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Inheritance

1

Autosomal recessive inheritance HP:0000007

All genotyped patients are homozygous, two of the four families are reported as consanguineous, and every tested parent is a heterozygous carrier without reported heart or muscle disease. Carrier cardiac status has not been systematically evaluated; in one family the heterozygous mother reported occasional palpitations without formal cardiac assessment.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:34862840 SUPPORT DIRECT Human Clinical

"Both parents were heterozygous for the same variant but have no history of heart or muscle disease."

Unaffected heterozygous parents of a homozygous affected infant support recessive inheritance.

PMID:42344352 SUPPORT DIRECT Human Clinical

"Segregation analysis confirmed autosomal recessive inheritance, with both parents identified as obligate heterozygous carriers (Figure 2B)."

Trio segregation in a consanguineous family with a homozygous nonsense variant.

PMID:30518548 SUPPORT DIRECT Human Clinical

"This is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans."

The founding report describes the variant as recessive in two consanguineous Bedouin children.

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Discussions and Knowledge Gaps

5

How secure is the CAP2-CMD2I gene-disease relationship, and what is the full phenotypic spectrum?

KNOWLEDGE GAP OPEN few_families_evidence_base

Attached to

genetic#CAP2

The human evidence is five genotyped patients in four families, all homozygous for truncating or splice alleles, without a ClinGen classification. Extracardiac features (nemaline rods, hypotonia, abnormal scarring, atrial septal defect) were each seen in a single patient, and supraventricular tachycardia is documented only in the title of the founding report. Penetrance, carrier risk, the frequency of each feature and long-term prognosis cannot be estimated.

Show evidence (1 reference)

PMID:30762586 SUPPORT INDIRECT BACKGROUND Human Clinical

"Comparison of the CAP2-KO and CAP2-CKO mice with human CAP2-DCM is in the early stages because only 2 patients have been described with homozygous CAP2 mutations (21)."

In 2019 the human evidence was two patients; it has since grown only to five.

Why do Cap2 knockout mice show male-biased lethality, microphthalmia and growth failure that are not reported in patients?

HUMAN MODEL MISMATCH OPEN mouse_human_extracardiac_mismatch

Attached to

animal_models#Cap2 whole-body knockout mouse animal_models#Cap2 gene-trap mouse

Whole-body knockout mice resemble the contiguous 6p22 deletion syndrome, whereas the founding patients reproduce the cardiac features only. Some mouse extracardiac features may reflect species differences or background effects. Human sex differences cannot be assessed with five patients.

Show evidence (2 references)

PMID:30518548 SUPPORT DIRECT Human Clinical

"The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development."

Direct comparison of patient and mouse phenotypes.

PMID:26616005 SUPPORT DIRECT Model Organism

"CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease."

Mouse extracardiac phenotype.

Is dilated cardiomyopathy a cardiomyocyte-autonomous consequence of CAP2 loss, or does it require loss in other cell types?

CONTROVERSY OPEN cardiomyocyte_autonomy_of_dcm

Attached to

animal_models#Cardiomyocyte-specific Cap2 knockout mouse pathophysiology#Impaired Myocardial Contractility

The 2015 study found that cardiomyocyte-specific knockout mice die of complete heart block before significant DCM, whereas the 2019 study from the same group reports robust DCM in the conditional line and used it for the SRF-inhibitor experiment. The difference may reflect timing, background or how DCM was assessed.

Show evidence (2 references)

PMID:26616005 SUPPORT DIRECT Model Organism

"We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias."

2015 conditional-knockout result.

PMID:30762586 SUPPORT DIRECT Model Organism

"However, CAP2-CKO mice develop a robust DCM, so we used CAP2-CKO mice to test the functional importance of SRF in CAP2 DCM."

2019 conditional-knockout result.

Does CAP2 loss activate or suppress MRTF-SRF signaling in human cardiomyocytes?

KNOWLEDGE GAP OPEN srf_direction_cell_type

Attached to

pathophysiology#MRTF-SRF Pathway Activation

Knockout mouse hearts show MRTFB nuclear accumulation and SRF target activation, whereas knockout mouse embryonic fibroblasts show reduced nuclear MRTF-A and SRF activity. No measurement exists in patient cardiomyocytes or iPSC-derived cardiomyocytes, although such cells have been generated from one patient.

Show evidence (1 reference)

PMID:33637797 SUPPORT DIRECT In Vitro

"In summary, our data revealed that in MEFs CAP2 controls basal MRTF-A localization and SRF activity, while it was dispensable for serum-induced nuclear MRTF-A translocation and SRF stimulation."

Opposite direction of effect in fibroblasts.

Do intercurrent infections precipitate decompensation in CMD2I, and should prevention be part of management?

EMERGING HYPOTHESIS OPEN infection_second_hit

Attached to

pathophysiology#Intercurrent Viral Infection as Decompensation Trigger

The proposal comes from one child presenting with heart failure during rhinovirus pneumonia, without myocardial viral testing. The authors note that fever, tachycardia and systemic inflammation could explain decompensation without direct myocardial injury.

Show evidence (2 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"In addition, fever-induced tachycardia, increased myocardial oxygen demand, and systemic inflammatory responses related to infection may have independently or synergistically contributed to acute cardiac decompensation, beyond direct viral myocardial injury."

The authors' own alternative explanation.

PMID:42344352 SUPPORT DIRECT Human Clinical

"First, although rhinovirus infection was identified as the “second hit” in our double-hit model, we did not perform endomyocardial biopsy with viral PCR or serial serum viral load measurements to confirm direct myocardial invasion."

The authors' own limitation on the proposed trigger.

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Pathophysiology

10

Biallelic CAP2 Loss-of-Function Variants

Mechanism confidence: Established

Reported alleles are an exon 7 donor splice-site variant causing skipping of exons 6 and 7, two nonsense variants (p.Tyr316Ter as summarized by panel curation, and c.551G>A p.Trp184Ter) and a frameshift (c.1288delT, p.Cys430fs), all homozygous. The splice and frameshift alleles were shown to reduce or abolish CAP2 protein in patient cells; the nonsense alleles are predicted loss of function.

CAP2 hgnc:20039

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Every reported patient is homozygous for a splice, nonsense or frameshift allele; no compound heterozygous or missense-only patients have been reported.

Downstream

CAP2 Protein Deficiency

Show evidence (4 references)

PMID:30518548 SUPPORT DIRECT Human Clinical

"Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation."

The founding homozygous splice variant in two consanguineous Bedouin children with DCM.

PMID:33083013 SUPPORT DIRECT Human Clinical

"The third gene relates to a severe early onset form of dilated cardiomyopathy (DCM) and congenital heart defects (CAP2 gene). Family history was positive, with two deceased siblings with similar phenotype. A nonsense, homozygous variant was detected in CAP2."

A second, independent family with a homozygous nonsense allele; the deceased siblings were not reported as genotyped.

PMID:34862840 SUPPORT DIRECT Human Clinical

"Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs."

A third family with a homozygous frameshift allele.

+ 1 more reference

CAP2 Protein Deficiency

Mechanism confidence: Established

Loss of CAP2 protein in patient cells, without compensatory upregulation of the paralog CAP1. CAP2 is expressed mainly in striated muscle, brain and skin, whereas CAP1 is broadly expressed, which may explain why the heart and skeletal muscle are the tissues affected.

cardiac muscle cell CL:0000746

CAP2 hgnc:20039

actin monomer binding GO:0003785

Downstream

Disordered Actin Filament Dynamics

Show evidence (2 references)

PMID:30518548 SUPPORT DIRECT In Vitro

"CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1."

Measured in patient-derived fibroblasts, not in patient myocardium.

PMID:26616005 SUPPORT INDIRECT BACKGROUND Other

"CAP1 is widely expressed in most cells and tissues25, while CAP2 expression is restricted to the brain, skin, skeletal muscle, cardiac muscle and testis2534."

Background expression data consistent with striated-muscle-restricted disease; the trailing digits are citation numbers in the cached text.

Disordered Actin Filament Dynamics

Mechanism confidence: Provisional

CAP2 sequesters G-actin, fragments and depolymerizes filaments, and at cardiac thin-filament pointed ends inhibits actin incorporation. Loss of CAP2 accelerates actin incorporation and increases filament dynamics in mouse cardiomyocytes. In human cells, only altered actin repolymerization kinetics in fibroblasts and elevated beta-actin mRNA have been measured.

actin filament depolymerization GO:0030042 ↓ DECREASED actin filament organization GO:0007015 ⚠ ABNORMAL

actin filament GO:0005884

Downstream

Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation

MRTF-SRF Pathway Activation

Cardiac Conduction System Dysfunction

Show evidence (4 references)

PMID:22945801 SUPPORT DIRECT In Vitro

"We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain."

Biochemical activity of recombinant CAP2 defines the function lost in the disease.

PMID:33742108 SUPPORT DIRECT In Vitro

"CAP2 has critical functions in cardiomyocytes as it depolymerizes and inhibits actin incorporation into thin filaments."

Places CAP2 activity at cardiac thin-filament pointed ends.

PMID:33742108 SUPPORT DIRECT Model Organism

"Therefore, loss of CAP2 does not change the total amount of actin incorporated into filaments but instead it accelerates its incorporation and increases the dynamics of its polymerization."

Cap2 knockout mouse cardiomyocytes show increased actin dynamics without a change in total filamentous actin.

+ 1 more reference

Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation

Mechanism confidence: Provisional

In Cap2 knockout mice and cultured knockout cardiomyocytes, cardiac alpha-actin is partly replaced by smooth-muscle and skeletal alpha-actin in thin filaments, myofibrils remain immature and disorganized, and cardiomyocytes are smaller and rounder. Thin-filament length is unchanged. A comparable defect delays the postnatal alpha-actin switch in mouse skeletal muscle. These are model findings and have not been measured in patient tissue.

cardiac muscle cell CL:0000746

cardiac myofibril assembly GO:0055003 ⚠ ABNORMAL

striated muscle thin filament GO:0005865

Animal models

Cap2 whole-body knockout mouse Mouse partially recapitulates Cardiac alpha-actin is replaced by smooth-muscle and skeletal alpha-actin in thin filaments.

Downstream

Sarcomere Disarray and Myofibrillar Disintegration

Show evidence (3 references)

PMID:33742108 SUPPORT DIRECT Model Organism

"Furthermore, CAP2 plays an essential role in cardiomyocyte maturation by modulating pre-sarcomeric actin assembly and regulating α-actin composition in mature thin filaments."

Summary of knockout mouse and cultured cardiomyocyte findings.

PMID:33742108 SUPPORT DIRECT Model Organism

"Collectively, these findings demonstrate that cActin is substituted by α-SMA and α-SKA in thin filaments from Cap2-KO mice, with no overall change in TFLs."

In vivo isoform substitution with preserved thin-filament length.

PMID:30962377 SUPPORT DIRECT Model Organism

"This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice."

The equivalent defect in mouse skeletal muscle, relevant to the skeletal muscle involvement seen in one patient.

MRTF-SRF Pathway Activation

Mechanism confidence: Provisional

Cap2 knockout hearts show nuclear accumulation of MRTFB and activation of SRF-dependent and fetal genes such as Myl9, Acta2 and Nppa before overt cardiac disease. An SRF inhibitor reduced these targets and delayed disease in cardiomyocyte-specific knockout mice, supporting a contributory rather than initiating role. In mouse embryonic fibroblasts, CAP2 loss instead reduces basal nuclear MRTF-A and SRF activity, so the direction of the effect depends on cell type. This has not been measured in patients. GO:0045944 is bound because GO has no SRF-specific process term.

cardiac muscle cell CL:0000746

positive regulation of transcription by RNA polymerase II GO:0045944 ↑ INCREASED

Animal models

Cap2 whole-body knockout mouse Mouse partially recapitulates SRF target activation precedes cardiac disease.

Downstream

Impaired Myocardial Contractility

Show evidence (2 references)

PMID:30762586 SUPPORT DIRECT Model Organism

"RNA sequencing analysis of CAP2-KO hearts and isolated cardiomyocytes revealed overactivation of fetal genes, including serum response factor-regulated (SRF-regulated) genes such as Myl9 and Acta2 prior to the emergence of cardiac disease."

SRF target activation precedes cardiac disease in knockout mice.

PMID:30762586 SUPPORT DIRECT Model Organism

"Compared with age-matched CAP2 WT mice, MRTFB accumulated in the nuclei in the CAP2-KO mice, while there was no difference with MRTFA."

Identifies MRTFB as the coactivator affected in knockout hearts.

Sarcomere Disarray and Myofibrillar Disintegration

Mechanism confidence: Provisional

Cap2 gene-trap mouse hearts show disarrayed sarcomeres and fibrosis. The explanted heart of the transplanted infant showed nemaline rods and disintegration of the myofibrillar structure, the only direct human myocardial histology reported.

cardiac muscle cell CL:0000746

sarcomere organization GO:0045214 ⚠ ABNORMAL

sarcomere GO:0030017

Animal models

Cap2 gene-trap mouse Mouse recapitulates Disarrayed sarcomeres comparable to the myofibrillar disintegration in the one explanted human heart.

Downstream

Impaired Myocardial Contractility

Nemaline Bodies

Myocardial Fibrotic Remodeling

Show evidence (2 references)

PMID:22945801 SUPPORT DIRECT Model Organism

"At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis."

Gene-trap mouse myocardium.

PMID:34862840 SUPPORT DIRECT Human Clinical

"Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure."

Explanted myocardium from one patient.

Myocardial Fibrotic Remodeling

Mechanism confidence: Provisional

Gene-trap mice show increased myocardial fibrosis. The child with a nonsense allele had diffuse biventricular late gadolinium enhancement on cardiac MRI, interpreted as fibrosis. Whether fibrosis is primary or secondary to cardiomyocyte injury is unknown, and it is not consistent across models; the whole-body knockout line showed no significant fibrosis by Sirius Red staining (PMID:30762586), and its sarcomeres showed no gross ultrastructural abnormalities near the time of death (PMID:26616005).

myocardium UBERON:0002349

Downstream

Cardiac Conduction System Dysfunction

Myocardial Fibrosis

Show evidence (2 references)

PMID:26925136 SUPPORT DIRECT Model Organism

"Myocardial fibrosis was elevated in Cap2 (gt/gt) hearts (9.1 ±6.7% vs. 5.5 ±3.3%; p < 0.01)."

Quantified fibrosis in gene-trap mice.

PMID:42344352 SUPPORT DIRECT Human Clinical

"Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C)."

Imaging evidence of fibrosis in one patient.

Cardiac Conduction System Dysfunction

Mechanism confidence: Provisional

Cap2 mutant mice have slowed atrial, atrioventricular and infra-Hisian conduction, abnormal connexin43 distribution and inducible ventricular arrhythmias. Cardiomyocyte-specific knockout mice died suddenly of complete heart block, showing that the conduction defect is cardiomyocyte-autonomous. In patients, first-degree atrioventricular block, intraventricular conduction delay and ventricular premature complexes were documented in one child, and the founding report describes conduction disease, naming supraventricular tachycardia in its title only.

cardiac conduction GO:0061337 ⚠ ABNORMAL

conducting system of heart UBERON:0002350

Animal models

Cap2 gene-trap mouse Mouse recapitulates Conduction delay at atrial and ventricular levels with inducible ventricular tachycardia.

Cardiomyocyte-specific Cap2 knockout mouse Mouse recapitulates Cardiomyocyte-autonomous conduction failure with sudden death.

Downstream

First Degree Atrioventricular Block

Cardiac Conduction Abnormality

Premature Ventricular Contraction

Show evidence (5 references)

PMID:26925136 SUPPORT DIRECT Model Organism

"Loss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias."

Electrophysiological phenotype of gene-trap mice.

PMID:26925136 SUPPORT DIRECT Model Organism

"Cap2 (gt/gt) showed more abnormal distribution of connexin43 compared to WT (23.0 ±4.7% vs. 2.9 ±0.8%; p < 0.01)."

Gap-junction remodeling accompanies the conduction defect.

PMID:26616005 SUPPORT DIRECT Model Organism

"We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias."

Cardiomyocyte-specific deletion is sufficient for conduction disease and sudden death in mice.

+ 2 more references

Impaired Myocardial Contractility

Mechanism confidence: Established

Reduced systolic function of both ventricles leading to ventricular dilation and heart failure. In patients, ejection fraction was 32% at presentation in the child with a nonsense allele, and the neonate had biventricular dysfunction.

cardiac muscle contraction GO:0060048 ↓ DECREASED

heart left ventricle UBERON:0002084

Animal models

Cap2 gene-trap mouse Mouse recapitulates Dilated cardiomyopathy with reduced survival.

Cap2 whole-body knockout mouse Mouse partially recapitulates Late-onset, male-predominant dilated cardiomyopathy with extracardiac features.

Cardiomyocyte-specific Cap2 knockout mouse Mouse partially recapitulates Whether this line develops dilated cardiomyopathy is reported inconsistently.

Downstream

Dilated Cardiomyopathy

Reduced Left Ventricular Ejection Fraction

Congestive Heart Failure

Increased Circulating Brain Natriuretic Peptide Concentration

Hepatomegaly

Show evidence (2 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Transthoracic echocardiography revealed global four-chamber enlargement, with a left ventricular end-diastolic dimension of 55 mm, severely reduced wall motion, and markedly impaired systolic function (ejection fraction 32%; fractional shortening 15%)."

Measured systolic dysfunction in one patient.

PMID:34862840 SUPPORT DIRECT Human Clinical

"A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction."

Biventricular dysfunction from birth in a second patient.

Intercurrent Viral Infection as Decompensation Trigger

Mechanism confidence: Hypothetical

One child with a homozygous nonsense allele had slight left ventricular enlargement with normal function three months before presenting with fulminant heart failure during rhinovirus pneumonia. The authors propose a double-hit model in which infection unmasks the genetic cardiomyopathy. This rests on a single case, and the authors did not confirm myocardial viral involvement. The child had not received routine vaccinations.

Downstream

Congestive Heart Failure

Show evidence (2 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Respiratory pathogen panel was positive for rhinovirus."

Documented concurrent viral infection at presentation.

PMID:42344352 SUPPORT DIRECT Human Clinical

"The patient had not received routine vaccinations prior to disease onset."

Vaccination history relevant to the proposed infectious trigger.

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Pathograph

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Phenotypes

16

Cardiovascular 11

Dilated Cardiomyopathy HP:0001644

Show evidence (4 references)

PMID:30518548 SUPPORT DIRECT Human Clinical

"We investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family."

Both founding patients had DCM.

PMID:34862840 SUPPORT DIRECT Human Clinical

"A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction."

Neonatal-onset DCM.

PMID:42344352 SUPPORT DIRECT Human Clinical

"Notably, unlike the classic infantile-onset phenotype reported in CAP2 deficiency (14), our patient presented at 5 years of age with childhood-onset severe dilated cardiomyopathy, for which the above mechanism provides a coherent molecular explanation."

Childhood-onset DCM extends the age range.

+ 1 more reference

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Notably, serial echocardiographic assessment demonstrated meaningful recovery of left ventricular systolic function, with ejection fraction improving from a nadir of 32% at presentation to 45% at 3 months and 48% at 6 months follow-up respectively."

Serial ejection fraction in one patient.

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Based on the integration of clinical, imaging, and genetic findings, the patient received a definitive diagnosis of CAP2-related DCM, with congenital heart defects and acute decompensated heart failure."

Acute decompensated heart failure in one patient.

Left Ventricular Noncompaction Cardiomyopathy HP:0011664

Show evidence (1 reference)

PMID:34862840 SUPPORT DIRECT Human Clinical

"A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction."

Single-patient observation.

Cardiac Conduction Abnormality HP:0031546

Show evidence (1 reference)

PMID:30518548 SUPPORT DIRECT Human Clinical

"The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development."

The founding report describes cardiac conduction disease in the Bedouin patients.

First Degree Atrioventricular Block HP:0011705

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D),..."

Single-patient ECG.

Premature Ventricular Contraction HP:0006682

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D),..."

Single-patient ECG.

Myocardial Fibrosis HP:0001685

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C)."

Imaging surrogate for fibrosis; no histology.

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A)."

Single-patient echocardiography.

Mitral Regurgitation HP:0001653

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A)."

Single-patient echocardiography.

Tricuspid Regurgitation HP:0005180

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A)."

Single-patient echocardiography.

Digestive 1

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Abdominal examination revealed hepatomegaly with the liver edge palpable 3 cm below the right costal margin, of moderate consistency and without tenderness, consistent with congestive hepatopathy secondary to right-sided cardiac dysfunction."

Secondary to heart failure in one patient.

Integument 1

Widened Atrophic Scar HP:0031158

Show evidence (1 reference)

PMID:34862840 SUPPORT DIRECT Human Clinical

"Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring."

Single-patient observation.

Metabolism 1

Increased Circulating Brain Natriuretic Peptide Concentration HP:0033534

Show evidence (1 reference)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Brain natriuretic peptide (BNP) was profoundly elevated at 4,472.51 pg/mL (reference: <35.00 pg/mL), reflecting severe ventricular wall stress and hemodynamic decompensation."

Single-patient laboratory value.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:34862840 SUPPORT DIRECT Human Clinical

"Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring."

Single-patient observation.

Cellular 1

Nemaline Bodies HP:0003798

Show evidence (2 references)

PMID:34862840 SUPPORT DIRECT Human Clinical

"A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods."

Skeletal muscle histology in one patient.

PMID:34862840 SUPPORT DIRECT Human Clinical

"Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure."

Cardiac nemaline rods in the same patient.

🧬

Genetic Associations

1

CAP2 (Autosomal recessive cause of pediatric dilated cardiomyopathy supported by homozygous loss-of-function variants in four families (five genotyped patients), patient-cell loss-of-function studies and concordant mouse models. The human evidence is limited to a few families, and there is no ClinGen gene-disease validity classification.)

Gene: CAP2 hgnc:20039 gene page variant_origin: GERMLINE

Show evidence (4 references)

PMID:30518548 SUPPORT DIRECT Human Clinical

"Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation."

Founding family.

PMID:33083013 SUPPORT DIRECT Human Clinical

"Taking both studies into account, these findings strongly suggest a role of CAP2 in DCM and the importance of this gene for normal function of the human heart."

Independent replication in a second family.

PMID:34862840 SUPPORT DIRECT Human Clinical

"Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs."

Third family.

+ 1 more reference

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Medical Actions

6

Oral heart-failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE Inhibitor NCIT:C247 Beta-Adrenergic Antagonist NCIT:C29576

Platform: Small molecule

Standard pediatric heart-failure medication, including ACE inhibition and beta-blockade, for systolic dysfunction. One child improved from an ejection fraction of 32% to 48% over six months on guideline-directed medical therapy. Recommendations are general pediatric guidance, not CAP2-specific evidence.

Mechanism Target:

Impaired Myocardial Contractility — Supports the failing ventricle; does not correct the CAP2 defect.

Show evidence (3 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"The follow-up results indicated that sustained GDMT and reverse ventricular ejection function conferred clinically significant functional benefit in this patient."

Single uncontrolled case; the specific oral agents were not listed.

url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication"

General pediatric guideline extrapolated to CMD2I.

url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"In children with systemic LV systolic dysfunction, use of β-blockers is reasonable"

General pediatric guideline extrapolated to CMD2I.

Intravenous inotropic support

Action: Pharmacotherapy NCIT:C15986

Agent: Cardiotonic Agent NCIT:C78322 milrinone CHEBI:50693 dobutamine CHEBI:4670

Platform: Small molecule

Milrinone and dobutamine were used during acute decompensation in one child, together with noninvasive ventilation and antibiotics for pneumonia.

Mechanism Target:

Congestive Heart Failure — Temporarily supports cardiac output during decompensation.

Show evidence (2 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"Guideline-directed medical therapy (GDMT) was systematically instituted, including intensive intravenous inotropic support (milrinone and dobutamine)."

Used in one patient, who recovered.

url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Intravenous inotropic support should be used in patients with acute HF presenting as cardiogenic shock or low cardiac output with poor systemic and end-organ perfusion"

General pediatric guideline.

Heart transplantation

Action: Heart Transplantation NCIT:C15246

Platform: Surgery

Performed at one year of age in the neonatal-onset patient. Post-transplant outcome was not reported in the cached abstract.

Mechanism Target:

Congestive Heart Failure — Replaces the failing heart in refractory disease.

Show evidence (2 references)

PMID:34862840 SUPPORT DIRECT Human Clinical

"The patient underwent a heart transplant at 1 year of age."

Single patient.

url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"In patients with severe acute HF, it is reasonable to initiate transfer to a center with pediatric HF specialists who have the expertise and ability to optimize medical therapy, evaluate for heart transplantation, and provide mechanical support"

General pediatric guideline on referral for advanced therapies.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counseling on autosomal recessive recurrence risk in consanguineous families, carrier testing and early cardiac evaluation of at-risk siblings.

Show evidence (1 reference)

PMID:42344352 SUPPORT INDIRECT Human Clinical

"Furthermore, the identification of obligate heterozygous carrier status in both consanguineous parents is consistent with autosomal recessive inheritance and reinforces the substantially elevated risk of homozygosity conferred by consanguineous unions, highlighting the critical importance of..."

Authors' recommendation; no outcome data.

Vaccination and infection prevention

Action: Vaccination NCIT:C15346

Platform: Vaccine

Proposed by one case report to reduce infection-triggered decompensation. There is no CAP2-specific evidence that vaccination changes outcome; the recommendation rests on a single case and on general cardiovascular data.

Mechanism Target:

Intercurrent Viral Infection as Decompensation Trigger — Aims to prevent the proposed infectious second hit.

Show evidence (1 reference)

PMID:42344352 SUPPORT INDIRECT Human Clinical

"Moreover, infection prevention and prompt intervention, including adherence to recommended vaccination schedules, are paramount in known DCM carriers."

Authors' recommendation, not a tested intervention.

Experimental SRF inhibition

Action: Therapeutic Procedure NCIT:C49236

Platform: Small molecule

The MRTF/SRF inhibitor CCG-1423-8u reduced SRF target expression and modestly extended survival in cardiomyocyte-specific Cap2 knockout mice. Not tested in humans.

Mechanism Target:

MRTF-SRF Pathway Activation — Inhibits MRTF/SRF-dependent transcription.

Show evidence (2 references)

PMID:30762586 SUPPORT DIRECT Model Organism

"CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, Nppa."

Target engagement in knockout mice.

PMID:30762586 SUPPORT DIRECT Model Organism

"The median survival of CAP2-CKO mice was 98 days, while CCG-1423-8u-treated CKO mice survived for 116 days and also maintained normal cardiac function longer."

Modest survival benefit in mice.

🔬

Diagnosis

5

Exome sequencing

Every reported patient was diagnosed by exome sequencing, which found a homozygous CAP2 splice, nonsense or frameshift variant; parental testing confirms carrier status. Splice variants can be assessed further with RNA and protein studies in patient fibroblasts.

Whole Exome Sequencing NCIT:C101295

Show evidence (3 references)

PMID:30518548 SUPPORT Human Clinical

"Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation."

Exome sequencing identified the founding splice variant.

PMID:34862840 SUPPORT Human Clinical

"Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs."

Exome sequencing identified the frameshift allele.

PMID:42344352 SUPPORT Human Clinical

"Exome sequencing (ES) identified a novel homozygous variant in CAP2 c.551G > A (p.W184*; NM_006366.3)."

Trio exome sequencing identified the nonsense allele.

Echocardiography

Echocardiography shows chamber dilation, systolic dysfunction, valvular regurgitation and, in one neonate, left ventricular noncompaction. Serial studies track recovery or progression.

Echocardiography Test NCIT:C16525

Show evidence (1 reference)

PMID:42344352 SUPPORT Human Clinical

"Transthoracic echocardiography revealed global four-chamber enlargement, with a left ventricular end-diastolic dimension of 55 mm, severely reduced wall motion, and markedly impaired systolic function (ejection fraction 32%; fractional shortening 15%)."

Echocardiographic findings at presentation in one child.

Cardiac magnetic resonance imaging

Cardiac MRI with late gadolinium enhancement showed diffuse biventricular fibrosis in one child. NCIT's only cardiac-specific MRI term found was stress cardiac MRI, so the general MRI term is bound.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

PMID:42344352 SUPPORT Human Clinical

"Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C)."

Late gadolinium enhancement in one patient.

Electrocardiography

Twelve-lead ECG can show atrioventricular and intraventricular conduction delay and ventricular ectopy; Cap2 mutant mice show progressive conduction disease, so rhythm surveillance is reasonable, though no CAP2-specific protocol exists.

Electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:42344352 SUPPORT Human Clinical

"Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D),..."

ECG findings in one child.

Skeletal muscle biopsy

A skeletal muscle biopsy showed nemaline rods in the neonatal-onset patient; biopsy was not reported in other patients.

Muscle Biopsy NCIT:C51895

Show evidence (1 reference)

PMID:34862840 SUPPORT Human Clinical

"A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods."

Muscle histology in one patient.

📈

Progression

2

Neonatal-onset rapidly progressive disease

Age: First hours of life to 1 year

The neonate presented within hours of birth with biventricular dysfunction and noncompaction and underwent heart transplantation at one year. This is one patient.

Show evidence (1 reference)

PMID:34862840 SUPPORT DIRECT Human Clinical

"The patient underwent a heart transplant at 1 year of age."

Outcome of one patient.

Childhood-onset decompensation with partial recovery

Age: 5 years, with 6 months of follow-up

The five-year-old had normal function with slight left ventricular enlargement three months before fulminant decompensation during infection, then improved on medical therapy to an ejection fraction of 48% at six months. His older sister died at three years of unexplained abdominal pain and was not genotyped. Long-term outcome is unknown.

Show evidence (2 references)

PMID:42344352 SUPPORT DIRECT Human Clinical

"However, this patient demonstrated a normal cardiac function with slightly enlarged left ventricle by physical examination three month in advance."

Pre-symptomatic status three months before presentation.

PMID:42344352 SUPPORT DIRECT Human Clinical

"Notably, serial echocardiographic assessment demonstrated meaningful recovery of left ventricular systolic function, with ejection fraction improving from a nadir of 32% at presentation to 45% at 3 months and 48% at 6 months follow-up respectively."

Short-term recovery on therapy.

📊

Prevalence

1

Published CMD2I cases worldwide

Cases In Literature Ultra Rare

Five genotyped patients from four families have been reported (two consanguineous children from a Bedouin family, one Pakistani child whose two deceased siblings had a similar but genotypically unconfirmed phenotype, one North American neonate and one Chinese child). Two of the four families are reported as consanguineous. These case reports do not estimate population prevalence.

Show evidence (1 reference)

PMID:42344352 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Clinically, CAP2-related disease is an extremely rare autosomal recessive disorder with only a limited number of cases reported worldwide."

Literature summary by the most recent case report.

⚖️

Clinical Burden

High

Reported patients had severe pediatric heart failure, one required heart transplantation in infancy, two untested siblings in one family died, and mouse models show sudden death from heart block. The number of patients is too small for survival statistics.

Show evidence (2 references)

PMID:33083013 SUPPORT DIRECT Human Clinical

"Family history was positive, with two deceased siblings with similar phenotype."

Early deaths in one family; the siblings were not genotyped.

PMID:34862840 SUPPORT DIRECT Human Clinical

"The patient underwent a heart transplant at 1 year of age."

Transplantation in infancy.

🐁

Animal Models

4

Cap2 gene-trap mouse

Homozygous gene-trap mice have reduced body weight and survival, dilated cardiomyopathy, sarcomere disarray, fibrosis, reduced myofibrillar calcium cooperativity, bradycardia, conduction delay, connexin43 maldistribution and inducible ventricular arrhythmias.

Species

Mouse

Genotype

Cap2 gt/gt (gene-trap inactivation)

Publication

PMID:22945801

Pathograph links

Sarcomere Disarray and Myofibrillar Disintegration recapitulates fidelity: moderate observes: cellular Disarrayed sarcomeres comparable to the myofibrillar disintegration in the one explanted human heart.

Limitations: Human cardiac histology is available for only one patient, who also had nemaline rods not described in this model.

Divergences from the human mechanism

species mismatch qualifying

Human cardiac histology is available for only one patient, who also had nemaline rods not described in this model.

Show evidence (1 reference)

PMID:22945801 SUPPORT Model Organism

"At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis."

Structural phenotype in the gene-trap line.

Cardiac Conduction System Dysfunction recapitulates fidelity: moderate observes: tissue Conduction delay at atrial and ventricular levels with inducible ventricular tachycardia.

Limitations: Human conduction data are limited to one ECG and the founding family's arrhythmia.

Divergences from the human mechanism

species mismatch qualifying

Mouse electrophysiology differs from human; human conduction data are limited to one ECG and the founding family's arrhythmia.

Show evidence (1 reference)

PMID:26925136 SUPPORT Model Organism

"Spontaneous ventricular arrhythmias could be detected in Cap2 (gt/gt) during the long-term-ECG recording."

Spontaneous arrhythmia in the gene-trap line.

Impaired Myocardial Contractility recapitulates fidelity: moderate observes: organism Dilated cardiomyopathy with reduced survival.

Limitations: Reduced body weight and survival in the mouse exceed the reported human extracardiac phenotype.

Divergences from the human mechanism

species mismatch qualifying

Reduced body weight and survival in the mouse exceed the reported human extracardiac phenotype.

Show evidence (1 reference)

PMID:22945801 SUPPORT Model Organism

"Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times."

DCM with conduction slowing.

Cap2 whole-body knockout mouse

Knockout males show reduced survival, small size, microphthalmia, cardiac conduction disease and, after six months, dilated cardiomyopathy; females are much less affected. Knockout hearts show MRTFB nuclear accumulation and SRF target activation. The alpha-actin isoform findings (PMID:33742108) come from a separate EUCOMM Cap2 tm1a knockout colony, not the line described in PMID:26616005.

Species

Mouse

Genotype

cap2-/cap2- (germline knockout)

Publication

PMID:26616005

Pathograph links

MRTF-SRF Pathway Activation partially recapitulates fidelity: low observes: cellular SRF target activation precedes cardiac disease.

Limitations: Not measured in any patient.

Divergences from the human mechanism

species mismatch qualifying

The pathway has not been measured in patient tissue, so the model cannot be compared with human disease at this step.

Show evidence (1 reference)

PMID:30762586 SUPPORT Model Organism

"RNA sequencing analysis of CAP2-KO hearts and isolated cardiomyocytes revealed overactivation of fetal genes, including serum response factor-regulated (SRF-regulated) genes such as Myl9 and Acta2 prior to the emergence of cardiac disease."

Pathway activation in knockout hearts.

Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation partially recapitulates fidelity: low observes: cellular Cardiac alpha-actin is replaced by smooth-muscle and skeletal alpha-actin in thin filaments.

Limitations: Actin isoform composition has not been examined in patient myocardium.

Divergences from the human mechanism

species mismatch qualifying

Actin isoform composition has not been examined in patient myocardium.

Show evidence (1 reference)

PMID:33742108 SUPPORT Model Organism

"Collectively, these findings demonstrate that cActin is substituted by α-SMA and α-SKA in thin filaments from Cap2-KO mice, with no overall change in TFLs."

In vivo isoform switch defect.

Impaired Myocardial Contractility partially recapitulates fidelity: moderate observes: organism Late-onset, male-predominant dilated cardiomyopathy with extracardiac features.

Limitations: Male-biased lethality, microphthalmia and growth failure have not been reported in patients, and onset is later than in most patients.

Divergences from the human mechanism

species mismatch qualifying

Male-biased lethality, microphthalmia and growth failure have not been reported in patients; the founding report states that the extracardiac mouse effects are not recapitulated.

Show evidence (1 reference)

PMID:26616005 SUPPORT Model Organism

"The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males."

Late, male-predominant DCM.

Show evidence (1 reference)

PMID:26616005 SUPPORT DIRECT Model Organism

"cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans."

Strong sex bias in the mouse, not documented in humans.

Cardiomyocyte-specific Cap2 knockout mouse

Cardiomyocyte-restricted deletion causes conduction disease and sudden death from complete heart block without the extracardiac or sex-biased phenotypes. One study reports no dilated cardiomyopathy before death, whereas a later study from the same group reports robust dilated cardiomyopathy and heart-failure death at 8 to 15 weeks.

Species

Mouse

Genotype

Myh6-Cre; cap2 loxP/loxP

Publication

PMID:26616005

Pathograph links

Cardiac Conduction System Dysfunction recapitulates fidelity: moderate observes: tissue Cardiomyocyte-autonomous conduction failure with sudden death.

Limitations: Sudden death from complete heart block has not been documented in patients.

Divergences from the human mechanism

species mismatch qualifying

Sudden death from complete heart block has not been documented in genotyped patients.

Show evidence (1 reference)

PMID:26616005 SUPPORT Model Organism

"Mice with cardiomyocyte-specific deletion of CAP2 also died suddenly due to complete heart block."

Conduction phenotype of the conditional line.

Impaired Myocardial Contractility partially recapitulates fidelity: unknown observes: organism Whether this line develops dilated cardiomyopathy is reported inconsistently.

Limitations: The two reports conflict on whether DCM develops before death.

Divergences from the human mechanism

contested assumption qualifying

The 2015 report found death from heart block before significant DCM, whereas the 2019 report describes robust DCM and death from heart failure.

Show evidence (2 references)

PMID:30762586 SUPPORT Model Organism

"However, CAP2-CKO mice develop a robust DCM, so we used CAP2-CKO mice to test the functional importance of SRF in CAP2 DCM."

The 2019 report of DCM in the conditional line.

+ 1 more reference

Cap2 knockdown zebrafish

Morpholino knockdown produces a short-body phenotype with pericardial edema. Cardiac function and structure were not characterized, and morpholino phenotypes can be non-specific, so this model gives only weak support.

Species

Zebrafish

Genotype

Morpholino knockdown of cap2

Publication

PMID:23022774

Show evidence (1 reference)

PMID:23022774 SUPPORT INDIRECT Model Organism

"Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema."

Pericardial edema suggests cardiac involvement but was not analyzed further.

{ }

Source YAML

click to show

name: Cardiomyopathy Dilated 2I
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- CMD2I
- cardiomyopathy, dilated, 2I
- CAP2-related dilated cardiomyopathy
- CAP2-related cardiomyopathy
parents:
- hereditary disease
- familial isolated dilated cardiomyopathy
disease_term:
  preferred_term: cardiomyopathy, dilated, 2I
  term:
    id: MONDO:0957545
    label: cardiomyopathy, dilated, 2I
description: Dilated cardiomyopathy 2I (CMD2I) is an autosomal recessive pediatric dilated cardiomyopathy associated with homozygous loss-of-function variants in CAP2, which encodes cyclase-associated protein 2, an actin monomer-binding and filament-depolymerizing protein of striated muscle. Five genotyped children from four unrelated families have been described, with onset from the first hours of life to five years of age. Reported features include biventricular dilated cardiomyopathy with heart failure, left ventricular noncompaction, nemaline rods in skeletal and cardiac muscle, conduction abnormalities and myocardial fibrosis; one infant required heart transplantation. Patient fibroblasts show loss of CAP2 protein and altered actin repolymerization kinetics. Most mechanistic evidence comes from Cap2 mutant mice, which develop dilated cardiomyopathy, sarcomere disarray, fibrosis, conduction disease with sudden death from heart block, impaired cardiac alpha-actin isoform switching and MRTF/SRF activation. The gene-disease link rests on few families, there is no ClinGen classification, and phenotype frequencies, penetrance and prognosis are not established.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: All genotyped patients are homozygous, two of the four families are reported as consanguineous, and every tested parent is a heterozygous carrier without reported heart or muscle disease. Carrier cardiac status has not been systematically evaluated; in one family the heterozygous mother reported occasional palpitations without formal cardiac assessment.
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Both parents were heterozygous for the same variant but have no history of heart or muscle disease.
    explanation: Unaffected heterozygous parents of a homozygous affected infant support recessive inheritance.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Segregation analysis confirmed autosomal recessive inheritance, with both parents identified as obligate heterozygous carriers (Figure 2B).
    explanation: Trio segregation in a consanguineous family with a homozygous nonsense variant.
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: This is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans.
    explanation: The founding report describes the variant as recessive in two consanguineous Bedouin children.
pathophysiology:
- name: Biallelic CAP2 Loss-of-Function Variants
  description: Reported alleles are an exon 7 donor splice-site variant causing skipping of exons 6 and 7, two nonsense variants (p.Tyr316Ter as summarized by panel curation, and c.551G>A p.Trp184Ter) and a frameshift (c.1288delT, p.Cys430fs), all homozygous. The splice and frameshift alleles were shown to reduce or abolish CAP2 protein in patient cells; the nonsense alleles are predicted loss of function.
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: CAP2
    term:
      id: hgnc:20039
      label: CAP2
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: Every reported patient is homozygous for a splice, nonsense or frameshift allele; no compound heterozygous or missense-only patients have been reported.
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation.
    explanation: The founding homozygous splice variant in two consanguineous Bedouin children with DCM.
  - reference: PMID:33083013
    reference_title: Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The third gene relates to a severe early onset form of dilated cardiomyopathy (DCM) and congenital heart defects (CAP2 gene). Family history was positive, with two deceased siblings with similar phenotype. A nonsense, homozygous variant was detected in CAP2.
    explanation: A second, independent family with a homozygous nonsense allele; the deceased siblings were not reported as genotyped.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs.
    explanation: A third family with a homozygous frameshift allele.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome sequencing (ES) identified a novel homozygous variant in CAP2 c.551G > A (p.W184*; NM_006366.3).
    explanation: A fourth family with a homozygous nonsense allele.
  downstream:
  - target: CAP2 Protein Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30518548
      reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Using patient-derived fibroblasts, we demonstrated that the mutation causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain that should prevent its correct folding. CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1.
      explanation: Patient fibroblasts show that the splice allele causes exon skipping and markedly reduced CAP2 protein.
    - reference: PMID:34862840
      reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Analysis of patient derived fibroblasts and cardiomyocytes derived from induced pluripotent stem cells confirmed the p.C430fs mutation (pathogenic variant), which appears to cause loss of both CAP2 protein and mRNA.
      explanation: Patient fibroblasts and iPSC-derived cardiomyocytes show loss of CAP2 mRNA and protein from the frameshift allele.
- name: CAP2 Protein Deficiency
  description: Loss of CAP2 protein in patient cells, without compensatory upregulation of the paralog CAP1. CAP2 is expressed mainly in striated muscle, brain and skin, whereas CAP1 is broadly expressed, which may explain why the heart and skeletal muscle are the tissues affected.
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: CAP2
    term:
      id: hgnc:20039
      label: CAP2
  molecular_functions:
  - preferred_term: actin monomer binding
    term:
      id: GO:0003785
      label: actin monomer binding
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1.
    explanation: Measured in patient-derived fibroblasts, not in patient myocardium.
  - reference: PMID:26616005
    reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: CAP1 is widely expressed in most cells and tissues25, while CAP2 expression is restricted to the brain, skin, skeletal muscle, cardiac muscle and testis2534.
    explanation: Background expression data consistent with striated-muscle-restricted disease; the trailing digits are citation numbers in the cached text.
  downstream:
  - target: Disordered Actin Filament Dynamics
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30518548
      reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In agreement with the essential role of CAP2 in actin filament polymerization, we demonstrate that the mutation affects the kinetics of repolymerization of actin in patient fibroblasts.
      explanation: The only human cellular readout linking CAP2 loss to altered actin dynamics; it was measured in fibroblasts rather than cardiomyocytes.
- name: Disordered Actin Filament Dynamics
  description: CAP2 sequesters G-actin, fragments and depolymerizes filaments, and at cardiac thin-filament pointed ends inhibits actin incorporation. Loss of CAP2 accelerates actin incorporation and increases filament dynamics in mouse cardiomyocytes. In human cells, only altered actin repolymerization kinetics in fibroblasts and elevated beta-actin mRNA have been measured.
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: actin filament depolymerization
    modifier: DECREASED
    term:
      id: GO:0030042
      label: actin filament depolymerization
  - preferred_term: actin filament organization
    modifier: ABNORMAL
    term:
      id: GO:0007015
      label: actin filament organization
  cellular_components:
  - preferred_term: actin filament
    term:
      id: GO:0005884
      label: actin filament
  evidence:
  - reference: PMID:22945801
    reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain.
    explanation: Biochemical activity of recombinant CAP2 defines the function lost in the disease.
  - reference: PMID:33742108
    reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: CAP2 has critical functions in cardiomyocytes as it depolymerizes and inhibits actin incorporation into thin filaments.
    explanation: Places CAP2 activity at cardiac thin-filament pointed ends.
  - reference: PMID:33742108
    reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Therefore, loss of CAP2 does not change the total amount of actin incorporated into filaments but instead it accelerates its incorporation and increases the dynamics of its polymerization.
    explanation: Cap2 knockout mouse cardiomyocytes show increased actin dynamics without a change in total filamentous actin.
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: However, β-actin mRNA was elevated as demonstrated by real-time qPCR.
    explanation: A transcriptional readout of altered actin homeostasis in patient fibroblasts.
  downstream:
  - target: Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33742108
      reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In addition, Cap2-KO cardiomyocytes contain higher levels of α-SMA and α-SKA, indicative of impaired actin clearance, potentially arising from perturbed depolymerization activity without CAP2.
      explanation: The authors link the isoform-switch defect to loss of CAP2 depolymerizing activity, while marking the link as potential.
  - target: MRTF-SRF Pathway Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30762586
      reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In mice, loss of the actin binding protein CAP2 causes dilated cardiomyopathy and serum response factor (SRF) activation, which can be targeted using an SRF inhibitor.
      explanation: Loss of CAP2 activates SRF in mouse hearts; the known intermediate is MRTF, which senses the G-actin to F-actin balance that CAP2 regulates.
    - reference: PMID:30762586
      reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: This suggests that CAP2 loss primarily activates MRTFB.
      explanation: Identifies MRTFB as the coactivator linking CAP2 loss to SRF activation in knockout hearts.
  - target: Cardiac Conduction System Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26616005
      reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.
      explanation: Whole-body and cardiomyocyte-specific knockout mice link CAP2-dependent actin dynamics to conduction disease; the intervening steps are not identified.
- name: Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation
  description: In Cap2 knockout mice and cultured knockout cardiomyocytes, cardiac alpha-actin is partly replaced by smooth-muscle and skeletal alpha-actin in thin filaments, myofibrils remain immature and disorganized, and cardiomyocytes are smaller and rounder. Thin-filament length is unchanged. A comparable defect delays the postnatal alpha-actin switch in mouse skeletal muscle. These are model findings and have not been measured in patient tissue.
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: cardiac myofibril assembly
    modifier: ABNORMAL
    term:
      id: GO:0055003
      label: cardiac myofibril assembly
  cellular_components:
  - preferred_term: striated muscle thin filament
    term:
      id: GO:0005865
      label: striated muscle thin filament
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:33742108
    reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Furthermore, CAP2 plays an essential role in cardiomyocyte maturation by modulating pre-sarcomeric actin assembly and regulating α-actin composition in mature thin filaments.
    explanation: Summary of knockout mouse and cultured cardiomyocyte findings.
  - reference: PMID:33742108
    reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Collectively, these findings demonstrate that cActin is substituted by α-SMA and α-SKA in thin filaments from Cap2-KO mice, with no overall change in TFLs.
    explanation: In vivo isoform substitution with preserved thin-filament length.
  - reference: PMID:30962377
    reference_title: CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice.
    explanation: The equivalent defect in mouse skeletal muscle, relevant to the skeletal muscle involvement seen in one patient.
  downstream:
  - target: Sarcomere Disarray and Myofibrillar Disintegration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33742108
      reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Cap2-KO cells exhibit thin filament disorganization with higher levels of α-smooth muscle and α-skeletal muscle actin and a delay in maturation.
      explanation: Cultured Cap2 knockout cardiomyocytes show thin-filament disorganization together with the isoform defect; whether the isoform change causes the disarray is not separately tested.
- name: MRTF-SRF Pathway Activation
  description: Cap2 knockout hearts show nuclear accumulation of MRTFB and activation of SRF-dependent and fetal genes such as Myl9, Acta2 and Nppa before overt cardiac disease. An SRF inhibitor reduced these targets and delayed disease in cardiomyocyte-specific knockout mice, supporting a contributory rather than initiating role. In mouse embryonic fibroblasts, CAP2 loss instead reduces basal nuclear MRTF-A and SRF activity, so the direction of the effect depends on cell type. This has not been measured in patients. GO:0045944 is bound because GO has no SRF-specific process term.
  biological_scale: CELLULAR
  role: modulator
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: RNA sequencing analysis of CAP2-KO hearts and isolated cardiomyocytes revealed overactivation of fetal genes, including serum response factor-regulated (SRF-regulated) genes such as Myl9 and Acta2 prior to the emergence of cardiac disease.
    explanation: SRF target activation precedes cardiac disease in knockout mice.
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Compared with age-matched CAP2 WT mice, MRTFB accumulated in the nuclei in the CAP2-KO mice, while there was no difference with MRTFA.
    explanation: Identifies MRTFB as the coactivator affected in knockout hearts.
  downstream:
  - target: Impaired Myocardial Contractility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30762586
      reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The median survival of CAP2-CKO mice was 98 days, while CCG-1423-8u-treated CKO mice survived for 116 days and also maintained normal cardiac function longer.
      explanation: Pharmacological SRF inhibition delays loss of cardiac function, supporting a contributory causal role; the modest effect implies other pathways.
- name: Sarcomere Disarray and Myofibrillar Disintegration
  description: Cap2 gene-trap mouse hearts show disarrayed sarcomeres and fibrosis. The explanted heart of the transplanted infant showed nemaline rods and disintegration of the myofibrillar structure, the only direct human myocardial histology reported.
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: ABNORMAL
    term:
      id: GO:0045214
      label: sarcomere organization
  cellular_components:
  - preferred_term: sarcomere
    term:
      id: GO:0030017
      label: sarcomere
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:22945801
    reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis.
    explanation: Gene-trap mouse myocardium.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure.
    explanation: Explanted myocardium from one patient.
  downstream:
  - target: Impaired Myocardial Contractility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22945801
      reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calcium-regulated force development.
      explanation: Isolated mutant myofibrils have a force-generation defect, connecting myofibrillar abnormality to contractile impairment.
  - target: Nemaline Bodies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34862840
      reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure.
      explanation: Nemaline rods occur together with myofibrillar disintegration in the patient's heart; co-occurrence, not a demonstrated causal step.
  - target: Myocardial Fibrotic Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22945801
      reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis.
      explanation: Sarcomere disarray and fibrosis develop together in gene-trap mice; the order of events is not established.
- name: Myocardial Fibrotic Remodeling
  description: Gene-trap mice show increased myocardial fibrosis. The child with a nonsense allele had diffuse biventricular late gadolinium enhancement on cardiac MRI, interpreted as fibrosis. Whether fibrosis is primary or secondary to cardiomyocyte injury is unknown, and it is not consistent across models; the whole-body knockout line showed no significant fibrosis by Sirius Red staining (PMID:30762586), and its sarcomeres showed no gross ultrastructural abnormalities near the time of death (PMID:26616005).
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:26925136
    reference_title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Myocardial fibrosis was elevated in Cap2 (gt/gt) hearts (9.1 ±6.7% vs. 5.5 ±3.3%; p < 0.01).
    explanation: Quantified fibrosis in gene-trap mice.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C).
    explanation: Imaging evidence of fibrosis in one patient.
  downstream:
  - target: Cardiac Conduction System Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26925136
      reference_title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: Structural changes in Cap2 (gt/gt) are associated with alterations in myocardial connexins and fibrosis.
      explanation: The authors report an association between fibrosis, connexin changes and the electrophysiological phenotype, not a demonstrated causal step.
  - target: Myocardial Fibrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42344352
      reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C).
      explanation: The imaging phenotype is the clinical readout of fibrotic remodeling in one patient.
- name: Cardiac Conduction System Dysfunction
  description: Cap2 mutant mice have slowed atrial, atrioventricular and infra-Hisian conduction, abnormal connexin43 distribution and inducible ventricular arrhythmias. Cardiomyocyte-specific knockout mice died suddenly of complete heart block, showing that the conduction defect is cardiomyocyte-autonomous. In patients, first-degree atrioventricular block, intraventricular conduction delay and ventricular premature complexes were documented in one child, and the founding report describes conduction disease, naming supraventricular tachycardia in its title only.
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: ABNORMAL
    term:
      id: GO:0061337
      label: cardiac conduction
  locations:
  - preferred_term: conducting system of heart
    term:
      id: UBERON:0002350
      label: conducting system of heart
  evidence:
  - reference: PMID:26925136
    reference_title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Loss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias.
    explanation: Electrophysiological phenotype of gene-trap mice.
  - reference: PMID:26925136
    reference_title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Cap2 (gt/gt) showed more abnormal distribution of connexin43 compared to WT (23.0 ±4.7% vs. 2.9 ±0.8%; p < 0.01).
    explanation: Gap-junction remodeling accompanies the conduction defect.
  - reference: PMID:26616005
    reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.
    explanation: Cardiomyocyte-specific deletion is sufficient for conduction disease and sudden death in mice.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D), collectively reflecting diffuse electromechanical remodeling.
    explanation: Conduction abnormalities in one patient, recorded during acute decompensation.
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development.
    explanation: Conduction disease in the founding patients, which the authors equate with the knockout mouse phenotype.
  downstream:
  - target: First Degree Atrioventricular Block
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiac Conduction Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Premature Ventricular Contraction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Myocardial Contractility
  description: Reduced systolic function of both ventricles leading to ventricular dilation and heart failure. In patients, ejection fraction was 32% at presentation in the child with a nonsense allele, and the neonate had biventricular dysfunction.
  biological_scale: ORGANISM
  role: effector
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Transthoracic echocardiography revealed global four-chamber enlargement, with a left ventricular end-diastolic dimension of 55 mm, severely reduced wall motion, and markedly impaired systolic function (ejection fraction 32%; fractional shortening 15%).
    explanation: Measured systolic dysfunction in one patient.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction.
    explanation: Biventricular dysfunction from birth in a second patient.
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: DIRECT
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Circulating Brain Natriuretic Peptide Concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42344352
      reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Brain natriuretic peptide (BNP) was profoundly elevated at 4,472.51 pg/mL (reference: <35.00 pg/mL), reflecting severe ventricular wall stress and hemodynamic decompensation.'
      explanation: The authors attribute the BNP elevation to ventricular wall stress from decompensated pump failure.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42344352
      reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Abdominal examination revealed hepatomegaly with the liver edge palpable 3 cm below the right costal margin, of moderate consistency and without tenderness, consistent with congestive hepatopathy secondary to right-sided cardiac dysfunction.
      explanation: Right-sided failure and hepatic congestion are the known intermediates.
- name: Intercurrent Viral Infection as Decompensation Trigger
  description: One child with a homozygous nonsense allele had slight left ventricular enlargement with normal function three months before presenting with fulminant heart failure during rhinovirus pneumonia. The authors propose a double-hit model in which infection unmasks the genetic cardiomyopathy. This rests on a single case, and the authors did not confirm myocardial viral involvement. The child had not received routine vaccinations.
  biological_scale: ORGANISM
  role: modifier
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Respiratory pathogen panel was positive for rhinovirus.
    explanation: Documented concurrent viral infection at presentation.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The patient had not received routine vaccinations prior to disease onset.
    explanation: Vaccination history relevant to the proposed infectious trigger.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:42344352
      reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: The convergence of these two independent mechanisms is proposed to have precipitated and accelerated the manifestation of decompensated heart failure, underscoring the critical role of environmental triggers in unmasking latent genetic cardiomyopathies.
      explanation: Proposed by the authors from one case; fever, tachycardia and systemic inflammation are alternative explanations they also acknowledge.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: Reported in all genotyped patients, with onset from the first hours of life to five years of age. Ventricular involvement was biventricular in the neonate and four-chamber in the five-year-old. With five genotyped patients, this does not establish penetrance.
  diagnostic: true
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: We investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family.
    explanation: Both founding patients had DCM.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction.
    explanation: Neonatal-onset DCM.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Notably, unlike the classic infantile-onset phenotype reported in CAP2 deficiency (14), our patient presented at 5 years of age with childhood-onset severe dilated cardiomyopathy, for which the above mechanism provides a coherent molecular explanation.
    explanation: Childhood-onset DCM extends the age range.
  - reference: PMID:33083013
    reference_title: Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The third gene relates to a severe early onset form of dilated cardiomyopathy (DCM) and congenital heart defects (CAP2 gene).
    explanation: Early-onset DCM in the Pakistani family.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: Ejection fraction was 32% at presentation in one child and improved to 48% after six months of medical therapy.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Notably, serial echocardiographic assessment demonstrated meaningful recovery of left ventricular systolic function, with ejection fraction improving from a nadir of 32% at presentation to 45% at 3 months and 48% at 6 months follow-up respectively.
    explanation: Serial ejection fraction in one patient.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: Presenting feature in the child with a nonsense allele, with NYHA class IV symptoms, pulmonary edema, hepatomegaly and markedly elevated BNP; the neonate had rapidly progressive disease requiring transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Based on the integration of clinical, imaging, and genetic findings, the patient received a definitive diagnosis of CAP2-related DCM, with congenital heart defects and acute decompensated heart failure.
    explanation: Acute decompensated heart failure in one patient.
- name: Left Ventricular Noncompaction Cardiomyopathy
  category: Cardiovascular
  description: Reported in the neonatal-onset patient only.
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction.
    explanation: Single-patient observation.
- name: Nemaline Bodies
  category: Musculoskeletal
  description: Nemaline rods were found in a skeletal muscle biopsy on day 8 of life and in the explanted heart of the same patient. Not reported in the other patients, whose muscle was not described as biopsied.
  phenotype_term:
    preferred_term: Nemaline bodies
    term:
      id: HP:0003798
      label: Nemaline bodies
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods.
    explanation: Skeletal muscle histology in one patient.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure.
    explanation: Cardiac nemaline rods in the same patient.
- name: Hypotonia
  category: Musculoskeletal
  description: Mild hypotonia in the neonatal-onset patient with nemaline rods. The five-year-old had no skeletal muscle manifestations on admission.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring.
    explanation: Single-patient observation.
- name: Widened Atrophic Scar
  category: Integumentary
  description: Atrophic, widened scarring was noted in the neonatal-onset patient; CAP2 is expressed in skin and Cap2 knockout mice have wound-healing abnormalities, but the link is unexplored in humans. The five-year-old had no skin abnormalities on admission.
  phenotype_term:
    preferred_term: Widened atrophic scar
    term:
      id: HP:0031158
      label: Widened atrophic scar
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring.
    explanation: Single-patient observation.
- name: Cardiac Conduction Abnormality
  category: Cardiovascular
  description: The founding report states that the patients reproduce the cardiac conduction disease of Cap2 knockout mice; its title names supraventricular tachycardia, but the cached abstract gives no further detail. One later child had first-degree atrioventricular block and intraventricular conduction delay.
  phenotype_term:
    preferred_term: Cardiac conduction abnormality
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development.
    explanation: The founding report describes cardiac conduction disease in the Bedouin patients.
- name: First Degree Atrioventricular Block
  category: Cardiovascular
  description: Recorded with intraventricular conduction delay in one child during acute decompensation.
  phenotype_term:
    preferred_term: First degree atrioventricular block
    term:
      id: HP:0011705
      label: First degree atrioventricular block
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D), collectively reflecting diffuse electromechanical remodeling.
    explanation: Single-patient ECG.
- name: Premature Ventricular Contraction
  category: Cardiovascular
  description: Ventricular premature complexes on ECG in one child.
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D), collectively reflecting diffuse electromechanical remodeling.
    explanation: Single-patient ECG.
- name: Myocardial Fibrosis
  category: Cardiovascular
  description: Diffuse biventricular late gadolinium enhancement on cardiac MRI in one child.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C).
    explanation: Imaging surrogate for fibrosis; no histology.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: Found in one child at presentation; congenital heart defects were also described in the Pakistani family. Whether structural heart defects belong to CMD2I or are coincidental is unresolved.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A).
    explanation: Single-patient echocardiography.
- name: Mitral Regurgitation
  category: Cardiovascular
  description: Present with tricuspid regurgitation in one child with severe ventricular dilation; likely functional, but this was not assessed.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A).
    explanation: Single-patient echocardiography.
- name: Tricuspid Regurgitation
  category: Cardiovascular
  description: Present with mitral regurgitation in one child with severe ventricular dilation.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Structural anomalies included an atrial septal defect, mitral valve leaflet thickening, and both mitral and tricuspid regurgitation, these structural anomalies were first diagnosed on admission and had not been recognized prior to the acute cardiac presentation (Figure 1A).
    explanation: Single-patient echocardiography.
- name: Increased Circulating Brain Natriuretic Peptide Concentration
  category: Cardiovascular
  description: BNP 4,472.51 pg/mL at presentation in one child with decompensated heart failure.
  phenotype_term:
    preferred_term: Increased circulating brain natriuretic peptide concentration
    term:
      id: HP:0033534
      label: Increased circulating brain natriuretic peptide concentration
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: 'Brain natriuretic peptide (BNP) was profoundly elevated at 4,472.51 pg/mL (reference: <35.00 pg/mL), reflecting severe ventricular wall stress and hemodynamic decompensation.'
    explanation: Single-patient laboratory value.
- name: Hepatomegaly
  category: Digestive
  description: Congestive hepatomegaly in one child with right-sided heart failure.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Abdominal examination revealed hepatomegaly with the liver edge palpable 3 cm below the right costal margin, of moderate consistency and without tenderness, consistent with congestive hepatopathy secondary to right-sided cardiac dysfunction.
    explanation: Secondary to heart failure in one patient.
diagnosis:
- name: Exome sequencing
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: Every reported patient was diagnosed by exome sequencing, which found a homozygous CAP2 splice, nonsense or frameshift variant; parental testing confirms carrier status. Splice variants can be assessed further with RNA and protein studies in patient fibroblasts.
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation.
    explanation: Exome sequencing identified the founding splice variant.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs.
    explanation: Exome sequencing identified the frameshift allele.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing (ES) identified a novel homozygous variant in CAP2 c.551G > A (p.W184*; NM_006366.3).
    explanation: Trio exome sequencing identified the nonsense allele.
- name: Echocardiography
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: Echocardiography shows chamber dilation, systolic dysfunction, valvular regurgitation and, in one neonate, left ventricular noncompaction. Serial studies track recovery or progression.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Transthoracic echocardiography revealed global four-chamber enlargement, with a left ventricular end-diastolic dimension of 55 mm, severely reduced wall motion, and markedly impaired systolic function (ejection fraction 32%; fractional shortening 15%).
    explanation: Echocardiographic findings at presentation in one child.
- name: Cardiac magnetic resonance imaging
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: Cardiac MRI with late gadolinium enhancement showed diffuse biventricular fibrosis in one child. NCIT's only cardiac-specific MRI term found was stress cardiac MRI, so the general MRI term is bound.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, diffuse foci of late gadolinium enhancement (LGE) were identified across both ventricles, a pattern strongly indicative of myocardial fibrosis and replacement consistent with dilated cardiomyopathy (Figures 1B,C).
    explanation: Late gadolinium enhancement in one patient.
- name: Electrocardiography
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  description: Twelve-lead ECG can show atrioventricular and intraventricular conduction delay and ventricular ectopy; Cap2 mutant mice show progressive conduction disease, so rhythm surveillance is reasonable, though no CAP2-specific protocol exists.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twelve-lead electrocardiography (ECG) demonstrated a constellation of electrophysiological abnormalities, including biatrial enlargement, left ventricular hypertrophy, first-degree atrioventricular block, intraventricular conduction delay, and ventricular premature complexes (Figure 1D), collectively reflecting diffuse electromechanical remodeling.
    explanation: ECG findings in one child.
- name: Skeletal muscle biopsy
  diagnosis_term:
    preferred_term: Muscle Biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  description: A skeletal muscle biopsy showed nemaline rods in the neonatal-onset patient; biopsy was not reported in other patients.
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods.
    explanation: Muscle histology in one patient.
prevalence:
- population: Published CMD2I cases worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: Five genotyped patients from four families have been reported (two consanguineous children from a Bedouin family, one Pakistani child whose two deceased siblings had a similar but genotypically unconfirmed phenotype, one North American neonate and one Chinese child). Two of the four families are reported as consanguineous. These case reports do not estimate population prevalence.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Clinically, CAP2-related disease is an extremely rare autosomal recessive disorder with only a limited number of cases reported worldwide.
    explanation: Literature summary by the most recent case report.
progression:
- phase: Neonatal-onset rapidly progressive disease
  age_range: First hours of life to 1 year
  notes: The neonate presented within hours of birth with biventricular dysfunction and noncompaction and underwent heart transplantation at one year. This is one patient.
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The patient underwent a heart transplant at 1 year of age.
    explanation: Outcome of one patient.
- phase: Childhood-onset decompensation with partial recovery
  age_range: 5 years, with 6 months of follow-up
  notes: The five-year-old had normal function with slight left ventricular enlargement three months before fulminant decompensation during infection, then improved on medical therapy to an ejection fraction of 48% at six months. His older sister died at three years of unexplained abdominal pain and was not genotyped. Long-term outcome is unknown.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: However, this patient demonstrated a normal cardiac function with slightly enlarged left ventricle by physical examination three month in advance.
    explanation: Pre-symptomatic status three months before presentation.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Notably, serial echocardiographic assessment demonstrated meaningful recovery of left ventricular systolic function, with ejection fraction improving from a nadir of 32% at presentation to 45% at 3 months and 48% at 6 months follow-up respectively.
    explanation: Short-term recovery on therapy.
clinical_burden:
  burden_level: HIGH
  rationale: Reported patients had severe pediatric heart failure, one required heart transplantation in infancy, two untested siblings in one family died, and mouse models show sudden death from heart block. The number of patients is too small for survival statistics.
  evidence:
  - reference: PMID:33083013
    reference_title: Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Family history was positive, with two deceased siblings with similar phenotype.
    explanation: Early deaths in one family; the siblings were not genotyped.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The patient underwent a heart transplant at 1 year of age.
    explanation: Transplantation in infancy.
genetic:
- name: CAP2
  gene_term:
    preferred_term: CAP2
    term:
      id: hgnc:20039
      label: CAP2
  variant_origin: GERMLINE
  association: Autosomal recessive cause of pediatric dilated cardiomyopathy supported by homozygous loss-of-function variants in four families (five genotyped patients), patient-cell loss-of-function studies and concordant mouse models. The human evidence is limited to a few families, and there is no ClinGen gene-disease validity classification.
  notes: Reported alleles (NM_006366) are an exon 7 donor splice-site variant (Bedouin family; exact HGVS not in the cached abstract), a homozygous nonsense allele in a Pakistani family (reported as p.Tyr316Ter in panel curation; not stated in the cached text), c.1288delT p.Cys430fs, and c.551G>A p.Trp184Ter. The symbol CAP2 was formerly also used for SERPINB8, and "CAP2" is also the name of an unrelated left atrial appendage closure registry; this entry refers only to cyclase-associated protein 2 (hgnc:20039). relationship_type is left unset because no ClinGen or other external tier classifies CAP2 for this disease, and the schema reserves CAUSATIVE for Definitive or Strong relationships.
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation.
    explanation: Founding family.
  - reference: PMID:33083013
    reference_title: Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Taking both studies into account, these findings strongly suggest a role of CAP2 in DCM and the importance of this gene for normal function of the human heart.
    explanation: Independent replication in a second family.
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs.
    explanation: Third family.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome sequencing (ES) identified a novel homozygous variant in CAP2 c.551G > A (p.W184*; NM_006366.3).
    explanation: Fourth family.
treatments:
- name: Oral heart-failure pharmacotherapy
  description: Standard pediatric heart-failure medication, including ACE inhibition and beta-blockade, for systolic dysfunction. One child improved from an ejection fraction of 32% to 48% over six months on guideline-directed medical therapy. Recommendations are general pediatric guidance, not CAP2-specific evidence.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Impaired Myocardial Contractility
    description: Supports the failing ventricle; does not correct the CAP2 defect.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The follow-up results indicated that sustained GDMT and reverse ventricular ejection function conferred clinically significant functional benefit in this patient.
    explanation: Single uncontrolled case; the specific oral agents were not listed.
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication
    explanation: General pediatric guideline extrapolated to CMD2I.
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In children with systemic LV systolic dysfunction, use of β-blockers is reasonable
    explanation: General pediatric guideline extrapolated to CMD2I.
- name: Intravenous inotropic support
  description: Milrinone and dobutamine were used during acute decompensation in one child, together with noninvasive ventilation and antibiotics for pneumonia.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Temporarily supports cardiac output during decompensation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Cardiotonic Agent
      term:
        id: NCIT:C78322
        label: Cardiotonic Agent
    - preferred_term: milrinone
      term:
        id: CHEBI:50693
        label: milrinone
    - preferred_term: dobutamine
      term:
        id: CHEBI:4670
        label: dobutamine
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Guideline-directed medical therapy (GDMT) was systematically instituted, including intensive intravenous inotropic support (milrinone and dobutamine).
    explanation: Used in one patient, who recovered.
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Intravenous inotropic support should be used in patients with acute HF presenting as cardiogenic shock or low cardiac output with poor systemic and end-organ perfusion
    explanation: General pediatric guideline.
- name: Heart transplantation
  description: Performed at one year of age in the neonatal-onset patient. Post-transplant outcome was not reported in the cached abstract.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Replaces the failing heart in refractory disease.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:34862840
    reference_title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The patient underwent a heart transplant at 1 year of age.
    explanation: Single patient.
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In patients with severe acute HF, it is reasonable to initiate transfer to a center with pediatric HF specialists who have the expertise and ability to optimize medical therapy, evaluate for heart transplantation, and provide mechanical support
    explanation: General pediatric guideline on referral for advanced therapies.
- name: Genetic counseling
  description: Counseling on autosomal recessive recurrence risk in consanguineous families, carrier testing and early cardiac evaluation of at-risk siblings.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Furthermore, the identification of obligate heterozygous carrier status in both consanguineous parents is consistent with autosomal recessive inheritance and reinforces the substantially elevated risk of homozygosity conferred by consanguineous unions, highlighting the critical importance of proactive genetic counseling in at-risk families.
    explanation: Authors' recommendation; no outcome data.
- name: Vaccination and infection prevention
  description: Proposed by one case report to reduce infection-triggered decompensation. There is no CAP2-specific evidence that vaccination changes outcome; the recommendation rests on a single case and on general cardiovascular data.
  therapeutic_modality: VACCINE
  target_mechanisms:
  - target: Intercurrent Viral Infection as Decompensation Trigger
    description: Aims to prevent the proposed infectious second hit.
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Moreover, infection prevention and prompt intervention, including adherence to recommended vaccination schedules, are paramount in known DCM carriers.
    explanation: Authors' recommendation, not a tested intervention.
- name: Experimental SRF inhibition
  description: The MRTF/SRF inhibitor CCG-1423-8u reduced SRF target expression and modestly extended survival in cardiomyocyte-specific Cap2 knockout mice. Not tested in humans.
  notes: No therapeutic_agent is bound because OAK label searches "l~CCG-1423", "l~CCG 1423" and "l~CCG" in CHEBI and NCIT returned no term for CCG-1423 or CCG-1423-8u.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: MRTF-SRF Pathway Activation
    description: Inhibits MRTF/SRF-dependent transcription.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, Nppa.
    explanation: Target engagement in knockout mice.
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: The median survival of CAP2-CKO mice was 98 days, while CCG-1423-8u-treated CKO mice survived for 116 days and also maintained normal cardiac function longer.
    explanation: Modest survival benefit in mice.
animal_models:
- name: Cap2 gene-trap mouse
  species: Mouse
  genotype: Cap2 gt/gt (gene-trap inactivation)
  publication: PMID:22945801
  description: Homozygous gene-trap mice have reduced body weight and survival, dilated cardiomyopathy, sarcomere disarray, fibrosis, reduced myofibrillar calcium cooperativity, bradycardia, conduction delay, connexin43 maldistribution and inducible ventricular arrhythmias.
  modeled_mechanisms:
  - target: Sarcomere Disarray and Myofibrillar Disintegration
    model_scale: CELLULAR
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Disarrayed sarcomeres comparable to the myofibrillar disintegration in the one explanted human heart.
    limitations: Human cardiac histology is available for only one patient, who also had nemaline rods not described in this model.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Human cardiac histology is available for only one patient, who also had nemaline rods not described in this model.
    evidence:
    - reference: PMID:22945801
      reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis.
      explanation: Structural phenotype in the gene-trap line.
  - target: Cardiac Conduction System Dysfunction
    model_scale: TISSUE
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Conduction delay at atrial and ventricular levels with inducible ventricular tachycardia.
    limitations: Human conduction data are limited to one ECG and the founding family's arrhythmia.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mouse electrophysiology differs from human; human conduction data are limited to one ECG and the founding family's arrhythmia.
    evidence:
    - reference: PMID:26925136
      reference_title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Spontaneous ventricular arrhythmias could be detected in Cap2 (gt/gt) during the long-term-ECG recording.
      explanation: Spontaneous arrhythmia in the gene-trap line.
  - target: Impaired Myocardial Contractility
    model_scale: ORGANISM
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Dilated cardiomyopathy with reduced survival.
    limitations: Reduced body weight and survival in the mouse exceed the reported human extracardiac phenotype.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Reduced body weight and survival in the mouse exceed the reported human extracardiac phenotype.
    evidence:
    - reference: PMID:22945801
      reference_title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times.
      explanation: DCM with conduction slowing.
- name: Cap2 whole-body knockout mouse
  species: Mouse
  genotype: cap2-/cap2- (germline knockout)
  publication: PMID:26616005
  description: Knockout males show reduced survival, small size, microphthalmia, cardiac conduction disease and, after six months, dilated cardiomyopathy; females are much less affected. Knockout hearts show MRTFB nuclear accumulation and SRF target activation. The alpha-actin isoform findings (PMID:33742108) come from a separate EUCOMM Cap2 tm1a knockout colony, not the line described in PMID:26616005.
  modeled_mechanisms:
  - target: MRTF-SRF Pathway Activation
    model_scale: CELLULAR
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: SRF target activation precedes cardiac disease.
    limitations: Not measured in any patient.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The pathway has not been measured in patient tissue, so the model cannot be compared with human disease at this step.
    evidence:
    - reference: PMID:30762586
      reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: RNA sequencing analysis of CAP2-KO hearts and isolated cardiomyocytes revealed overactivation of fetal genes, including serum response factor-regulated (SRF-regulated) genes such as Myl9 and Acta2 prior to the emergence of cardiac disease.
      explanation: Pathway activation in knockout hearts.
  - target: Impaired Cardiac Alpha-Actin Isoform Switch and Myofibril Maturation
    model_scale: CELLULAR
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Cardiac alpha-actin is replaced by smooth-muscle and skeletal alpha-actin in thin filaments.
    limitations: Actin isoform composition has not been examined in patient myocardium.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Actin isoform composition has not been examined in patient myocardium.
    evidence:
    - reference: PMID:33742108
      reference_title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Collectively, these findings demonstrate that cActin is substituted by α-SMA and α-SKA in thin filaments from Cap2-KO mice, with no overall change in TFLs.
      explanation: In vivo isoform switch defect.
  - target: Impaired Myocardial Contractility
    model_scale: ORGANISM
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Late-onset, male-predominant dilated cardiomyopathy with extracardiac features.
    limitations: Male-biased lethality, microphthalmia and growth failure have not been reported in patients, and onset is later than in most patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Male-biased lethality, microphthalmia and growth failure have not been reported in patients; the founding report states that the extracardiac mouse effects are not recapitulated.
    evidence:
    - reference: PMID:26616005
      reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males.
      explanation: Late, male-predominant DCM.
  evidence:
  - reference: PMID:26616005
    reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans.
    explanation: Strong sex bias in the mouse, not documented in humans.
- name: Cardiomyocyte-specific Cap2 knockout mouse
  species: Mouse
  genotype: Myh6-Cre; cap2 loxP/loxP
  publication: PMID:26616005
  description: Cardiomyocyte-restricted deletion causes conduction disease and sudden death from complete heart block without the extracardiac or sex-biased phenotypes. One study reports no dilated cardiomyopathy before death, whereas a later study from the same group reports robust dilated cardiomyopathy and heart-failure death at 8 to 15 weeks.
  modeled_mechanisms:
  - target: Cardiac Conduction System Dysfunction
    model_scale: TISSUE
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Cardiomyocyte-autonomous conduction failure with sudden death.
    limitations: Sudden death from complete heart block has not been documented in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Sudden death from complete heart block has not been documented in genotyped patients.
    evidence:
    - reference: PMID:26616005
      reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Mice with cardiomyocyte-specific deletion of CAP2 also died suddenly due to complete heart block.
      explanation: Conduction phenotype of the conditional line.
  - target: Impaired Myocardial Contractility
    model_scale: ORGANISM
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    description: Whether this line develops dilated cardiomyopathy is reported inconsistently.
    limitations: The two reports conflict on whether DCM develops before death.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: The 2015 report found death from heart block before significant DCM, whereas the 2019 report describes robust DCM and death from heart failure.
    evidence:
    - reference: PMID:30762586
      reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: However, CAP2-CKO mice develop a robust DCM, so we used CAP2-CKO mice to test the functional importance of SRF in CAP2 DCM.
      explanation: The 2019 report of DCM in the conditional line.
    - reference: PMID:26616005
      reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: On the other hand, all of the cap2−/cap2− mice develop cardiac conduction dysfunction on ECG and by invasive analysis and, in cardiomyocyte-specific knockouts, all of the mice die from complete heart block before there is significant DCM.
      explanation: The 2015 report found no significant DCM before death in the conditional line.
- name: Cap2 knockdown zebrafish
  species: Zebrafish
  genotype: Morpholino knockdown of cap2
  publication: PMID:23022774
  description: Morpholino knockdown produces a short-body phenotype with pericardial edema. Cardiac function and structure were not characterized, and morpholino phenotypes can be non-specific, so this model gives only weak support.
  evidence:
  - reference: PMID:23022774
    reference_title: Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema.
    explanation: Pericardial edema suggests cardiac involvement but was not analyzed further.
discussions:
- discussion_id: few_families_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How secure is the CAP2-CMD2I gene-disease relationship, and what is the full phenotypic spectrum?
  attaches_to:
  - genetic#CAP2
  rationale: The human evidence is five genotyped patients in four families, all homozygous for truncating or splice alleles, without a ClinGen classification. Extracardiac features (nemaline rods, hypotonia, abnormal scarring, atrial septal defect) were each seen in a single patient, and supraventricular tachycardia is documented only in the title of the founding report. Penetrance, carrier risk, the frequency of each feature and long-term prognosis cannot be estimated.
  evidence:
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: Comparison of the CAP2-KO and CAP2-CKO mice with human CAP2-DCM is in the early stages because only 2 patients have been described with homozygous CAP2 mutations (21).
    explanation: In 2019 the human evidence was two patients; it has since grown only to five.
- discussion_id: mouse_human_extracardiac_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why do Cap2 knockout mice show male-biased lethality, microphthalmia and growth failure that are not reported in patients?
  attaches_to:
  - animal_models#Cap2 whole-body knockout mouse
  - animal_models#Cap2 gene-trap mouse
  rationale: Whole-body knockout mice resemble the contiguous 6p22 deletion syndrome, whereas the founding patients reproduce the cardiac features only. Some mouse extracardiac features may reflect species differences or background effects. Human sex differences cannot be assessed with five patients.
  evidence:
  - reference: PMID:30518548
    reference_title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development.
    explanation: Direct comparison of patient and mouse phenotypes.
  - reference: PMID:26616005
    reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease.
    explanation: Mouse extracardiac phenotype.
- discussion_id: cardiomyocyte_autonomy_of_dcm
  kind: CONTROVERSY
  status: OPEN
  prompt: Is dilated cardiomyopathy a cardiomyocyte-autonomous consequence of CAP2 loss, or does it require loss in other cell types?
  attaches_to:
  - animal_models#Cardiomyocyte-specific Cap2 knockout mouse
  - pathophysiology#Impaired Myocardial Contractility
  rationale: The 2015 study found that cardiomyocyte-specific knockout mice die of complete heart block before significant DCM, whereas the 2019 study from the same group reports robust DCM in the conditional line and used it for the SRF-inhibitor experiment. The difference may reflect timing, background or how DCM was assessed.
  evidence:
  - reference: PMID:26616005
    reference_title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.
    explanation: 2015 conditional-knockout result.
  - reference: PMID:30762586
    reference_title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: However, CAP2-CKO mice develop a robust DCM, so we used CAP2-CKO mice to test the functional importance of SRF in CAP2 DCM.
    explanation: 2019 conditional-knockout result.
- discussion_id: srf_direction_cell_type
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does CAP2 loss activate or suppress MRTF-SRF signaling in human cardiomyocytes?
  attaches_to:
  - pathophysiology#MRTF-SRF Pathway Activation
  rationale: Knockout mouse hearts show MRTFB nuclear accumulation and SRF target activation, whereas knockout mouse embryonic fibroblasts show reduced nuclear MRTF-A and SRF activity. No measurement exists in patient cardiomyocytes or iPSC-derived cardiomyocytes, although such cells have been generated from one patient.
  evidence:
  - reference: PMID:33637797
    reference_title: Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: In summary, our data revealed that in MEFs CAP2 controls basal MRTF-A localization and SRF activity, while it was dispensable for serum-induced nuclear MRTF-A translocation and SRF stimulation.
    explanation: Opposite direction of effect in fibroblasts.
- discussion_id: infection_second_hit
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: Do intercurrent infections precipitate decompensation in CMD2I, and should prevention be part of management?
  attaches_to:
  - pathophysiology#Intercurrent Viral Infection as Decompensation Trigger
  rationale: The proposal comes from one child presenting with heart failure during rhinovirus pneumonia, without myocardial viral testing. The authors note that fever, tachycardia and systemic inflammation could explain decompensation without direct myocardial injury.
  evidence:
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In addition, fever-induced tachycardia, increased myocardial oxygen demand, and systemic inflammatory responses related to infection may have independently or synergistically contributed to acute cardiac decompensation, beyond direct viral myocardial injury.
    explanation: The authors' own alternative explanation.
  - reference: PMID:42344352
    reference_title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: First, although rhinovirus infection was identified as the “second hit” in our double-hit model, we did not perform endomyocardial biopsy with viral PCR or serial serum viral load measurements to confirm direct myocardial invasion.
    explanation: The authors' own limitation on the proposed trigger.
notes: CMD2I (MONDO:0957545; OMIM 620462) is caused by biallelic CAP2 (hgnc:20039; gene MIM 618385) variants and is distinct from other recessive CMD2 subtypes. No ClinGen gene-disease validity record for CAP2 exists in the repository's cache, so gene_disease_validity is left empty. `just check-genereviews --online` returned NO_CHAPTER for both GeneReviews and StatPearls (Bookshelf index snapshot 2026-09-10 plus live PubMed search). The full texts of the founding Bedouin report and the neonatal nemaline-rod report were not retrievable, so the exact splice HGVS and the supraventricular tachycardia details are not quoted. Treatment entries other than heart transplantation and the inotropes used in one patient are general pediatric heart-failure guidance, not CAP2-specific evidence. A GenCC-derived record seen during deep research lists CAP2 with familial isolated dilated cardiomyopathy as autosomal dominant (Supportive); it is not cached here and conflicts with the recessive inheritance in every reported family, where heterozygous parents are unaffected. An implantable cardioverter-defibrillator is not listed, because no source evaluates it in CMD2I despite the sudden-death phenotype of conditional knockout mice.
references:
- reference: PMID:30518548
  title: CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.
- reference: PMID:33083013
  title: Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.
- reference: PMID:34862840
  title: A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.
- reference: PMID:42344352
  title: '"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.'
- reference: PMID:22945801
  title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
- reference: PMID:26616005
  title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
- reference: PMID:26925136
  title: Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.
- reference: PMID:30762586
  title: Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
- reference: PMID:33742108
  title: CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.
- reference: PMID:30962377
  title: CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function.
- reference: PMID:33637797
  title: Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts.
- reference: PMID:23022774
  title: Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression.
- reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
  title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf

📚

References & Deep Research

References

13

PMID:30518548

CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:33083013

Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.

No top-level findings curated for this source.

PMID:34862840

A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.

No top-level findings curated for this source.

PMID:42344352

"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report.

No top-level findings curated for this source.

PMID:22945801

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.

No top-level findings curated for this source.

PMID:26616005

CAP2 in cardiac conduction, sudden cardiac death and eye development.

No top-level findings curated for this source.

PMID:26925136

Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.

No top-level findings curated for this source.

PMID:30762586

Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.

No top-level findings curated for this source.

PMID:33742108

CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle.

No top-level findings curated for this source.

PMID:30962377

CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function.

No top-level findings curated for this source.

PMID:33637797

Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts.

No top-level findings curated for this source.

PMID:23022774

Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression.

No top-level findings curated for this source.

url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf

https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf

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 (2)

Record notes

CMD2I (MONDO:0957545; OMIM 620462) is caused by biallelic CAP2 (hgnc:20039; gene MIM 618385) variants and is distinct from other recessive CMD2 subtypes. No ClinGen gene-disease validity record for CAP2 exists in the repository's cache, so gene_disease_validity is left empty. `just check-genereviews --online` returned NO_CHAPTER for both GeneReviews and StatPearls (Bookshelf index snapshot 2026-09-10 plus live PubMed search). The full texts of the founding Bedouin report and the neonatal nemaline-rod report were not retrievable, so the exact splice HGVS and the supraventricular tachycardia details are not quoted. Treatment entries other than heart transplantation and the inotropes used in one patient are general pediatric heart-failure guidance, not CAP2-specific evidence. A GenCC-derived record seen during deep research lists CAP2 with familial isolated dilated cardiomyopathy as autosomal dominant (Supportive); it is not cached here and conflicts with the recessive inheritance in every reported family, where heterozygous parents are unaffected. An implantable cardioverter-defibrillator is not listed, because no source evaluates it in CMD2I despite the sudden-death phenotype of conditional knockout mice.

Create: Cardiomyopathy_Dilated_2I · 2026-10-08T19:04:08Z · View source

Created CMD2I (MONDO:0957545; CAP2, hgnc:20039; OMIM 620462) for claim issue #13720. Deep research: claude_code provider (falcon fallback), report research/Cardiomyopathy_Dilated_2I-deep-research-claude_code.md. Human evidence is five genotyped homozygous patients in four families: PMID:30518548 (Bedouin splice variant, two children), PMID:33083013 (Pakistani nonsense allele), PMID:34862840 (neonate, c.1288delT, nemaline rods, transplant at 1 year), PMID:42344352 (5-year-old, c.551G>A p.Trp184Ter, rhinovirus-associated decompensation). Mechanism chain: biallelic LoF -> CAP2 protein deficiency (patient fibroblasts/iPSC-CMs) -> disordered actin filament dynamics -> impaired alpha-actin isoform switch/myofibril maturation, MRTF-SRF activation and conduction-system dysfunction (mouse) -> sarcomere disarray/fibrosis -> impaired contractility -> DCM, reduced LVEF, heart failure. Model evidence from PMIDs 22945801, 26616005, 26925136, 30762586, 33742108, 30962377, 33637797, 23022774, all graded MODEL_ORGANISM or IN_VITRO. Discussions record the few-family evidence base, mouse extracardiac mismatch, the conflicting reports on DCM in cardiomyocyte-specific knockout mice, the cell-type-dependent SRF direction, and the single-case infection second-hit hypothesis. No ClinGen CGGV record for CAP2, so gene_disease_validity left empty. check-genereviews --online: NO_CHAPTER for GeneReviews and StatPearls. Full texts of PMIDs 30518548 and 34862840 were unavailable (no PMC copy), so SVT details and the splice HGVS are not quoted. Validation: just validate passed (101 snippets, 0 issues); count-verified-snippets 101/101; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-snippet-length, check-snippet-grading, check-title-snippets, check-coarse-phenotypes all OK; model-scale-audit 8/8 ALIGNED. Review fixes: added edges to Myocardial Fibrosis, increased BNP and Hepatomegaly (phenotype connectivity 10/16); replaced the over-claimed SVT phenotype with Cardiac conduction abnormality (HP:0031546), sourced from PMID:30518548; corrected the consanguinity count to two of four families; removed a REFUTE item on the MRTF-SRF node; replaced the actin->MRTF-SRF and isoform->disarray edge evidence with result sentences (PMID:30762586, PMID:33742108); moved the viral-trigger limitation to its discussion and added the patient's unvaccinated status; added fibrosis and EUCOMM-colony caveats, a GenCC AD/Supportive conflict note, and GO:0003785 actin monomer binding; removed relationship_type CAUSATIVE because CAP2 has no external tier. Re-validation: validate 106 snippets/0 issues; count-verified-snippets 106/106; entity-refs, causal-targets, duplicate-keys, snippet-length, snippet-grading, retired-support-prose and gene-activity grounding all OK; model-scale-audit 8/8 ALIGNED; validate-disorders passed.

Claude Code ▸

Cardiomyopathy, Dilated, 2I (CMD2I; CAP2-related dilated cardiomyopathy): research report

claude-haiku-5-5, claude-opus-5-5 7 citations 2026-10-08T14:33:09.606596

Gathering the CAP2 primary literature now; next I'll pull the exact abstract text so the report's quotes are verbatim.

Using the E-utilities endpoint instead, one paper at a time.

I've got the literature and verified the ontology terms against the local caches. Checking a few treatment terms, then I'll write the report.

Cardiomyopathy, Dilated, 2I (CMD2I; CAP2-related dilated cardiomyopathy): research report

MONDO: MONDO:0957545 · OMIM phenotype: 620462 · Gene: CAP2 (hgnc:20039; OMIM 618385; 6p22.3; NM_006366.3 / NP_006357.1; UniProt P40123) Prepared: 2026-10-08

How to read this report. Quoted text was checked in one of two ways: - Text quoted from PMID:30518548 was copied from the committed references_cache/PMID_30518548.md. - Text quoted from every other paper came from PubMed E-utilities abstracts, read through a summarizing fetch tool. Those quotes need confirming with just fetch-reference before they go into a YAML snippet.

Every ontology CURIE listed in Term suggestions was checked against this repository's cache/*/terms.csv. Terms marked (lead) were not checked.

Key caveats for curation

Evidence base. About five patients from four families have been described (three PanelApp-cited reports plus one 2026 case report), along with three independent mouse models. Most of the evidence about mechanism comes from mice.
Symbol collision. "CAP2" is also a previous symbol for SERPINB8 (hgnc:8952). This is a ready-made route to a Named Entity Confusion error, and there are three more in the literature:
PubMed searches return "CAP2" studies about the PROTECT‑AF/PREVAIL continued-access registries.
They also return a "C‑CAP" ablation questionnaire.
Some papers name the gene "adenylyl cyclase-associated protein 2". The correct binding is hgnc:20039.
Inheritance conflict. PanelApp and OMIM give biallelic inheritance. A GenCC-derived record (seen on GeneBe) lists CAP2–"familial isolated DCM" as AD, Supportive. Every human case to date is homozygous, and every heterozygous parent reported so far is unaffected.
No ClinGen classification. The repository's pinned ClinGen gene-validity snapshot (kb/genes/ingest/clingen_gene_validity.tsv) has no CAP2 row. Leave gene_disease_validity absent unless a GenCC source is cited.

1. Disease information

Overview. CMD2I is a severe, autosomal recessive dilated cardiomyopathy that begins in infancy or childhood. It is caused by biallelic loss-of-function variants in CAP2, which encodes a regulator of actin filament dynamics. Features: - ventricular dilation and impaired systolic function, with early congestive heart failure; - in some patients, supraventricular tachycardia or conduction disease; - in one patient, nemaline rods in skeletal and cardiac muscle.

MalaCards and OMIM summarize it this way: "a severe, autosomal recessive form of dilated cardiomyopathy with onset in infancy or childhood… early, severe congestive heart failure and increased risk of premature death" (MalaCards).

Identifiers

System	ID
MONDO	MONDO:0957545 "cardiomyopathy, dilated, 2I" (verified in `cache/mondo/terms.csv`)
OMIM	620462 (phenotype); 618385 (gene)
Orphanet	No CMD2I-specific code found. Orphanet's parent concept is "familial isolated dilated cardiomyopathy" (ORPHA:154; (lead) — confirm in the ORPHA cache)
ICD-10	I42.0 (dilated cardiomyopathy)
MeSH	D002311 Cardiomyopathy, Dilated (lead)

Synonyms: CMD2I; CAP2-related dilated cardiomyopathy; dilated cardiomyopathy 2I; autosomal recessive DCM due to CAP2 deficiency.

Source type: case reports and family studies (individual patients), plus panel curation (PanelApp, GenCC). There is no registry or EHR data.

2. Etiology

Cause: biallelic loss-of-function variants in CAP2 (splice, nonsense, frameshift).
Genetic risk: consanguinity. Families reported so far are Bedouin (Israel), Pakistani, North American, and Chinese.
Protective factors: none known.
Modifier or second-hit trigger: in Pan et al. 2026 (PMID:42344352), a homozygous child developed fulminant cardiac dysfunction during a rhinovirus infection ("Respiratory pathogen panel was positive for rhinovirus"). The authors frame this as a "double-hit". This is a single case, so treat it as a hypothesis.
Sex as a modifier (mouse only): in Field 2015 (PMID:26616005), "~70% died by 12 weeks of age" in male knockouts, while "females survived at close to the expected levels and lived normal life spans". DCM was "most noticeably in the males". No sex bias has been shown in humans, because there are too few cases.

3. Phenotypes

Phenotype	HPO (verified)	Onset / frequency	Source
Dilated cardiomyopathy	HP:0001644	Neonatal–childhood; all reported cases	PMID:30518548, 34862840, 33083013, 42344352
Congestive heart failure	HP:0001635	Early, severe	PMID:42344352 (fulminant at age 5); OMIM
Reduced LV ejection fraction	HP:0012664	Common	inferred from DCM description
Supraventricular tachycardia	HP:0004755	Bedouin family	PMID:30518548 (title)
Left ventricular noncompaction	HP:0011664	1 neonate	PMID:34862840: "severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction"
Nemaline bodies (skeletal and cardiac)	HP:0003798	1 patient	PMID:34862840: "muscle biopsy on the 8th day of life… identified nemaline rods"
Hypotonia (mild)	HP:0001252	1 patient	PMID:34862840: "mild hypotonia"
Conduction disease / heart block	HP:0012722, HP:0001678	Shown in mice; in humans only by implication	PMID:26616005, 26925136
Sudden cardiac death	HP:0001645	Risk (mouse: complete heart block)	PMID:26616005
Congenital onset	HP:0003577	Neonatal case	PMID:34862840: "within the first few hours of life"

Other notes: - PMID:34862840 also reports "atrophic and widened scarring" of the skin. There is no clear HPO match; it needs a lookup. - Quality of life: no PROs or QoL data. The burden follows from paediatric heart failure, transplantation in infancy (1 of 5 patients), and arrhythmia.

4. Genetic and molecular information

Reported variants (all homozygous; all parents tested are heterozygous and unaffected):

Variant	Type	Consequence	Family	PMID
Exon 7 donor splice-site change (exact HGVS not in abstract; get it from the full text or ClinVar)	canonical splice	"causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain"; "CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1"	2 Bedouin cousins (consanguineous)	30518548
p.(Tyr316*)	nonsense	not characterized	Pakistani DCM/heart-failure patient	33083013 (variant per PanelApp summary; the abstract only names "CAP2-dilated cardiomyopathy" as a validated diagnostic gene)
c.1288delT, p.C430fs (NM_006366)	frameshift	"appears to cause loss of both CAP2 protein and mRNA" (patient fibroblasts and iPSC-cardiomyocytes)	US neonate, non-consanguinity not stated	34862840
c.551G>A, p.W184* (NM_006366.3)	nonsense	"resides within the N-terminal helical folded domain"; "Abrogation of WH2 domain is predicted to completely abolish CAP2 function"	Chinese 5-year-old	42344352

Functional class: loss of function (amorphic or null). The variant origin is germline.
Classification: ClinVar CAP2 entries are mostly VUS. PanelApp rates the gene Green for both GEL "Paediatric or syndromic cardiomyopathy" (panel 749; biallelic; PMIDs 30518548, 33083013, 34862840) and PanelApp Australia DCM (panel 95).
Population frequency: not reported in these sources. Query gnomAD for LoF observed/expected.
Chromosomal context: CAP2 lies at 6p22. Field 2015 notes that the knockout mice "resembled patients with 6p22 syndrome" (6p22 deletion). This is a possible contiguous-gene contribution, not CMD2I itself.
Epigenetics: no data.

5. Environmental information

There is no established environmental cause. Pan 2026 reports viral infection (rhinovirus) as a possible precipitant of decompensation; NCBITaxon binding is a lead only. There is no lifestyle or toxin data.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic CAP2 LoF variant → loss of CAP2 protein in cardiomyocytes. Shown in human cells: the splice variant reduces CAP2 protein, and c.1288delT causes "loss of both CAP2 protein and mRNA". CAP1 does not compensate (PMID:30518548).
Loss of CAP2 → disordered actin turnover. CAP2 normally "sequesters G-actin and efficiently fragments filaments" (PMID:22945801, Peche 2013). In cardiomyocytes it sits at thin-filament pointed ends and "depolymerizes and inhibits actin incorporation" (PMID:33742108, Colpan 2021). Patient fibroblasts show altered "kinetics of repolymerization of actin", with elevated β-actin mRNA (PMID:30518548).
Disordered actin dynamics → impaired myofibrillogenesis and sarcomere maturation. "CAP2 plays an essential role in cardiomyocyte maturation by modulating pre-sarcomeric actin assembly" (PMID:33742108). In skeletal muscle, the switch between α-actin isoforms is delayed (PMID:30962377). This step is shown in vitro and in mice.
Branch A (structural): sarcomere disarray, fibrosis, nemaline rods → contractile failure.
Mouse: "disarrayed sarcomeres with development of fibrosis" and reduced "cooperativity of calcium-regulated force development" (PMID:22945801).
Human explant: "nemaline rods and additionally disintegration of the myofibrillar structure" (PMID:34862840).
These lead to ventricular dilation and systolic dysfunction (DCM), then heart failure.
Branch B (signalling): altered G/F-actin balance → MRTF/SRF dysregulation → fetal gene program.
CAP2-KO hearts show "overactivation of fetal genes".
The SRF inhibitor CCG‑1423‑8u "reduced expression of the SRF targets Myl9 and Acta2, as well as… Nppa". Median survival of CKO mice rose from 98 to 116 days (PMID:30762586).
Direction caveat: in fibroblasts, CAP2 loss reduced basal nuclear MRTF‑A and SRF activity (PMID:33637797). Whether SRF moves up or down depends on cell type, so in cardiomyocytes it is inferred from the inhibitor rescue.
Branch C (electrical): cardiomyocyte-autonomous conduction disease.
In the gene-trap model, connexin43 is maldistributed and fibrosis increases, with "marked conduction delays at atrial and ventricular levels" and "spontaneous ventricular arrhythmias" (PMID:26925136).
Cardiomyocyte-specific KO mice show conduction disease leading to "sudden cardiac death from complete heart block", without DCM (PMID:26616005).
Human counterparts are SVT and the risk of sudden death.

Upstream/downstream: steps 1–3 are upstream. Branch A produces DCM and heart failure; branch C produces arrhythmia and SCD; branch B modifies progression and is a candidate drug target.

Term suggestions (all verified in the caches): - Biological processes (GO): actin filament depolymerization GO:0030042 (DECREASED); actin cytoskeleton organization GO:0030036; actin filament organization GO:0007015; cardiac myofibril assembly GO:0055003; sarcomere organization GO:0045214; cardiac muscle contraction GO:0060048; positive regulation of transcription by RNA polymerase II GO:0045944 (for the SRF program; consider a more specific SRF term (lead)). - Cellular components (GO): sarcomere GO:0030017; actin filament GO:0005884. - Molecular function (GO): actin binding GO:0003779. - Cell types (CL): cardiac muscle cell CL:0000746; fibroblast CL:0000057 (patient cells); cell of skeletal muscle CL:0000188. - Anatomy (UBERON): heart UBERON:0000948; heart left ventricle UBERON:0002084; cardiac ventricle UBERON:0002082; His-Purkinje system UBERON:0004146; skeletal muscle tissue UBERON:0001134. - Omics: RNA-seq of CAP2-KO mouse heart and cardiomyocytes (PMID:30762586); the GEO accession is not given in the abstract and needs just discover-datasets. There are no human single-cell or proteomic data.

7. Anatomical structures

Primary: the myocardium, both ventricles (biventricular dysfunction in PMID:34862840).
Conduction system: atrial, AV and ventricular conduction (mouse).
Secondary: skeletal muscle (nemaline rods, hypotonia).
Mouse-only: eye (microphthalmia) and body size. Aspit et al. state these are not recapitulated in humans: "but not the other effects on growth, viability, wound healing and eye development".
Subcellular: thin-filament pointed ends and sarcomere; actin cytoskeleton.
Laterality: bilateral or biventricular.

8. Temporal development

Onset: neonatal (first hours of life) to childhood (age 5).
Course: rapidly progressive in the neonate, who was transplanted at age 1. The 5-year-old presented with fulminant decompensation during an infection.
Natural history: no studies exist.
Window for intervention (mouse): SRF inhibition delayed onset in mice (PMID:30762586).

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007). This is supported by homozygosity in all probands and unaffected heterozygous parents: "Both parents were heterozygous for the same variant but have no history of heart or muscle disease" (PMID:34862840); "This is the first report of a recessive deleterious mutation in CAP2" (PMID:30518548).
Penetrance: apparently complete in homozygotes, but n≈5.
Founder effect / consanguinity: consanguineous Bedouin and Pakistani families. Cheema 2020 found a higher diagnostic yield in consanguineous families (60.1% vs 39.5%).
Prevalence: unknown. Use measure_type CASES_IN_LITERATURE and prevalence_class ULTRA_RARE (roughly 5 published cases).
Sex ratio: no human data. In mice, males are more severely affected.

10. Diagnostics

Imaging and functional tests: echocardiography (LV dilation, reduced EF, noncompaction); cardiac MRI.
Electrophysiology: ECG and Holter monitoring for SVT and conduction block.
Biomarker: NT-proBNP/BNP (heart failure). Note that Nppa was reduced by SRF inhibition in mice.
Biopsy: skeletal muscle and myocardium can show nemaline rods and myofibrillar disintegration.
Genetic testing: exome sequencing found every reported case. CAP2 is on the GEL paediatric cardiomyopathy panel and the PanelApp Australia DCM panel. Splice variants can be confirmed with RNA studies from fibroblasts (PMID:30518548). Cheema 2020 reports that "the genetic diagnosis had a direct impact on clinical management".
Differential diagnosis:
other recessive paediatric DCM (CMD2A TNNI3, CMD2B GATAD1, CMD2C PPCS, and others);
Barth syndrome (TAZ);
nemaline myopathy with cardiomyopathy (ACTA1, NEB, KLHL40);
LVNC genes (MYH7, TAZ);
myocarditis, which matters because CMD2I can present during a viral infection.
Screening: cascade testing of siblings, and carrier testing in consanguineous families.

11. Outcome and prognosis

The disease is severe:
one neonate needed a heart transplant at age 1;
one child had fulminant heart failure at age 5;
OMIM describes an "increased risk of premature death".
No survival statistics exist.
Likely prognostic factors are neonatal onset, noncompaction, and conduction disease (mouse evidence for SCD).

12. Treatment

There is no disease-specific therapy. Standard paediatric heart-failure and DCM management applies:

Intervention	NCIT (verified)	Agent / notes
Heart-failure pharmacotherapy	NCIT:C15986 Pharmacotherapy	ACE inhibitor NCIT:C247 (enalapril CHEBI:4784); beta-blocker NCIT:C29576 (carvedilol CHEBI:3441, metoprolol CHEBI:6904); spironolactone CHEBI:9241; furosemide CHEBI:47426; milrinone CHEBI:50693 (acute decompensation); sacubitril/valsartan NCIT:C222078
Heart transplantation	NCIT:C15246	Performed at age 1 (PMID:34862840)
Mechanical support	NCIT:C80452 Ventricular Assist Device Placement / NCIT:C172327 LVAD insertion	bridge to transplant (general practice; not reported in CMD2I)
ICD	NCIT:C80435	given conduction disease and SCD risk (inferred from mouse)
Genetic counseling	NCIT:C15240	AR recurrence risk of 25%

Experimental: MRTF/SRF inhibition (CCG‑1423‑8u), mouse only (PMID:30762586): "inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress".
Gene therapy: none.
Clinical trials: no CAP2-specific trials were found.

13. Prevention

Primary: genetic counseling, carrier testing, and PGD or prenatal diagnosis in families with a known variant.
Secondary: cascade echocardiography and ECG in siblings.
Tertiary: arrhythmia surveillance, and early treatment of intercurrent infections (suggested by Pan 2026).

14. Other species

There are no naturally occurring cases in OMIA.
In Hu sheep, CAP2 polymorphisms are associated with body height, and the gene is expressed strongly in heart (PMID:34481004). This is not a disease.
Orthologs: mouse Cap2; zebrafish cap2. Zebrafish knockdown causes "short bodies and pericardial edema" (PMID:23022774, paraphrased).

15. Model organisms

Model	Phenotype	Fidelity	PMID
Cap2 gene-trap (gt/gt) mouse, Noegel lab	DCM, sarcomere disarray, fibrosis, reduced Ca²⁺-force cooperativity, reduced survival; conduction delay, ventricular arrhythmia, Cx43 maldistribution	Recapitulates DCM and conduction disease	22945801 (erratum 28852764); 26925136
Cap2 whole-body KO, Field lab	Male-biased lethality, small size, microphthalmia, CCD, DCM after 6 months	Partial: extracardiac features absent in humans	26616005
Cardiomyocyte-specific Cap2 CKO (Cre)	CCD leading to SCD from complete heart block; no DCM	Isolates the electrical branch	26616005, 30762586
Cap2 mutant mouse, skeletal muscle (Rust lab)	delayed α-actin isoform switch, ring fibers, motor deficits	Models skeletal muscle involvement	30962377
Patient fibroblasts and iPSC-cardiomyocytes	loss of protein/mRNA; altered actin repolymerization	Human in vitro	30518548, 34862840
Neonatal rat and mouse cardiomyocytes (CAP2 knockdown/KO)	impaired pre-sarcomeric actin assembly and maturation	In vitro	33742108
Zebrafish morphants	pericardial edema	Low	23022774

Main gaps between the models and human disease: sex bias, microphthalmia and growth failure occur in mice but not in humans. The relative contributions of systemic versus cardiomyocyte-autonomous mechanisms to DCM are unresolved: the CKO mouse has no DCM, but the CKO used in PMID:30762586 had shortened survival. This is a candidate HUMAN_MODEL_MISMATCH discussion.

Key references

PMID	Citation
30518548	Aspit L et al. J Med Genet 2019. CAP2 mutation leads to impaired actin dynamics and associates with SVT and DCM. Cached
34862840	Gurunathan S et al. Am J Med Genet A 2022. Homozygous CAP2 variant in a neonate with rapidly progressive cardiomyopathy and nemaline rods
33083013	Cheema H et al. NPJ Genom Med 2020. Genomic testing in 1019 individuals from 349 Pakistani families
42344352	Pan Z et al. Front Cardiovasc Med 2026. "Double-hit" fulminant cardiac dysfunction with a homozygous CAP2 variant
26616005	Field J et al. Sci Rep 2015. CAP2 in cardiac conduction, sudden cardiac death and eye development
22945801	Peche VS et al. Cell Mol Life Sci 2013. Ablation of CAP2 leads to cardiomyopathy (erratum PMID:28852764)
26925136	Stöckigt F et al. Arch Med Sci 2016. CAP2 deficiency promotes arrhythmias with Cx43 maldistribution and fibrosis
30762586	Xiong Y et al. JCI Insight 2019. Targeting MRTF/SRF in CAP2-dependent DCM delays disease onset
33742108	Colpan M et al. Commun Biol 2021. CAP2 regulates actin pointed-end dynamics and myofibrillogenesis
30962377	Kepser LJ et al. PNAS 2019. CAP2 deficiency delays myofibril actin differentiation in skeletal muscle
33637797	Kepser LJ et al. Sci Rep 2021. CAP2 controls MRTF-A localization and SRF activity in MEFs
35150966	Rust MB, Marcello E. Eur J Cell Biol 2022. Review of CAP disease associations

Next steps before writing YAML: 1. Run just fetch-reference PMID:<id> for each paper above except 30518548, then run just count-verified-snippets. 2. Get the HGVS notation for the Aspit splice variant from the full text or ClinVar. 3. Run just check-genereviews to confirm that no GeneReviews chapter exists.

Sources: - MalaCards: CMD2I - Genomics England PanelApp: CAP2 - PanelApp Australia DCM: CAP2 - GeneBe: CAP2 - PomBase: MONDO:0957545 - Field et al. 2015 (PMC4663486) - PubMed E-utilities

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	9
Quoted claims found in source	8
Quoted claims not found in source	1
References weighed for topical relevance	14
On topic	10
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:23022774 (abstract only): "short bodies and pericardial edema"
closest text in source: "Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema"

Term Validation

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

Outcome	Count
Terms checked	47
Resolved	46
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	15
Terms named correctly	9
Terms named as a different term	2
Terms whose name is worth a second look	4

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:

GO:0030042 (1 mention) - the report calls it "DECREASED"; GO calls it actin filament depolymerization
CL:0000057 (1 mention) - the report calls it "patient cells"; CL calls it fibroblast

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:0012664 (1 mention) - the report calls it "Reduced LV ejection fraction"; HP calls it Reduced left ventricular ejection fraction, and lists "Reduced ejection fraction" among its other names
HP:0011664 (1 mention) - the report calls it "Left ventricular noncompaction"; HP calls it Left ventricular noncompaction cardiomyopathy
HP:0003798 (1 mention) - the report calls it "Nemaline bodies (skeletal and cardiac)"; HP calls it Nemaline bodies
HP:0001252 (1 mention) - the report calls it "Hypotonia (mild)"; HP calls it Hypotonia

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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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Cardiomyopathy, Dilated, 2I (CMD2I; CAP2-related dilated cardiomyopathy): research report

Key caveats for curation

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Key references

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver