| Knowledge-base field | Curated summary | Ontology suggestions | Evidence type |
|---|---|---|---|
| Identity / identifiers | **Dilated cardiomyopathy 1CC (DCM1CC)**, a rare NEXN-associated genetic cardiomyopathy. **MONDO:** MONDO:0013147. Subtype-specific OMIM, Orphanet, ICD-10/11, and MeSH identifiers were not verified in the available evidence; general DCM codes should not be treated as subtype-specific. (pqac-00000000) | MONDO:0013147; HP:0001644 Dilated cardiomyopathy | Aggregated disease-resource evidence |
| Causal gene / inheritance | **NEXN** (nexilin F-actin binding protein; ENSG00000162614). Heterozygous variants can cause autosomal-dominant, incompletely penetrant DCM; biallelic loss-of-function variants cause autosomal-recessive fetal, neonatal, or childhood cardiomyopathy that is often more severe. Seven heterozygotes in one family included 2 with DCM, 3 with other cardiac findings, and 2 without abnormalities. (pqac-00000000, pqac-00000046) | NEXN; HP:0000006 Autosomal dominant inheritance; HP:0000007 Autosomal recessive inheritance; HP:0003829 Incomplete penetrance | Human families and disease-target resource |
| Hallmark phenotype | Left-ventricular or biventricular dilation with systolic dysfunction; clinical manifestations may include heart failure, fetal hydrops, cardiomegaly, arrhythmia, mitral/atrioventricular-valve regurgitation, and endomyocardial fibroelastosis. Severity ranges from subclinical or transient DCM to fatal neonatal failure. (pqac-00000013, pqac-00000043, pqac-00000056) | HP:0001644 Dilated cardiomyopathy; HP:0004308 Ventricular dilatation; HP:0001677 Abnormality of cardiac contraction; HP:0001635 Congestive heart failure; HP:0001789 Hydrops fetalis; HP:0001622 Premature death | Human cases; animal models |
| Onset / course | Biallelic disease may begin prenatally in the second or third trimester and progress to neonatal failure, although survival with persistent dysfunction into childhood is documented. Heterozygous disease may present in infancy, adulthood, or remain clinically silent; published adult heterozygous cases had mean presentation near 50 years. Course may be progressive, stable, or partly reversible. (pqac-00000013, pqac-00000029, pqac-00000056) | HP:0011461 Fetal onset; HP:0003623 Neonatal onset; HP:0011463 Childhood onset; HP:0003581 Adult onset; HP:0003674 Onset in infancy | Human cases and literature synthesis |
| Key reported variants | Examples include **c.1302del, p.(Ile435Serfs*3)**, associated with nonsense-mediated decay and lethal fetal cardiomyopathy; **c.1174C>T, p.(Arg392\*)**, class 4/likely pathogenic; **c.1156dup, p.(Met386fs)**, class 4/likely pathogenic and absent from gnomAD in the report; **c.1579_1584del, p.(Glu527_Glu528del)**, class 3/VUS; and heterozygous **p.(Gly650del)**. Classification is variant-specific and should be re-evaluated using current ACMG/AMP and ClinVar evidence. (pqac-00000013, pqac-00000020, pqac-00000046) | SO:0001589 Frameshift variant; SO:0001587 Stop-gained variant; SO:0001822 In-frame deletion; HP:0034345 Abnormal cardiovascular-system electrophysiology where applicable | Human segregation, clinical sequencing, RNA analysis |
| Mechanism | NEXN stabilizes actin-associated cardiac structures and functions in cardiomyocyte junctional membrane complexes. Loss disrupts JPH2/RyR2-associated T-tubule–sarcoplasmic-reticulum organization, reduces or prolongs Ca²⁺ transients, impairs excitation–contraction coupling, and causes contractile failure, chamber dilation, remodeling, and sometimes fibroelastosis. Z-disc destabilization is supported by human and zebrafish evidence; the relative importance of Z-discs versus junctional membrane complexes remains an evolving model. (pqac-00000007, pqac-00000041, pqac-00000048) | GO:0051015 Actin filament binding; GO:0030018 Z disc; GO:0030315 T-tubule; GO:0006941 Striated muscle contraction; GO:0006874 Intracellular calcium-ion homeostasis; CL:0000746 Cardiac muscle cell | Human functional, mouse, and zebrafish evidence |
| Diagnostics | Establish the DCM phenotype using history and three-generation pedigree, examination, ECG, echocardiography, and cardiac MRI; BNP/troponin and ambulatory rhythm monitoring support severity and arrhythmic assessment. Exclude coronary, loading-condition, valvular, congenital, infectious, metabolic, toxic, and inflammatory causes. Use a curated cardiomyopathy gene panel including **NEXN**, with deletion/duplication analysis; WES/WGS is appropriate for negative, atypical, or suspected recessive cases. Confirm segregation and offer cascade testing with genetic counseling. (pqac-00000022, pqac-00000023, pqac-00000024) | NCIT:C16502 Echocardiography; NCIT:C16809 Electrocardiography; NCIT:C16810 Magnetic Resonance Imaging; NCIT:C15709 Genetic Testing | Guidelines/reviews; real-world case sequencing |
| Treatment | No approved NEXN-specific therapy. Treat the expressed phenotype using guideline-directed heart-failure therapy—typically renin–angiotensin-system inhibition/ARNI, evidence-based β-blocker, mineralocorticoid-receptor antagonist, and SGLT2 inhibitor as age and clinical status permit—plus diuretics for congestion. Consider ivabradine, ICD/CRT, ventricular-assist support, or transplantation according to standard indications. Reported NEXN cases improved with conventional therapy, but responses are not genotype-specific efficacy estimates. (pqac-00000013, pqac-00000021, pqac-00000059) | NCIT:C15313 Pharmacologic Substance; NCIT:C66889 Implantable Cardioverter-Defibrillator; NCIT:C804 Heart Transplantation; NCIT:C99547 Ventricular Assist Device | Guideline-based general DCM care; human case reports |
| Epidemiology | Subtype-specific incidence and prevalence are **unavailable**. NEXN disease is rare. In one Han Chinese idiopathic-DCM cohort, 41/118 patients had a pathogenic/likely pathogenic variant in any tested gene and NEXN represented 4.8% of identified variants; these figures do not establish population prevalence. (pqac-00000031, pqac-00000032) | MONDO:0013147; ORDO term unavailable in reviewed evidence | Single clinical cohort; no population-based NEXN estimate |
| Prognosis | Prognosis is highly variable and appears related to zygosity and variant effect. A heterozygous infant recovered systolic function and remained asymptomatic at age 11 despite mild MRI dilation; a homozygous p.Arg392\* infant died after approximately two weeks. Two 2024 biallelic fetal-onset cases survived to ages 2 and 15 years with persistent but partly improved dysfunction, showing that biallelic disease is not uniformly lethal. Robust NEXN-specific survival rates are unavailable. (pqac-00000013, pqac-00000056) | HP:0003680 Variable expressivity; HP:0003829 Incomplete penetrance; HP:0001622 Premature death | Human longitudinal cases and families |
| Models / experimental therapy | Constitutive or cardiomyocyte-specific **Nexn** knockout mice develop rapidly progressive DCM, T-tubule defects, fibroelastosis, and early death. CRISPR **nexn−/−** zebrafish have reduced fractional shortening and compensatory induction of sarcomeric transcripts. In 2024, one neonatal systemic AAV9-Nexn dose restored approximately 30% of protein, normalized cardiac measures, and extended knockout-mouse survival beyond 1.5 years; durability declined later. This is **preclinical**, and no relevant human NEXN interventional trial was identified. (pqac-00000010, pqac-00000011, pqac-00000036, pqac-00000063) | NCBITaxon:10090 Mus musculus; NCBITaxon:7955 Danio rerio; NCIT:C162641 Adeno-Associated Virus Vector; GO:0006351 DNA-templated transcription | Mouse, zebrafish, transcriptomics, preclinical gene replacement |


*Table: Compact curation of the identity, genetics, phenotype, mechanism, clinical management, prognosis, and experimental models of NEXN-associated dilated cardiomyopathy. Unsupported subtype-specific identifiers and epidemiologic estimates are explicitly marked unavailable.*