	The primary lesion is sarcomeric; CSRP3 acts as modifier. Shows secondary MLP depletion, not primary CMH12	PMID:35384713 [cached; IN_VITRO]
Cell binding assays (C58G with α-actinin and N-RAP)	Reduced binding, zinc-finger misfolding	Reductionist	PMID:15205937 [cached; IN_VITRO]

Resources: MGI (Csrp3 alleles), IMPC, ZFIN.

Key uncertainties for curators

Mode of inheritance. OMIM says AD, ClinGen says SD, and Janin 2018 and Lipari 2020 argue for AR. A heterozygous truncation cosegregates in a Chinese family (PMID:34558151), which conflicts with a purely recessive model. Encode multiple inheritance blocks, each with its own evidence.
ClinGen Definitive is recorded against general HCM (MONDO:0005045). Check mapping scope before copying it onto CMH12.
W4R should not be modelled as causal. Put it in genetic as relationship_type: MODIFIER.
Several canonical papers are not cached: Arber 1997, Knöll 2002, Bos 2006, Geier 2008, Ingles 2019 and Theis 2006. Fetch them before citing; the Arber PMID in particular was not confirmed.
No GeneReviews chapter specific to CMH12 is expected. Confirm with just check-genereviews; the general "Hypertrophic Cardiomyopathy Overview" chapter probably applies.

Sources

Cached in this worktree: PMID:12642359, 15205937, 15781201 (letter; no abstract text), 19376126, 30012424, 30048712, 31919335, 33035702, 34558151, 35384713, 37431535, 41893039; ClinGen CGGV assertions 012b9b15 (HCM, Definitive) and beaafc90 (DCM 1M, Limited).
Web: Arber 1997 (JCI reference list) · edoc.unibas.ch · Knöll 2002 abstract (Arizona) · Mount Sinai abstract page · WikiGenes 12507422 · LOVD CMH12 · MedGen 393755 · OMIM 600824 mirror · GenCC CSRP3 · PanelApp CSRP3 · Ingles 2019 (PMC6410971) · medRxiv ClinGen re-curation · Geier 2008 (ORA Oxford) · MDC edoc · Bos 2006 (PMC2756511) · Theis 2006 (dkNET) · OMIM 607487 mirror

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	18
On topic	15
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	40
Resolved	38
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	2
Terms named correctly	0
Terms named as a different term	1
Terms whose name is worth a second look	1

Terms the report names something else

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

MONDO:0005045 (3 mentions) - the report calls it "ClinGen Definitive is recorded against general HCM"; MONDO calls it hypertrophic cardiomyopathy

Terms whose name is worth a second look

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

HP:0000006 (1 mention) - the report calls it "Suggested inheritance blocks: Autosomal dominant"; HP calls it Autosomal dominant inheritance

Prefixes with no resolver

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

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Research report: Hypertrophic Cardiomyopathy 12 (CMH12, CSRP3-related HCM)

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic / molecular information

5. Environmental information

6. Mechanism / pathophysiology

Ordered causal chain

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome / prognosis

12. Treatment

13. Prevention

14. Other species / natural disease

15. Model organisms

Key uncertainties for curators

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver