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

1. 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.
2. 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:
3. PubMed searches return "CAP2" studies about the PROTECT‑AF/PREVAIL continued-access registries.
4. They also return a "C‑CAP" ablation questionnaire.
5. Some papers name the gene "adenylyl cyclase-associated protein 2". The correct binding is hgnc:20039.
6. 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.
7. 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

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

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):

• 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

1. 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).
2. 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).
3. 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.
4. Branch A (structural): sarcomere disarray, fibrosis, nemaline rods → contractile failure.
5. Mouse: "disarrayed sarcomeres with development of fibrosis" and reduced "cooperativity of calcium-regulated force development" (PMID:22945801).
6. Human explant: "nemaline rods and additionally disintegration of the myofibrillar structure" (PMID:34862840).
7. These lead to ventricular dilation and systolic dysfunction (DCM), then heart failure.
8. Branch B (signalling): altered G/F-actin balance → MRTF/SRF dysregulation → fetal gene program.
9. CAP2-KO hearts show "overactivation of fetal genes".
10. 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).
11. 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.
12. Branch C (electrical): cardiomyocyte-autonomous conduction disease.
13. 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).
14. Cardiomyocyte-specific KO mice show conduction disease leading to "sudden cardiac death from complete heart block", without DCM (PMID:26616005).
15. 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:

• 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

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

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.

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.

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.