| Field | Curated value | Evidence scope/caveat |
|---|---|---|
| Disease entity | **Dilated cardiomyopathy 1II**; **MONDO:0014073** | Rare molecular subtype of dilated cardiomyopathy (DCM); Open Targets maps the entity specifically to **CRYAB**. (pqac-00000000) |
| Synonyms | **Cardiomyopathy, dilated, 1II**; **DCM1II**; **CRYAB-related dilated cardiomyopathy**; **αB-crystallin-related DCM** | “αB-crystallinopathy” is broader and also includes myofibrillar myopathy, cataract, restrictive cardiomyopathy, and hypertrophic cardiomyopathy; it is not synonymous with isolated DCM1II. (pqac-00000002, pqac-00000006) |
| Causal gene/protein | **CRYAB** (alias **HSPB5**), encoding αB-crystallin, a small heat-shock protein and molecular chaperone | CRYAB is highly expressed in cardiac and skeletal muscle and supports proteostasis, desmin/intermediate-filament organization, titin stability, stress responses, and cell survival. (pqac-00000006, pqac-00000008) |
| Genomic location | **Chromosome 11**; CRYAB locus reported as approximately 3.2 kb | Precise cytoband, transcript, genome build, and HGNC identifier should be normalized from HGNC/Ensembl before database loading. (pqac-00000003) |
| Inheritance/origin | Usually modeled as **autosomal dominant, germline** inheritance for isolated CRYAB-associated DCM | Evidence is based on very few families; a more recent patient had an apparently de novo heterozygous variant. CRYAB alleles can also cause recessive or dominant non-DCM phenotypes. (pqac-00000002, pqac-00000003, pqac-00000006) |
| Key DCM-associated variant | **CRYAB p.Arg157His (R157H)**, heterozygous missense | Reported in a 71-year-old patient with DCM and a family history of DCM/sudden cardiac death; exact penetrance and population frequency are not established here. (pqac-00000002, pqac-00000017) |
| Key DCM-associated variant | **CRYAB p.Gly154Ser (G154S)**, heterozygous missense | Reported in a 48-year-old woman with DCM and an affected father; the same allele has also been associated with late-onset distal myopathy and respiratory involvement, indicating variable expressivity. (pqac-00000002, pqac-00000018, pqac-00000025) |
| Principal cardiac phenotype | Left-ventricular dilation, reduced systolic function/ejection fraction, progressive heart failure; arrhythmia or sudden cardiac death may occur in affected families | Subtype-specific frequencies cannot be calculated from the sparse cases. A newer CRYAB case showed biventricular/biatrial dilation, fibrosis, severe atrioventricular-valve regurgitation, and restrictive physiology, expanding but not defining DCM1II. (pqac-00000001, pqac-00000002, pqac-00000003) |
| R157H mechanism | Impaired binding of αB-crystallin to the cardiac **N2B domain of titin/connectin** and impaired localization to titin’s I-band, leading plausibly to deficient sarcomeric stress protection | This is variant-specific biochemical evidence. R157H reportedly retains chaperone activity and does not characteristically form cytoplasmic aggregates, so an aggregate-first model should not be assumed. (pqac-00000017) |
| G154S mechanism | Human cardiac mechanism remains incompletely defined; desmin/CRYAB-positive aggregates have been observed in G154S-associated myopathy | Transient human-G154S overexpression in zebrafish caused myofiber loss, sarcomere disorganization, protein aggregates, motor impairment, altered BMP activity, and increased mortality. Wild-type overexpression also caused abnormalities, and the residue is not conserved in zebrafish, limiting causal extrapolation to human DCM. (pqac-00000025, pqac-00000027) |
| R120G model evidence | **CRYAB p.Arg120Gly (R120G)** models demonstrate dominant-negative chaperone dysfunction, CRYAB/desmin aggregation, proteasome and autophagy stress, mitochondrial abnormalities, apoptosis, fibrosis, ventricular dysfunction, dilation, and heart-failure death | R120G primarily causes desmin-related myofibrillar disease and is **not the same allele as R157H or G154S**. Its proteotoxic pathway is valuable supporting biology but must not be asserted as the demonstrated mechanism of every DCM1II allele. (pqac-00000017, pqac-00000023, pqac-00000024) |
| Onset/course | Documented isolated-DCM cases were adult or late onset (approximately ages 48 and 71 in key reports); progression ranges from mild dysfunction to advanced heart failure | No adequately powered natural-history cohort exists. Childhood and multisystem CRYAB disease occurs with other alleles, but should not be used to assign a typical DCM1II onset. (pqac-00000002, pqac-00000006) |
| Penetrance/expressivity | **Unknown; likely age-dependent and variable** | Too few segregating families are available for a reliable penetrance estimate. Cardiac-only, skeletal-muscle, respiratory, ocular, and combined phenotypes demonstrate marked allelic and intrafamilial heterogeneity. (pqac-00000002, pqac-00000006) |
| Diagnostic approach | Establish DCM by history/examination, ECG, echocardiography, CMR tissue characterization, BNP/NT-proBNP and troponin; exclude coronary disease, hypertension/loading abnormalities, valvular/congenital disease, toxins, infection, and inflammatory/metabolic causes; then perform cardiomyopathy-panel testing including **CRYAB**, with ACMG/AMP interpretation and familial segregation/cascade testing | This is primarily guideline-level **general DCM** practice. CRYAB variants require careful phenotype matching because the gene has broad allelic heterogeneity and limited isolated-DCM case evidence. (pqac-00000003, pqac-00000013, pqac-00000016) |
| Standard treatment | Guideline-directed DCM/HFrEF therapy: ARNI or ACE inhibitor/ARB, evidence-based β-blocker, mineralocorticoid-receptor antagonist, SGLT2 inhibitor, and diuretics for congestion; consider ICD/CRT, ventricular-assist device, transplantation, rehabilitation, and treatment of triggers according to standard indications | These interventions are supported for **general DCM/HFrEF**, not specifically validated for CRYAB-related DCM. (pqac-00000003, pqac-00000010) |
| Genotype-directed therapy | **No approved CRYAB-specific drug, RNA therapy, gene therapy, or gene-editing treatment** | Autophagy/TFEB enhancement, proteasome modulation, anti-aggregation compounds, and redox-pathway interventions are preclinical—predominantly R120G-model findings—and are not established clinical treatments for DCM1II. (pqac-00000018, pqac-00000023, pqac-00000024) |
| Suggested HPO terms | **Dilated cardiomyopathy (HP:0001644)**; left-ventricular dilatation; decreased left-ventricular ejection fraction; congestive heart failure; cardiac fibrosis; arrhythmia; sudden cardiac death; elevated creatine kinase; possible distal muscle weakness/cataract for syndromic alleles | Exact HPO identifiers other than HP:0001644 should be validated against the current HPO release; extracardiac terms are allele-dependent and not universal DCM1II features. (pqac-00000001, pqac-00000002) |
| Suggested GO terms | Protein folding/chaperone-mediated protein folding; response to heat/oxidative stress; intermediate-filament organization; sarcomere organization; regulation of apoptosis; autophagy; ubiquitin-dependent protein catabolism; mitochondrial organization; **Z disc**, **I band**, cytosol, protein-containing complex | These annotations combine normal CRYAB biology and broader CRYAB-mutant models; variant-specific support differs substantially. (pqac-00000006, pqac-00000008, pqac-00000023) |
| Suggested CL terms | **Cardiac muscle cell/cardiomyocyte (CL:0000746)**; ventricular cardiac muscle cell; cardiac fibroblast | Cardiomyocytes are the directly supported primary cell type; fibroblast involvement is downstream/inferred from fibrosis rather than demonstrated as the initiating lesion. (pqac-00000017, pqac-00000024) |
| Suggested UBERON terms | **Heart (UBERON:0000948)**; myocardium; left ventricle; ventricular myocardium; interventricular septum; cardiac conduction system; skeletal muscle and lens for syndromic alleles | The left ventricle/myocardium is primary in DCM; biventricular and biatrial disease can develop secondarily. Exact substructure identifiers should be release-validated. (pqac-00000001, pqac-00000003) |
| Evidence limitations | Disease-specific evidence consists mainly of individual patients/small families, one low-prevalence 200-proband screen, biochemical studies, and variant-mismatched animal/cell models; subtype-specific prevalence, incidence, penetrance, survival, treatment response, protective factors, and validated biomarkers are unavailable | General DCM statistics or therapeutic outcomes must not be represented as DCM1II-specific. Current databases link MONDO:0014073 to CRYAB, but clinical validity and individual variant classifications should be rechecked in contemporary ClinGen/ClinVar resources. (pqac-00000000, pqac-00000004, pqac-00000013) |


*Table: Compact curation of the identity, genetics, phenotype, mechanism, diagnosis, treatment, ontology mappings, and major evidence limitations of CRYAB-associated dilated cardiomyopathy 1II.*