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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

The reported CMD1II families are heterozygous for a single CRYAB missense or stop-loss allele, and transmission is vertical: the index p.Arg157His patient had familial dilated cardiomyopathy, and in the stop-loss family the proband's child carries the same variant. Penetrance and expressivity are unknown and are almost certainly age-dependent, since the described cardiac probands presented in adulthood while the transmitting-family lens phenotype was congenital. The recessive CRYAB route that produces fatal infantile hypertonic myofibrillar myopathy is a different entity and is curated on `Myofibrillar_Myopathy`, not here.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:16483541 SUPPORT Human Clinical

"A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"

Documents the founding allele in a familial, rather than sporadic, dilated cardiomyopathy case, which is the basis for the dominant model.

PMID:38212463 SUPPORT Human Clinical

"He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant."

Records parent-to-child transmission of a heterozygous CRYAB allele, supporting dominant inheritance and showing the age-dependence of which organ declares itself first.

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Mechanistic Hypotheses

2

Loss of alpha-B crystallin support for the cardiac titin N2B spring

titin_n2b_interaction_defect EMERGING

The route directly supported for the founding CMD1II allele. Alpha-B crystallin associates with the heart-specific N2B domain and the adjacent I26/I27 domains of titin/connectin; p.Arg157His selectively reduces binding to N2B without visibly redistributing the protein inside cardiomyocytes. On this model the lesion is a failure to protect the titin spring under mechanical and thermal stress, and cardiac restriction follows from the fact that N2B is the heart-specific element. It is labelled EMERGING rather than established because the binding defect has been measured but the step from that defect to human myocardial disease has not been demonstrated in patient tissue or in an allele-matched model.

Pathograph links

CRYAB Variant Altering the Cardiac Client Interface of Alpha-B Crystallin -> Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain DIRECT The measured consequence of p.Arg157His is a reduced interaction with the heart-specific titin N2B domain.

Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain -> Cardiomyocyte Sarcomeric Stress-Protection Deficit INDIRECT KNOWN INTERMEDIATES An unchaperoned titin spring is proposed to leave the sarcomere less able to tolerate mechanical and thermal stress. This step is inference from the binding data, not a measured cellular result.

Chaperone failure with alpha-B crystallin and desmin aggregation

proteotoxic_aggregation ALTERNATIVE

The route that dominates the alpha-B crystallinopathy literature and that underlies the myofibrillar myopathy pathograph: a dominant-negative chaperone allele forms insoluble alpha-B crystallin and desmin aggregates that overload protein quality control, disorganize the sarcomere and drive cardiomyocyte injury. It is listed here as an alternative rather than the canonical route because the evidence for it comes almost entirely from p.Arg120Gly, which is a desmin-related myopathy allele and not a reported cause of isolated dilated cardiomyopathy. It becomes plausible for CMD1II specifically with the stop-loss allele, whose extended, more hydrophobic product is predicted to aggregate.

Pathograph links

CRYAB Variant Altering the Cardiac Client Interface of Alpha-B Crystallin -> Alpha-B Crystallin and Desmin Aggregate Accumulation DIRECT An aggregation-competent CRYAB allele forms insoluble deposits with desmin. This edge is well supported for p.Arg120Gly and predicted, not demonstrated, for the CMD1II stop-loss allele.

Alpha-B Crystallin and Desmin Aggregate Accumulation -> Cardiomyocyte Sarcomeric Stress-Protection Deficit DIRECT Aggregate burden and desmin filament disruption compromise the cardiomyocyte's contractile apparatus.

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Discussions and Knowledge Gaps

2

Does the p.Arg120Gly proteotoxic model of cardiac alpha-B crystallinopathy describe the mechanism of the alleles that actually cause isolated dilated cardiomyopathy?

HUMAN MODEL MISMATCH OPEN cmd1ii_model_allele_mismatch

Attached to

pathophysiology#Alpha-B Crystallin and Desmin Aggregate Accumulation pathophysiology#Cardiomyocyte Sarcomeric Stress-Protection Deficit

Evidence for the aggregation route is not absent — it is abundant, detailed and in the wrong allele. Every in vivo and cell system cited for cardiac alpha-B crystallinopathy uses p.Arg120Gly, which causes desmin-related myopathy and which the founding CMD1II paper singles out as behaving differently: p.Arg120Gly loses binding to both the heart-specific N2B domain and the striated-muscle-specific I26/I27 domains and forms intracellular aggregates, while p.Arg157His loses only the N2B interaction and does not redistribute. The mouse model compounds the mismatch by producing a hypertrophic rather than a dilated phenotype, and by producing it from a transgene whose expression level sets the severity. So the well-supported mechanism belongs to a neighbouring disease, and the disease curated here has a binding measurement and no allele-matched model at all. This is the reason the two routes are separated into hypothesis groups instead of being merged into one chain.

Proposed experiments

Knock-in mouse carrying the CRYAB p.Arg157His allele at endogenous expression

exp_cmd1ii_r157h_knockin_mouse

Generate a heterozygous knock-in of p.Arg157His or its murine equivalent and phenotype the heart for chamber dimensions, ejection fraction, fibrosis and aggregate burden. This is the experiment that would show whether the titin N2B binding defect is sufficient to cause dilated cardiomyopathy, and whether it does so without the aggregation that defines the neighbouring myofibrillar disease.

Would support

pathophysiology#Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain

Would refute

pathophysiology#Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain

Supporting outcome

Progressive left ventricular dilation with reduced ejection fraction in heterozygous knock-in animals, with no alpha-B crystallin or desmin aggregates on immunohistochemistry.

Refuting outcome

Normal cardiac dimensions and function through the animals' lifespan, indicating that the measured binding defect is not by itself sufficient to produce disease.

Patient-derived iPSC cardiomyocytes under mechanical load

exp_cmd1ii_ipsc_cardiomyocyte_titin_strain

Differentiate cardiomyocytes from a p.Arg157His carrier and an isogenic corrected control, and measure titin-based passive stiffness, sarcomere integrity and contractile function under increasing mechanical and thermal stress. This tests the stress-protection step directly in human cells, which is the step currently carried as inference.

Would support

pathophysiology#Cardiomyocyte Sarcomeric Stress-Protection Deficit

Supporting outcome

Variant cardiomyocytes show sarcomere disorganization and contractile failure at stress levels the isogenic control tolerates.

Do CRYAB alleles partition cleanly enough into cardiac-restricted and myofibrillar groups to justify two knowledge-base entries rather than one?

KNOWLEDGE GAP OPEN cmd1ii_entity_boundary

Attached to

disease#Dilated Cardiomyopathy 1II genetic#CRYAB

This entry is curated as a sibling of the alpha-B crystallinopathy subtype of `Myofibrillar_Myopathy` rather than as a subtype of it, on the strength of a single allele-versus-allele biochemical comparison and a small number of cardiac-restricted patients. The counter-evidence is real and is recorded rather than argued away: p.Gly154Ser was first reported in isolated cardiomyopathy and later found in a family with late-onset distal vacuolar myopathy and no cardiac dysfunction, so at least one allele sits on both sides of the boundary. What would settle it is a systematic genotype-phenotype study across reported CRYAB carriers, and a ClinGen Gene-Disease Validity curation of the CRYAB-dilated cardiomyopathy relationship, which the ClinGen release cached in this repository does not contain. Until then the split is a mechanistic judgement, not a demonstrated partition, and a future curator with better data should feel free to reverse it.

Proposed experiments

Systematic genotype-phenotype survey of reported CRYAB variant carriers

exp_cmd1ii_genotype_phenotype_survey

Assemble every published CRYAB carrier with allele, cardiac imaging, skeletal-muscle assessment and ophthalmic examination, and test whether cardiac-restricted disease associates with alleles that spare the striated-muscle-specific titin domains. This is the analysis that would turn the present mechanistic argument into an empirical one.

Show evidence (2 references)

PMID:20171888 REFUTE Human Clinical

"the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction"

Counts against a clean allelic partition: an allele reported in isolated cardiomyopathy also produces aggregate-positive distal myopathy with no cardiac involvement, which is the myofibrillar phenotype in a supposedly cardiac allele.

PMID:16483541 SUPPORT In Vitro

"its disease-causing mechanism is different from the mutation found in desmin-related myopathy"

The primary statement that the founding CMD1II allele acts by a different mechanism from the myofibrillar myopathy allele, which is the basis for curating the two as separate entities.

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Pathophysiology

6

CRYAB Variant Altering the Cardiac Client Interface of Alpha-B Crystallin

A heterozygous germline CRYAB allele changes how alpha-B crystallin engages its client proteins in the cardiomyocyte. For p.Arg157His the change is narrow: an evolutionarily conserved residue is substituted, and the resulting protein still distributes normally in cardiomyocytes. For the stop-loss allele the change is to the C-terminus, extending the protein by 19 residues and raising predicted hydrophobicity. These are different molecular consequences that converge on the same organ, which is why the two downstream routes are curated as separate hypothesis groups rather than one chain.

Chaperone failure with alpha-B crystallin and desmin aggregation Loss of alpha-B crystallin support for the cardiac titin N2B spring

CRYAB hgnc:2389

Genetic context allele_type: MISSENSE variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

p.Arg157His is a heterozygous germline missense allele altering a residue conserved across the alpha-crystallins. Its measured defect is a selective loss of one protein-protein interaction rather than a loss of chaperone activity or of correct subcellular localization, so the loss-of-function category should be read as loss of a specific client interaction, not as global chaperone failure. The separately reported stop-loss allele is not a missense variant and is described in the genetic block instead.

heat shock protein binding GO:0031072

I band GO:0031674

Downstream

Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain The measured consequence of p.Arg157His is a reduced interaction with the heart-specific titin N2B domain.

Alpha-B Crystallin and Desmin Aggregate Accumulation An aggregation-competent CRYAB allele forms insoluble deposits with desmin. This edge is well supported for p.Arg120Gly and predicted, not demonstrated, for the CMD1II stop-loss allele.

Show evidence (2 references)

PMID:16483541 SUPPORT Human Clinical

"A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"

Identifies the trigger variant in a dilated cardiomyopathy family.

PMID:9731540 SUPPORT INDIRECT Human Clinical

"AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity."

Establishes the normal biology this node perturbs. Indirect because the paper's disease context is desmin-related myopathy rather than isolated dilated cardiomyopathy.

Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain

Alpha-B crystallin associates with the heart-specific N2B element of titin/connectin and with the adjacent I26/I27 domains. In the p.Arg157His mutant the N2B interaction is selectively lost. The contrast with p.Arg120Gly is the informative part: that allele loses binding to both N2B and the striated-muscle-specific I26/I27 domains, which is consistent with its combined cardiac and skeletal phenotype, while a defect confined to the heart-specific element offers a molecular reason for a cardiac-restricted presentation. This is the mechanistic argument for curating CMD1II as its own entity rather than as a myofibrillar myopathy subtype.

Loss of alpha-B crystallin support for the cardiac titin N2B spring

alpha-B crystallin binding to the titin N2B domain GO:0031432 ↓ DECREASED

I band GO:0031674

Downstream

Cardiomyocyte Sarcomeric Stress-Protection Deficit An unchaperoned titin spring is proposed to leave the sarcomere less able to tolerate mechanical and thermal stress. This step is inference from the binding data, not a measured cellular result.

Show evidence (2 references)

PMID:16483541 SUPPORT In Vitro

"alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin"

Establishes the normal interaction that this node reports as lost, and names the domain whose heart specificity underlies the tissue restriction.

PMID:16483541 SUPPORT In Vitro

"In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein."

The direct allele-versus-allele comparison. It is the single most important piece of evidence for the lump/split decision recorded in this entry.

Alpha-B Crystallin and Desmin Aggregate Accumulation

Insoluble deposits containing both alpha-B crystallin and desmin accumulate in the sarcoplasm, overloading protein quality control and disorganizing the myofibrillar lattice. This is the alpha-B crystallinopathy mechanism as it is usually described, and it is the mechanism `Myofibrillar_Myopathy` curates. It is retained here as an alternative route because a CMD1II stop-loss allele is predicted to aggregate, but no aggregate pathology has been demonstrated in myocardium from a patient carrying a CMD1II allele.

Chaperone failure with alpha-B crystallin and desmin aggregation

cardiomyocyte CL:0000746

intermediate filament cytoskeleton organization GO:0045104 ↓ DECREASED

Z disc GO:0030018

Animal models

CryAB R120G cardiomyocyte-targeted transgenic mouse Mouse recapitulates Reproduces alpha-B crystallin and desmin aggregation with desmin filament disruption and myofibrillar misalignment in cardiomyocytes in vivo.

Downstream

Cardiomyocyte Sarcomeric Stress-Protection Deficit Aggregate burden and desmin filament disruption compromise the cardiomyocyte's contractile apparatus.

Show evidence (1 reference)

PMID:11440982 SUPPORT INDIRECT Model Organism

"The data show that the R120G mutation causes a desminopathy, is dominant negative, and results in cardiac hypertrophy."

Establishes the dominant-negative aggregation mechanism, and at the same time shows why it is an imperfect model for this entry: the cardiac phenotype reported is hypertrophy, not dilation.

Cardiomyocyte Sarcomeric Stress-Protection Deficit

The convergence point of the two routes: a cardiomyocyte whose sarcomere is less able to withstand mechanical and oxidative load, either because the titin spring has lost its chaperone or because aggregates and a disrupted desmin network have degraded the contractile apparatus. This is the primary cardiomyocyte insult of the maladaptive-remodeling module, reached by a chaperone route rather than by a sarcomeric-protein or toxic route.

cardiomyocyte CL:0000746

sarcomere organization GO:0045214 ↓ DECREASED

myocardium UBERON:0002349

Animal models

CryAB R120G Drosophila heart model Drosophila melanogaster partially recapitulates Cardiac expression of the mutant chaperone is sufficient to impair contractile function and increase chamber dimensions.

Downstream

Adverse Ventricular Remodeling and Myocardial Fibrosis Sustained cardiomyocyte injury drives compensatory hypertrophy, fibroblast activation and interstitial fibrosis — the shared remodeling response of the module this node conforms to.

Show evidence (1 reference)

PMID:23818860 SUPPORT INDIRECT Model Organism

"expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions"

Shows that a mutant CRYAB allele expressed in cardiac tissue is sufficient to impair contractile function and dilate the chamber. Indirect on two counts: the allele is p.Arg120Gly and the organism is an invertebrate with a heart tube rather than a four-chambered heart.

Adverse Ventricular Remodeling and Myocardial Fibrosis

Progressive chamber remodeling with interstitial and subendocardial fibrosis, wall thinning and chamber enlargement. Nothing about this stage is CRYAB-specific; it is the shared final route of the maladaptive-remodeling module, entered here from a chaperone lesion.

cardiac fibroblast CL:0002548

cardiac muscle hypertrophy in response to stress GO:0014898 ↑ INCREASED interstitial collagen deposition by activated cardiac fibroblasts GO:0030198 ↑ INCREASED

heart left ventricle UBERON:0002084

Downstream

Myocardial fibrosis Fibroblast activation and matrix deposition at this stage are what is seen as interstitial and subendocardial fibrosis in the tissue.

Left Ventricular Dilation and Systolic Dysfunction Remodeling and fibrosis produce the chamber dilation and impaired contraction that define the clinical diagnosis.

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Confirms that remodeling in this disease class converges on impaired contractility. Indirect because it is a class-level statement.

Left Ventricular Dilation and Systolic Dysfunction

The clinical endpoint: a dilated, poorly contracting left or biventricular chamber, with the heart-failure syndrome and arrhythmic risk that follow. In the reported CRYAB cases this presented in adulthood, at ages 32 and older, and in one family alongside a history of sudden cardiac death.

heart UBERON:0000948

Animal models

CryAB R120G cardiomyocyte-targeted transgenic mouse Mouse fails to recapitulate The model does not reproduce the dilated phenotype that defines this entry.

Downstream

Dilated cardiomyopathy The organ-level lesion is what is observed and coded as the clinical phenotype.

Reduced left ventricular ejection fraction Ejection fraction is the measured expression of the organ-level lesion, and is the parameter every treatment decision in this entry is indexed to.

Sudden cardiac death The dilated, scarred ventricle is an arrhythmic substrate. The intermediate step — ventricular arrhythmia — is not separately modeled here because no CRYAB-specific arrhythmia mechanism or incidence has been reported.

Congestive heart failure Impaired contraction produces the congestive heart-failure syndrome that brings most of these patients to attention.

Show evidence (1 reference)

PMID:16483541 SUPPORT Human Clinical

"A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"

Anchors the organ-level endpoint in the founding CMD1II family.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Cardiovascular 6

Dilated cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:16483541 SUPPORT Human Clinical

"A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"

Reports dilated cardiomyopathy in the index CRYAB p.Arg157His patient.

PMID:38212463 SUPPORT Human Clinical

"The proband, diagnosed with DCM at age 32"

Independent CRYAB carrier with the same cardiac phenotype.

Reduced left ventricular ejection fraction HP:0012664

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction"

Impaired contraction is definitional for the disease class. Indirect because the source is a class-level review and not a CRYAB cohort.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM"

Heart failure is the managed clinical state of this disease class. Indirect because it is a class-level statement.

Myocardial fibrosis HP:0001685

Show evidence (2 references)

PMID:29323059 SUPPORT INDIRECT Human Clinical

"The histomorphological changes of DCM include myocyte hypertrophy, nucleomegaly, and interstitial fibrosis."

Reports interstitial fibrosis as a histological finding of dilated cardiomyopathy in human myocardium (34 endomyocardial biopsies and 7 explanted hearts against 41 control hearts). Indirect because the cohort is unselected dilated cardiomyopathy and contains no CRYAB carrier.

PMID:33928704 SUPPORT INDIRECT Human Clinical

"The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value"

Establishes that myocardial fibrosis is measurable in living dilated cardiomyopathy patients and carries prognostic weight, which is why the phenotype is worth recording even though no CRYAB carrier's fibrotic burden is quotable from the sources this entry cites. Indirect for the same reason: the cohort is not CRYAB-selected.

Restrictive physiology UNKNOWN Restrictive cardiomyopathy HP:0001723

Show evidence (1 reference)

DOI:10.1002/ccr3.70213 SUPPORT DIRECT Human Clinical

"We report a case of dilated cardiomyopathy with restrictive physiology due to a CRYAB mutation."

Direct report of a CRYAB carrier presenting with dilated cardiomyopathy and restrictive physiology. This is the source that bounds the entry's statements about unmeasured myocardium: it establishes that a published CRYAB carrier exists beyond the founding series, while its abstract-only cache carries no tissue or imaging finding to quote.

Sudden cardiac death UNKNOWN HP:0001645

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias"

Establishes life-threatening arrhythmia as a recognized risk of this disease class. Indirect because no CRYAB-specific arrhythmia incidence has been reported.

Eye 1

Cataract OCCASIONAL HP:0000518

Show evidence (2 references)

PMID:38212463 SUPPORT Human Clinical

"had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms"

Documents cataract with dilated cardiomyopathy and, in the same sentence, the absence of myopathy that keeps this presentation outside the myofibrillar myopathy entry.

PMID:9731540 SUPPORT INDIRECT Human Clinical

"a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle"

Gives the expression basis for lens involvement alongside cardiac and skeletal muscle. Indirect because it is an expression statement rather than an observation of cataract in a CMD1II patient.

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Genetic Associations

1

CRYAB

Gene: CRYAB hgnc:2389 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:16483541 SUPPORT Human Clinical

"the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins"

Establishes that the founding CMD1II allele alters a residue conserved across the alpha-crystallin family, the conservation argument on which its pathogenicity partly rests.

PMID:20171888 SUPPORT INDIRECT Human Clinical

"has been identified earlier in patients with isolated cardiomyopathy"

Confirms that p.Gly154Ser was first reported in isolated cardiomyopathy, which is why it is listed here as a CMD1II allele. Indirect because the cited report is itself a skeletal-myopathy family and refers back to the cardiac cases rather than describing them.

PMID:38212463 SUPPORT Human Clinical

"The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues"

Documents a non-missense route to CRYAB-related dilated cardiomyopathy, widening the allelic spectrum beyond the two reported missense variants.

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Medical Actions

5

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) NCIT:C190796 dapagliflozin CHEBI:85078 carvedilol CHEBI:3441 spironolactone CHEBI:9241

Platform: Small molecule

There is no genotype-directed therapy for CRYAB-related dilated cardiomyopathy. Management is the standard heart-failure regimen — an angiotensin receptor-neprilysin inhibitor or ACE inhibitor, an evidence-based beta-blocker, a mineralocorticoid receptor antagonist, an SGLT2 inhibitor, and diuretics for congestion. The supporting trials enrolled unselected patients with reduced ejection fraction; none was CRYAB-stratified, and the benefit is recorded here as class-level rather than disease-specific.

Mechanism Target:

Adverse Ventricular Remodeling and Myocardial Fibrosis — Neurohormonal blockade and SGLT2 inhibition act on the shared remodeling stage of the pathograph rather than on the CRYAB lesion upstream of it.

Show evidence (1 reference)

PMID:25176015 SUPPORT INDIRECT Human Clinical

"LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure."

Establishes the benefit of neprilysin inhibition in heart failure with reduced ejection fraction. Indirect for this entry because the trial population was unselected for genotype.

Show evidence (2 references)

PMID:25176015 SUPPORT INDIRECT Human Clinical

"we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less"

Defines the trial population whose results are being extended to CRYAB carriers, making the extrapolation explicit.

PMID:31535829 SUPPORT INDIRECT Human Clinical

"the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes."

Supports SGLT2 inhibition as a component of the regimen. Indirect because the trial was not genotype-stratified.

Implantable Cardioverter Defibrillator

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

Platform: Device

Device therapy for prevention of sudden cardiac death, indicated by general cardiomyopathy and arrhythmia guidelines. Noted here because a family history of sudden cardiac death accompanied the founding p.Arg157His report; no CRYAB-specific risk-stratification rule exists, so the standard ejection-fraction-based indication applies.

Mechanism Target:

Left Ventricular Dilation and Systolic Dysfunction — The device does not modify the myocardial disease; it intercepts the arrhythmic outcome of the established organ-level lesion.

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias"

Supports defibrillator use in this disease class. Indirect because it is a class-level recommendation with no CRYAB-specific threshold.

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

States the device indication for dilated cardiomyopathy generally.

Cardiac Resynchronization Therapy

Action: cardiac resynchronization therapy Ontology label: Cardiac Resynchronization Therapy NCIT:C80436

Platform: Device

Biventricular pacing for a dilated, dyssynchronous ventricle with systolic dysfunction and conduction delay. The indication follows general heart-failure criteria and not genotype; no reported CRYAB carrier has been described as receiving it, and no CRYAB-specific conduction phenotype has been established that would change the threshold.

Mechanism Target:

MODULATES Left Ventricular Dilation and Systolic Dysfunction — Resynchronizing contraction improves the mechanical efficiency of an already-dilated ventricle. It does not act on the chaperone lesion upstream.

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

Establishes resynchronization as part of standard management of this disease class. Indirect because the quoted sentence frames both devices in terms of arrhythmia prevention, whereas resynchronization's action on this node is mechanical.

Show evidence (1 reference)

PMID:42475150 SUPPORT INDIRECT Other

"Device therapies, such as implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT), and left ventricular assist devices (LVADs), are critical for advanced cases."

Names resynchronization among the device therapies used in advanced heart failure with reduced ejection fraction. Indirect because the population is unselected for genotype.

Advanced Heart Failure Therapy (mechanical circulatory support and transplantation)

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Platform: Surgery

For disease refractory to medical and device therapy the remaining options are durable mechanical circulatory support and heart transplantation. This is curated as the endpoint of the generic dilated-cardiomyopathy pathway: no CRYAB carrier has been reported to have received either, and nothing in the titin-interaction or aggregation routes predicts a different response, so no genotype-specific claim is made. Note that both the cardiac and the myofibrillar CRYAB presentations can involve respiratory muscle weakness in the syndromic alleles, which is a candidate-selection consideration rather than a contraindication.

Mechanism Target:

MODULATES Left Ventricular Dilation and Systolic Dysfunction — Both options replace or unload the failing chamber rather than treating the myocardial disease that produced it.

Show evidence (1 reference)

PMID:42475150 SUPPORT INDIRECT Other

"left ventricular assist devices (LVADs), are critical for advanced cases"

Establishes mechanical circulatory support as part of the management of advanced heart failure with reduced ejection fraction, which is the state this node describes at its worst. Indirect because the population is unselected for genotype.

Genetic Counseling and Cascade Testing of First-Degree Relatives

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Once a pathogenic CRYAB variant is established in a proband, targeted testing of first-degree relatives identifies carriers for cardiac surveillance. The stop-loss family makes the case concretely: the proband's child carried the same variant and had already declared the ocular phenotype while remaining cardiologically unremarkable, which is exactly the situation surveillance exists for.

Show evidence (1 reference)

PMID:38212463 SUPPORT INDIRECT Human Clinical

"He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant."

Demonstrates that familial variant testing identifies at-risk relatives before cardiac disease appears. Indirect because the report describes the finding rather than evaluating a surveillance programme.

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Diagnosis

4

Echocardiography

First-line and usually sufficient to establish the phenotype: left ventricular internal dimensions and ejection fraction identify the dilated, hypocontractile chamber. The diagnosis is a clinical one and requires excluding loading conditions and coronary disease adequate to explain the findings, so the study is necessary but not sufficient on its own. Nothing about the imaging is CRYAB-specific.

transthoracic echocardiography NCIT:C16525

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling"

Names echocardiography as the required modality for assessing the ventricular dysfunction that defines this disease class.

PMID:31073128 SUPPORT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

States the exclusions that make the imaging finding necessary but not sufficient for the diagnosis.

Cardiac Magnetic Resonance Imaging with Late Gadolinium Enhancement

CMR adds tissue characterisation to the chamber measurements, and with it the risk stratification that drives management in nonischemic dilated cardiomyopathy. In a meta-analysis of 103 studies and 29,687 patients, both the presence and the extent of late gadolinium enhancement predicted all-cause mortality and arrhythmic events, while ejection fraction — the number echocardiography gives you — did not predict either. No CMR finding from a CRYAB carrier is quotable from any source this entry cites, so this entry can say what the study would be for without saying what it shows in this genotype; see the `Myocardial fibrosis` phenotype, which is unmeasured here for the same reason, and which records the one CRYAB-specific case report that this entry cannot read past the abstract of.

cardiac magnetic resonance imaging with late gadolinium enhancement NCIT:C16809

Show evidence (2 references)

PMID:39298146 SUPPORT INDIRECT Human Clinical

"Late gadolinium enhancement (LGE) presence and extent (per 1%) were associated with higher all-cause mortality"

Establishes late gadolinium enhancement as the prognostic signal CMR adds beyond echocardiography. Indirect because the pooled cohorts are unselected nonischemic dilated cardiomyopathy, not CRYAB carriers.

PMID:39298146 SUPPORT INDIRECT Human Clinical

"Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"

The negative result that makes CMR worth curating separately from echocardiography: the echo-derived measure does not carry the mortality signal that late gadolinium enhancement does. Indirect for the same reason as the item above.

Natriuretic Peptide Measurement

Plasma BNP or NT-proBNP supports detection and staging of heart failure in a carrier with symptoms or borderline imaging, and is the practical serum marker for longitudinal follow-up. Its strength is exclusion rather than confirmation — a normal value rules heart failure out well, a raised one does not rule it in, which is why imaging remains the confirmatory step. High-sensitivity troponin and the routine metabolic, thyroid and iron studies that accompany a first cardiomyopathy workup are part of the same panel but are not separately evidenced in this entry. No CRYAB-specific threshold or distribution exists.

NT-proBNP measurement NCIT:C96610

Show evidence (2 references)

PMID:25740799 SUPPORT INDIRECT Human Clinical

"At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure."

Quantified basis for using natriuretic peptides as the rule-out test in suspected heart failure. Indirect twice over: the setting is acute care rather than the chronic surveillance this entry describes, and the cohorts are unselected for genotype.

PMID:25740799 SUPPORT INDIRECT Human Clinical

"Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required."

States the limit of the biomarker directly, which is why this entry orders the workup imaging-first and treats the peptide as an adjunct.

Cardiomyopathy Multigene Panel Sequencing

The confirmatory test is molecular. A curated cardiomyopathy panel that includes CRYAB is the appropriate first-line test, because dilated cardiomyopathy is genetically heterogeneous and the CRYAB phenotypes overlap other cardiomyopathies and the myofibrillar myopathies; both reported CMD1II ascertainments came through sequencing rather than through a clinical suspicion of alpha-B crystallinopathy. Exome or genome sequencing is the fallback for panel-negative familial disease. Interpretation is the hard part here, not detection: the number of reported CRYAB cardiac probands is very small, no ClinGen Gene-Disease Validity classification exists for the CRYAB-dilated cardiomyopathy relationship, and a novel CRYAB missense variant in a DCM proband will often be a variant of uncertain significance. Once a variant is established in a family, targeted cascade testing directs surveillance of relatives.

cardiomyopathy multigene panel sequencing NCIT:C15709

Show evidence (3 references)

PMID:20301486 SUPPORT Other

"Provide the evaluation strategy of a proband with nonsyndromic DCM"

The GeneReviews chapter states the proband evaluation strategy that a gene-specific entry such as this one sits inside. Evidence source is OTHER because GeneReviews is an expert-authored review resource; note that the cached PubMed record for this chapter carries only its stated purpose, so no clinical-characteristics text could be mined from it.

PMID:20301486 SUPPORT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome"

The GeneReviews purpose statement for relatives of a DCM proband: genetic risk assessment driving cardiac surveillance. This is the basis for the cascade-testing treatment recorded in this entry.

PMID:38212463 SUPPORT Human Clinical

"we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant"

Documents the sequencing route by which a CRYAB variant actually reached a dilated cardiomyopathy proband, and the diagnostic yield it sat in.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No population prevalence or incidence figure exists for the CRYAB-attributed form of dilated cardiomyopathy. The reported human material is a small number of index patients and families. The nearest thing to a denominator is a whole-genome-sequencing series of 159 unrelated dilated cardiomyopathy probands in which a single CRYAB variant was found, and an earlier consecutive series of 200 unrelated probands whose title reports low prevalence; neither is a population estimate and neither should be stored as one.

Show evidence (1 reference)

PMID:38212463 SUPPORT INDIRECT Human Clinical

"we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant"

Gives the only clean cohort denominator available for CRYAB in dilated cardiomyopathy — one variant carrier among 159 sequenced probands. It is indirect because a single-centre diagnostic yield is not a population prevalence.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1II:

CRYAB-related myofibrillar myopathy (alpha-B crystallinopathy with skeletal muscle disease) Not Yet Curated MONDO:0012130

Overlapping Features This is the differential this entry exists to draw. The same gene produces a myofibrillar myopathy in which skeletal muscle, not the heart, is the presenting problem, and in which cardiac involvement — when present — sits alongside distal and proximal weakness, cataract and respiratory failure. The boundary is allelic rather than clinical: p.Arg120Gly loses binding to both the heart-specific titin N2B domain and the striated-muscle-specific I26/I27 domains and forms intracellular aggregates, whereas the founding CMD1II allele p.Arg157His loses only the N2B interaction and leaves the protein's distribution in cardiomyocytes unchanged. The boundary is also porous: p.Gly154Ser was reported first in isolated cardiomyopathy and later in a family with late-onset distal vacuolar myopathy and no cardiac dysfunction at all, so allele alone does not settle it. Curated in this knowledge base as `Myofibrillar_Myopathy`, subtype MFM2.

Distinguishing Features

Distal and later proximal skeletal-muscle weakness, dysphagia and respiratory muscle involvement, with elevated creatine kinase; absent in the reported cardiac-restricted CRYAB probands.
Protein aggregates containing alpha-B crystallin and desmin on skeletal muscle biopsy, which the founding CMD1II allele does not produce.
A neurological examination and a creatine kinase measurement separate the two at the bedside before any molecular result is available.

Show evidence (2 references)

PMID:16483541 SUPPORT In Vitro

"In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein."

The allele-versus-allele comparison that distinguishes the two entities at the molecular level.

PMID:20171888 REFUTE Human Clinical

"the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction"

Recorded as REFUTE against the claim that the differential is cleanly allelic: one allele appears on both sides of the line, which is exactly the uncertainty the `cmd1ii_entity_boundary` discussion carries.

Syndromic alpha-B crystallinopathy with congenital cataract

Overlapping Features A CRYAB stop-loss allele, p.(Ter176TrpextTer19), produced dilated cardiomyopathy together with bilateral congenital cataracts and no myopathy — a third pattern that is neither the cardiac-restricted presentation nor myofibrillar myopathy. It matters diagnostically because the lens finding may be the first and, in a young relative, the only manifestation: the proband's ten-year-old child carried the same variant, had congenital cataracts, and was cardiologically unremarkable. A cataract in a CRYAB carrier is therefore an indication for cardiac surveillance rather than a reason to reclassify the family.

Distinguishing Features

Bilateral congenital cataract accompanying dilated cardiomyopathy, with no skeletal myopathy.
The cardiac-restricted p.Arg157His presentation has no reported ocular finding; myofibrillar myopathy pairs cataract with muscle weakness.

Show evidence (1 reference)

PMID:38212463 SUPPORT Human Clinical

"had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms"

Documents the combination — cataract plus dilated cardiomyopathy, without myopathy — that defines this presentation and separates it from the myofibrillar entity.

Dilated cardiomyopathy caused by another gene

Overlapping Features CRYAB is a minor contributor to a genetically crowded phenotype. Sarcomeric and desmosomal genes, and TTN and LMNA above all, account for far more familial dilated cardiomyopathy than CRYAB does, and several of them carry management consequences that CRYAB does not — LMNA in particular changes the defibrillator threshold. A CRYAB variant found on a panel should not close the analysis of the rest of the panel.

Distinguishing Features

Conduction disease or early ventricular arrhythmia points to LMNA or FLNC rather than CRYAB.
Skeletal-muscle or ocular findings point back toward the CRYAB spectrum.
Segregation and gene-level validity evidence, not the variant call alone, should settle attribution.

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome."

Establishes the genetic heterogeneity that makes gene-level attribution the diagnostic problem. Indirect because it is a class-level statement that does not mention CRYAB.

Acquired (nongenetic) dilated cardiomyopathy

Overlapping Features Myocarditis, toxic exposure, endocrine and autoimmune disease, tachycardia mediation, peripartum onset and ischemic disease all produce the same chamber phenotype. Because CMD1II presents in adulthood in a small number of families and has no distinguishing cardiac feature of its own, these are the causes that must be excluded before a CRYAB variant is treated as explanatory.

Distinguishing Features

A history of toxic exposure, recent infection or pregnancy, or a regional rather than global wall motion abnormality.
Coronary imaging, and endomyocardial biopsy where inflammation or infiltration remains plausible.
A three-generation pedigree is the cheapest discriminator; its absence should raise the bar for calling a CRYAB variant causal.

Show evidence (2 references)

PMID:31073128 SUPPORT INDIRECT Other

"Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases."

Enumerates the acquired causes that share the phenotype. Indirect because it is a class-level statement rather than a differential drawn against CRYAB.

PMID:31073128 SUPPORT INDIRECT Other

"immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected"

Names the test that adjudicates the inflammatory arm of this differential. Indirect because it is a class-level recommendation.

🐁

Animal Models

2

CryAB R120G cardiomyocyte-targeted transgenic mouse

The reference model of cardiac alpha-B crystallinopathy. It is included here because it is the only in vivo evidence for the aggregation route, and it is explicitly NOT a model of CMD1II: the allele causes desmin-related myopathy rather than isolated dilated cardiomyopathy, the phenotype reported is hypertrophic rather than dilated, and the effect is dose-dependent on a transgene rather than produced at endogenous expression.

Species

Mouse

Genotype

Cardiomyocyte-restricted transgenic overexpression of CryAB p.Arg120Gly

Publication

PMID:11440982

Pathograph links

Alpha-B Crystallin and Desmin Aggregate Accumulation recapitulates fidelity: moderate Reproduces alpha-B crystallin and desmin aggregation with desmin filament disruption and myofibrillar misalignment in cardiomyocytes in vivo.

Limitations: p.Arg120Gly is a desmin-related myopathy allele and is not a reported cause of isolated dilated cardiomyopathy, and the phenotype is produced by transgenic overexpression, with a high-expressing line reaching 100% mortality by early adulthood. Severity is therefore an expression artefact as much as an allele effect.

Readouts

Cardiomyocyte desmin filament integrity and myofibril alignment

Direction: DECREASED

Interpretation: Structural correlate of the aggregation node in this model.

Show evidence (1 reference)

PMID:11440982 SUPPORT Model Organism

"The desmin filaments in the cardiomyocytes were overtly affected, myofibril alignment was significantly impaired"

Reports the histological measurement that grounds this readout.

Show evidence (1 reference)

PMID:11440982 SUPPORT Model Organism

"The data show that the R120G mutation causes a desminopathy, is dominant negative, and results in cardiac hypertrophy."

Supports treating this model as informative for the aggregation node, while naming the hypertrophic phenotype that limits its relevance to dilated cardiomyopathy.

Left Ventricular Dilation and Systolic Dysfunction fails to recapitulate fidelity: low The model does not reproduce the dilated phenotype that defines this entry.

Limitations: The reported cardiac response in this transgenic line is hypertrophic, at both the molecular and the cellular level, rather than dilated. Curating it as a model of dilated cardiomyopathy would misrepresent the published result.

Show evidence (1 reference)

PMID:11440982 SUPPORT Model Organism

"a hypertrophic response occurred at both the molecular and cellular levels"

States the phenotype the model produces, which is not the dilated phenotype of this disease.

CryAB R120G Drosophila heart model

An invertebrate model in which cardiac expression of the mutant chaperone impairs contractile function and enlarges the heart tube, and in which the phenotype is suppressed by reducing NADPH-generating enzyme activity — evidence that reductive stress is part of the downstream pathology.

Species

Drosophila melanogaster

Genotype

Cardiac expression of human CryAB p.Arg120Gly

Publication

PMID:23818860

Pathograph links

Cardiomyocyte Sarcomeric Stress-Protection Deficit partially recapitulates fidelity: low Cardiac expression of the mutant chaperone is sufficient to impair contractile function and increase chamber dimensions.

Limitations: The allele is p.Arg120Gly rather than a CMD1II allele, the organ is a Drosophila heart tube rather than a four-chambered mammalian heart, and the protein is expressed heterologously.

Readouts

Cardiac function and heart tube dimension

Direction: ALTERED

Interpretation: Functional correlate of the cardiomyocyte insult node in this model.

Show evidence (1 reference)

PMID:23818860 SUPPORT Model Organism

"expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions"

Reports the functional and dimensional measurements behind this readout.

Show evidence (1 reference)

PMID:23818860 SUPPORT Model Organism

"we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it"

Supports treating the model as informative for the cardiomyocyte insult node, since the phenotype is modifiable in the direction the redox hypothesis predicts.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1II
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
synonyms:
- CMD1II
- DCM1II
- dilated cardiomyopathy type 1II
- cardiomyopathy, dilated, 1II
- CRYAB familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in CRYAB
- alpha-B crystallin-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1II (CMD1II, OMIM 615184) is the CRYAB-attributed node
  of the familial isolated dilated cardiomyopathy series. CRYAB encodes
  alpha-B crystallin (HSPB5), an ATP-independent small heat-shock protein that
  is abundant in the lens and in cardiac and skeletal muscle, and that binds
  desmin, actin and — the point on which this entry turns — the heart-specific
  N2B spring element of titin/connectin.


  This entry is deliberately separate from myofibrillar myopathy, and the
  reason is mechanistic rather than nosological. MONDO gives MONDO:0014073 two
  parents: familial isolated dilated cardiomyopathy, and the CRYAB-related
  myofibrillar myopathy-cataract-cardiomyopathy spectrum. The knowledge base
  already curates the second of those as `Myofibrillar_Myopathy`, whose MFM2
  subtype is alpha-B crystallinopathy and whose pathograph is built end to end
  around protein aggregation — chaperone-assisted selective autophagy failure,
  desmin network disruption, myofibrillar disintegration at the Z-disc, and
  ectopic aggregate accumulation. The founding CMD1II allele does not fit that
  pathograph. Inagaki and colleagues showed that p.Arg157His, found in a
  familial dilated cardiomyopathy patient, reduces binding to the heart-specific
  titin N2B domain while leaving the distribution of the protein in
  cardiomyocytes unchanged, whereas the myofibrillar-myopathy allele p.Arg120Gly
  loses binding to both N2B and the striated-muscle-specific I26/I27 domains and
  does form intracellular aggregates. They state explicitly that the
  disease-causing mechanism of Arg157His is different from that of the allele
  found in desmin-related myopathy. Recording CMD1II as a `has_subtypes` entry
  on `Myofibrillar_Myopathy` would therefore assert an aggregate-first
  myofibrillar mechanism that the primary literature specifically denies for the
  index allele, and would assert skeletal-muscle involvement that the reported
  cardiac-restricted patients do not have. The two entries are curated as
  siblings under alpha-B crystallinopathy rather than parent and child.


  The allelic boundary is real but not absolute, and this entry does not pretend
  otherwise. p.Gly154Ser was first reported in isolated cardiomyopathy and was
  later found in a family with late-onset distal vacuolar myopathy with protein
  aggregates and no cardiac dysfunction at all — the same allele on either side
  of the line. A stop-loss allele, p.(Ter176TrpextTer19), was found in one of
  159 sequenced dilated cardiomyopathy probands and produced dilated
  cardiomyopathy with bilateral congenital cataracts but no myopathy, adding a
  third pattern. So CRYAB alleles distribute across cardiac, skeletal-muscle and
  ocular presentations in a way that correlates with the allele but is not
  determined by it. Two mechanistic routes are curated here as explicit
  hypothesis groups — a titin-interaction route supported directly for
  p.Arg157His, and a proteotoxic aggregation route supported mainly by
  p.Arg120Gly model systems that are not CMD1II alleles.


  The mechanistic model evidence is allele-mismatched. Essentially all of the
  cell and animal work on cardiac alpha-B crystallinopathy uses p.Arg120Gly,
  which causes desmin-related myopathy rather than isolated dilated
  cardiomyopathy, and does so by overexpression. No knock-in or patient-derived
  model of p.Arg157His or p.Gly154Ser cardiac disease has been reported. That
  mismatch is carried as a HUMAN_MODEL_MISMATCH discussion rather than smoothed
  over, and the animal-model links say which node they model and which they do
  not.
disease_term:
  preferred_term: dilated cardiomyopathy 1II
  term:
    id: MONDO:0014073
    label: dilated cardiomyopathy 1II
parents:
- Dilated Cardiomyopathy
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence or incidence figure exists for the CRYAB-attributed
    form of dilated cardiomyopathy. The reported human material is a small number
    of index patients and families. The nearest thing to a denominator is a
    whole-genome-sequencing series of 159 unrelated dilated cardiomyopathy
    probands in which a single CRYAB variant was found, and an earlier
    consecutive series of 200 unrelated probands whose title reports low
    prevalence; neither is a population estimate and neither should be stored as
    one.
  evidence:
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant"
    explanation: >-
      Gives the only clean cohort denominator available for CRYAB in dilated
      cardiomyopathy — one variant carrier among 159 sequenced probands. It is
      indirect because a single-centre diagnostic yield is not a population
      prevalence.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The reported CMD1II families are heterozygous for a single CRYAB missense or
    stop-loss allele, and transmission is vertical: the index p.Arg157His patient
    had familial dilated cardiomyopathy, and in the stop-loss family the proband's
    child carries the same variant. Penetrance and expressivity are unknown and
    are almost certainly age-dependent, since the described cardiac probands
    presented in adulthood while the transmitting-family lens phenotype was
    congenital. The recessive CRYAB route that produces fatal infantile hypertonic
    myofibrillar myopathy is a different entity and is curated on
    `Myofibrillar_Myopathy`, not here.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"
    explanation: >-
      Documents the founding allele in a familial, rather than sporadic, dilated
      cardiomyopathy case, which is the basis for the dominant model.
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant."
    explanation: >-
      Records parent-to-child transmission of a heterozygous CRYAB allele,
      supporting dominant inheritance and showing the age-dependence of which
      organ declares itself first.
genetic:
- name: CRYAB
  notes: >-
    CRYAB encodes alpha-B crystallin (HSPB5), a small heat-shock protein and
    ATP-independent molecular chaperone abundant in the lens and in cardiac and
    skeletal muscle. The alleles curated here as CMD1II are the heterozygous
    missense variant p.Arg157His, which impairs the interaction with the
    heart-specific titin N2B domain, and p.Gly154Ser, first reported in isolated
    cardiomyopathy. A stop-loss allele extending the protein by 19 residues has
    since been reported in dilated cardiomyopathy with congenital cataract. The
    aggregate-forming myofibrillar-myopathy allele p.Arg120Gly is deliberately
    NOT curated as a CMD1II allele; it belongs to `Myofibrillar_Myopathy`, and
    conflating the two is the specific error this entry exists to avoid. No
    ClinGen Gene-Disease Validity assertion for a CRYAB-dilated cardiomyopathy
    relationship is present in the ClinGen release cached in this repository, so
    the clinical validity of the relationship has not been expert-panel graded
    and should be treated as unsettled.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: CRYAB
    term:
      id: hgnc:2389
      label: CRYAB
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins"
    explanation: >-
      Establishes that the founding CMD1II allele alters a residue conserved
      across the alpha-crystallin family, the conservation argument on which its
      pathogenicity partly rests.
  - reference: PMID:20171888
    reference_title: "The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "has been identified earlier in patients with isolated cardiomyopathy"
    explanation: >-
      Confirms that p.Gly154Ser was first reported in isolated cardiomyopathy,
      which is why it is listed here as a CMD1II allele. Indirect because the
      cited report is itself a skeletal-myopathy family and refers back to the
      cardiac cases rather than describing them.
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues"
    explanation: >-
      Documents a non-missense route to CRYAB-related dilated cardiomyopathy,
      widening the allelic spectrum beyond the two reported missense variants.
mechanistic_hypotheses:
- hypothesis_group_id: titin_n2b_interaction_defect
  hypothesis_label: Loss of alpha-B crystallin support for the cardiac titin N2B spring
  status: EMERGING
  description: >-
    The route directly supported for the founding CMD1II allele. Alpha-B
    crystallin associates with the heart-specific N2B domain and the adjacent
    I26/I27 domains of titin/connectin; p.Arg157His selectively reduces binding
    to N2B without visibly redistributing the protein inside cardiomyocytes. On
    this model the lesion is a failure to protect the titin spring under
    mechanical and thermal stress, and cardiac restriction follows from the fact
    that N2B is the heart-specific element. It is labelled EMERGING rather than
    established because the binding defect has been measured but the step from
    that defect to human myocardial disease has not been demonstrated in patient
    tissue or in an allele-matched model.
- hypothesis_group_id: proteotoxic_aggregation
  hypothesis_label: Chaperone failure with alpha-B crystallin and desmin aggregation
  status: ALTERNATIVE
  description: >-
    The route that dominates the alpha-B crystallinopathy literature and that
    underlies the myofibrillar myopathy pathograph: a dominant-negative chaperone
    allele forms insoluble alpha-B crystallin and desmin aggregates that overload
    protein quality control, disorganize the sarcomere and drive cardiomyocyte
    injury. It is listed here as an alternative rather than the canonical route
    because the evidence for it comes almost entirely from p.Arg120Gly, which is
    a desmin-related myopathy allele and not a reported cause of isolated dilated
    cardiomyopathy. It becomes plausible for CMD1II specifically with the
    stop-loss allele, whose extended, more hydrophobic product is predicted to
    aggregate.
pathophysiology:
- name: CRYAB Variant Altering the Cardiac Client Interface of Alpha-B Crystallin
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous germline CRYAB allele changes how alpha-B crystallin engages
    its client proteins in the cardiomyocyte. For p.Arg157His the change is
    narrow: an evolutionarily conserved residue is substituted, and the resulting
    protein still distributes normally in cardiomyocytes. For the stop-loss
    allele the change is to the C-terminus, extending the protein by 19 residues
    and raising predicted hydrophobicity. These are different molecular
    consequences that converge on the same organ, which is why the two downstream
    routes are curated as separate hypothesis groups rather than one chain.
  genes:
  - preferred_term: CRYAB
    term:
      id: hgnc:2389
      label: CRYAB
  genetic_context:
    allele_type: MISSENSE
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      p.Arg157His is a heterozygous germline missense allele altering a residue
      conserved across the alpha-crystallins. Its measured defect is a selective
      loss of one protein-protein interaction rather than a loss of chaperone
      activity or of correct subcellular localization, so the loss-of-function
      category should be read as loss of a specific client interaction, not as
      global chaperone failure. The separately reported stop-loss allele is not
      a missense variant and is described in the genetic block instead.
  molecular_functions:
  - preferred_term: heat shock protein binding
    term:
      id: GO:0031072
      label: heat shock protein binding
  cellular_components:
  - preferred_term: I band
    term:
      id: GO:0031674
      label: I band
  downstream:
  - target: Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain
    causal_link_type: DIRECT
    hypothesis_groups:
    - titin_n2b_interaction_defect
    description: >-
      The measured consequence of p.Arg157His is a reduced interaction with the
      heart-specific titin N2B domain.
    evidence:
    - reference: PMID:16483541
      reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional analysis revealed that the mutation decreased the binding to titin/connectin heart-specific N2B domain without affecting distribution of the mutant crystallin protein in cardiomyocytes."
      explanation: >-
        States both halves of this edge: binding to N2B falls, and subcellular
        distribution does not change, so the edge is a binding defect and not a
        mislocalization or aggregation defect.
  - target: Alpha-B Crystallin and Desmin Aggregate Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - proteotoxic_aggregation
    description: >-
      An aggregation-competent CRYAB allele forms insoluble deposits with desmin.
      This edge is well supported for p.Arg120Gly and predicted, not demonstrated,
      for the CMD1II stop-loss allele.
    evidence:
    - reference: PMID:9731540
      reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin"
      explanation: >-
        Demonstrates the aggregation edge for a CRYAB missense allele. Indirect
        for this entry because the allele tested is p.Arg120Gly, a
        desmin-related myopathy allele rather than a CMD1II allele.
    - reference: PMID:38212463
      reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      directness: INDIRECT
      snippet: "which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin"
      explanation: >-
        The only support that an aggregation route operates in a CMD1II allele is
        a structural prediction for the stop-loss product, which is why this edge
        is curated as an alternative hypothesis rather than the canonical chain.
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"
    explanation: >-
      Identifies the trigger variant in a dilated cardiomyopathy family.
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity."
    explanation: >-
      Establishes the normal biology this node perturbs. Indirect because the
      paper's disease context is desmin-related myopathy rather than isolated
      dilated cardiomyopathy.
- name: Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain
  biological_scale: MOLECULAR
  description: >-
    Alpha-B crystallin associates with the heart-specific N2B element of
    titin/connectin and with the adjacent I26/I27 domains. In the p.Arg157His
    mutant the N2B interaction is selectively lost. The contrast with
    p.Arg120Gly is the informative part: that allele loses binding to both N2B
    and the striated-muscle-specific I26/I27 domains, which is consistent with
    its combined cardiac and skeletal phenotype, while a defect confined to the
    heart-specific element offers a molecular reason for a cardiac-restricted
    presentation. This is the mechanistic argument for curating CMD1II as its own
    entity rather than as a myofibrillar myopathy subtype.
  molecular_functions:
  - preferred_term: alpha-B crystallin binding to the titin N2B domain
    term:
      id: GO:0031432
      label: titin binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: I band
    term:
      id: GO:0031674
      label: I band
  downstream:
  - target: Cardiomyocyte Sarcomeric Stress-Protection Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - titin_n2b_interaction_defect
    description: >-
      An unchaperoned titin spring is proposed to leave the sarcomere less able
      to tolerate mechanical and thermal stress. This step is inference from the
      binding data, not a measured cellular result.
    evidence:
    - reference: PMID:16483541
      reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "the Arg157His mutation may be involved in the pathogenesis of DCM via impaired accommodation to the heart-specific N2B domain of titin/connectin"
      explanation: >-
        The authors themselves frame the step from binding defect to disease as a
        proposal, and the quoted hedge is reproduced rather than removed.
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin"
    explanation: >-
      Establishes the normal interaction that this node reports as lost, and
      names the domain whose heart specificity underlies the tissue restriction.
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein."
    explanation: >-
      The direct allele-versus-allele comparison. It is the single most important
      piece of evidence for the lump/split decision recorded in this entry.
- name: Alpha-B Crystallin and Desmin Aggregate Accumulation
  biological_scale: CELLULAR
  description: >-
    Insoluble deposits containing both alpha-B crystallin and desmin accumulate
    in the sarcoplasm, overloading protein quality control and disorganizing the
    myofibrillar lattice. This is the alpha-B crystallinopathy mechanism as it is
    usually described, and it is the mechanism `Myofibrillar_Myopathy` curates.
    It is retained here as an alternative route because a CMD1II stop-loss allele
    is predicted to aggregate, but no aggregate pathology has been demonstrated
    in myocardium from a patient carrying a CMD1II allele.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: intermediate filament cytoskeleton organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  downstream:
  - target: Cardiomyocyte Sarcomeric Stress-Protection Deficit
    causal_link_type: DIRECT
    hypothesis_groups:
    - proteotoxic_aggregation
    description: >-
      Aggregate burden and desmin filament disruption compromise the
      cardiomyocyte's contractile apparatus.
    evidence:
    - reference: PMID:11440982
      reference_title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "The desmin filaments in the cardiomyocytes were overtly affected, myofibril alignment was significantly impaired"
      explanation: >-
        Shows the aggregation-to-myofibril-disorganization step in cardiomyocytes
        in vivo. Indirect because the mouse expresses p.Arg120Gly from a
        transgene, not a CMD1II allele at endogenous level.
  evidence:
  - reference: PMID:11440982
    reference_title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The data show that the R120G mutation causes a desminopathy, is dominant negative, and results in cardiac hypertrophy."
    explanation: >-
      Establishes the dominant-negative aggregation mechanism, and at the same
      time shows why it is an imperfect model for this entry: the cardiac
      phenotype reported is hypertrophy, not dilation.
- name: Cardiomyocyte Sarcomeric Stress-Protection Deficit
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The convergence point of the two routes: a cardiomyocyte whose sarcomere is
    less able to withstand mechanical and oxidative load, either because the
    titin spring has lost its chaperone or because aggregates and a disrupted
    desmin network have degraded the contractile apparatus. This is the primary
    cardiomyocyte insult of the maladaptive-remodeling module, reached by a
    chaperone route rather than by a sarcomeric-protein or toxic route.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: DECREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Adverse Ventricular Remodeling and Myocardial Fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained cardiomyocyte injury drives compensatory hypertrophy, fibroblast
      activation and interstitial fibrosis — the shared remodeling response of
      the module this node conforms to.
    evidence:
    - reference: PMID:29323059
      reference_title: "Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The histomorphological changes of DCM include myocyte hypertrophy, nucleomegaly, and interstitial fibrosis."
      explanation: >-
        Names the two tissue changes this edge asserts — myocyte hypertrophy and
        interstitial fibrosis — in endomyocardial biopsy and explanted-heart
        material from dilated cardiomyopathy patients. Indirect because the
        cohort is unselected dilated cardiomyopathy, not CRYAB carriers.
  evidence:
  - reference: PMID:23818860
    reference_title: "The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions"
    explanation: >-
      Shows that a mutant CRYAB allele expressed in cardiac tissue is sufficient
      to impair contractile function and dilate the chamber. Indirect on two
      counts: the allele is p.Arg120Gly and the organism is an invertebrate with
      a heart tube rather than a four-chambered heart.
- name: Adverse Ventricular Remodeling and Myocardial Fibrosis
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Progressive chamber remodeling with interstitial and subendocardial fibrosis,
    wall thinning and chamber enlargement. Nothing about this stage is
    CRYAB-specific; it is the shared final route of the maladaptive-remodeling
    module, entered here from a chaperone lesion.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy in response to stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: interstitial collagen deposition by activated cardiac fibroblasts
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  downstream:
  - target: Myocardial fibrosis
    causal_link_type: DIRECT
    description: >-
      Fibroblast activation and matrix deposition at this stage are what is seen
      as interstitial and subendocardial fibrosis in the tissue.
    evidence:
    - reference: PMID:29323059
      reference_title: "Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Morphometric analysis revealed significant increase in nuclear area, myocyte width, percentage of fibrosis and reduction in capillary myocyte ratio in cases as compared to controls."
      explanation: >-
        Quantifies the fibrotic burden of remodeled dilated-cardiomyopathy
        myocardium against control hearts. Indirect because no CRYAB carrier is
        in the series.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Remodeling and fibrosis produce the chamber dilation and impaired
      contraction that define the clinical diagnosis.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction"
      explanation: >-
        Defines the endpoint this edge produces, in the terms the clinical
        diagnosis uses.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."
    explanation: >-
      Confirms that remodeling in this disease class converges on impaired
      contractility. Indirect because it is a class-level statement.
- name: Left Ventricular Dilation and Systolic Dysfunction
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  role: consequence
  description: >-
    The clinical endpoint: a dilated, poorly contracting left or biventricular
    chamber, with the heart-failure syndrome and arrhythmic risk that follow. In
    the reported CRYAB cases this presented in adulthood, at ages 32 and older,
    and in one family alongside a history of sudden cardiac death.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      The organ-level lesion is what is observed and coded as the clinical
      phenotype.
    evidence:
    - reference: PMID:38212463
      reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The proband, diagnosed with DCM at age 32"
      explanation: >-
        Records the clinical diagnosis in a CRYAB variant carrier, with the age
        at which it was made.
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
    description: >-
      Ejection fraction is the measured expression of the organ-level lesion,
      and is the parameter every treatment decision in this entry is indexed to.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction"
      explanation: >-
        Dilation and impaired contraction are given as one clinical entity, which
        is the edge asserted here. Indirect because the source is a class-level
        review.
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The dilated, scarred ventricle is an arrhythmic substrate. The intermediate
      step — ventricular arrhythmia — is not separately modeled here because no
      CRYAB-specific arrhythmia mechanism or incidence has been reported.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias"
      explanation: >-
        Establishes life-threatening arrhythmia as a recognized consequence of
        the established organ-level lesion in this disease class. Indirect
        because it is a management statement and no CRYAB arrhythmic risk
        estimate exists.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired contraction produces the congestive heart-failure syndrome that
      brings most of these patients to attention.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."
      explanation: >-
        Links dilated cardiomyopathy to heart failure as its clinical
        consequence. Indirect because it is a class-level statement rather than a
        CRYAB observation.
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"
    explanation: >-
      Anchors the organ-level endpoint in the founding CMD1II family.
phenotypes:
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular or biventricular dilation with impaired systolic function,
    not explained by loading conditions or coronary disease. This is the defining
    and, in the cardiac-restricted alleles, essentially the only phenotype.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient"
    explanation: >-
      Reports dilated cardiomyopathy in the index CRYAB p.Arg157His patient.
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband, diagnosed with DCM at age 32"
    explanation: >-
      Independent CRYAB carrier with the same cardiac phenotype.
- name: Reduced left ventricular ejection fraction
  category: Cardiovascular
  description: >-
    Impaired contraction is part of the diagnostic definition of the disease and
    is the parameter that treatment decisions are indexed to. No CRYAB-specific
    distribution of ejection fraction has been reported.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction"
    explanation: >-
      Impaired contraction is definitional for the disease class. Indirect
      because the source is a class-level review and not a CRYAB cohort.
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    The clinical syndrome that follows established systolic dysfunction —
    dyspnoea, fatigue, exercise intolerance and congestion.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM"
    explanation: >-
      Heart failure is the managed clinical state of this disease class.
      Indirect because it is a class-level statement.
- name: Cataract
  category: Ophthalmological
  description: >-
    Alpha-B crystallin is a lens protein as well as a muscle protein, and some
    CRYAB alleles declare themselves in the lens. In the reported stop-loss family
    the cataracts were bilateral and congenital, and were the only manifestation
    in the transmitting proband's child. Cataract is allele-dependent and is not
    a feature of the p.Arg157His cardiac-restricted presentation.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms"
    explanation: >-
      Documents cataract with dilated cardiomyopathy and, in the same sentence,
      the absence of myopathy that keeps this presentation outside the
      myofibrillar myopathy entry.
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle"
    explanation: >-
      Gives the expression basis for lens involvement alongside cardiac and
      skeletal muscle. Indirect because it is an expression statement rather than
      an observation of cataract in a CMD1II patient.
- name: Myocardial fibrosis
  category: Cardiovascular
  description: >-
    Interstitial and subendocardial fibrosis accompanying adverse remodeling.
    THIS IS A CLASS-LEVEL PHENOTYPE, NOT A CRYAB OBSERVATION. Interstitial
    fibrosis is a near-universal histological finding in dilated cardiomyopathy
    and is detectable in life as late gadolinium enhancement, but no quantified
    fibrotic burden for a CRYAB carrier is available in any source this entry
    cites, so the magnitude of this phenotype in CMD1II is unmeasured here. That
    is a statement about the reachable literature, not a claim that no such
    patient has been imaged: Orlando et al. 2025 (DOI:10.1002/ccr3.70213) report
    a CRYAB-associated dilated cardiomyopathy with restrictive physiology, and
    that record is cached abstract-only, so whatever tissue or imaging findings
    the full text may carry are not quotable here and cannot settle this either
    way. The phenotype is carried because it is the tissue correlate of the
    remodeling node the entry conforms to, and it is graded INDIRECT throughout
    for exactly that reason.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:29323059
    reference_title: "Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The histomorphological changes of DCM include myocyte hypertrophy, nucleomegaly, and interstitial fibrosis."
    explanation: >-
      Reports interstitial fibrosis as a histological finding of dilated
      cardiomyopathy in human myocardium (34 endomyocardial biopsies and 7
      explanted hearts against 41 control hearts). Indirect because the cohort
      is unselected dilated cardiomyopathy and contains no CRYAB carrier.
  - reference: PMID:33928704
    reference_title: "The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value"
    explanation: >-
      Establishes that myocardial fibrosis is measurable in living dilated
      cardiomyopathy patients and carries prognostic weight, which is why the
      phenotype is worth recording even though no CRYAB carrier's fibrotic
      burden is quotable from the sources this entry cites. Indirect for the
      same reason: the cohort is not CRYAB-selected.
- name: Restrictive physiology
  category: Cardiovascular
  description: >-
    Restrictive filling superimposed on a dilated, hypocontractile ventricle.
    Reported in a single CRYAB carrier (Orlando et al. 2025), which is the only
    CRYAB-specific clinical description this entry can cite beyond the founding
    p.Arg157His and p.Gly154Ser series. The cached record is abstract-only, so
    the report establishes that the presentation occurred without supplying the
    filling pressures, chamber volumes or imaging that would let this entry say
    how often it occurs or how severe it is; the frequency is left UNKNOWN for
    that reason rather than inferred from one case. The phenotype has no
    incoming causal edge because the abstract states no mechanism for the
    restrictive filling, and none of the entry's other sources addresses it.
  phenotype_term:
    preferred_term: Restrictive physiology
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  frequency: UNKNOWN
  evidence:
  - reference: DOI:10.1002/ccr3.70213
    reference_title: "An Unusual Case of <scp>11αB</scp> ‐Crystallin ( <scp>CRYAB</scp> ) Mutation as a Cause of Dilated Cardiomyopathy With Restrictive Physiology: A Case Report and Focused Review of the Literature"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "We report a case of dilated cardiomyopathy with restrictive physiology due to a CRYAB mutation."
    explanation: >-
      Direct report of a CRYAB carrier presenting with dilated cardiomyopathy
      and restrictive physiology. This is the source that bounds the entry's
      statements about unmeasured myocardium: it establishes that a published
      CRYAB carrier exists beyond the founding series, while its abstract-only
      cache carries no tissue or imaging finding to quote.
- name: Sudden cardiac death
  category: Cardiovascular
  description: >-
    A family history of sudden cardiac death accompanied the founding
    p.Arg157His report, and sudden death is a recognized outcome of dilated
    cardiomyopathy generally. No CRYAB-specific arrhythmic risk estimate exists,
    so no CRYAB-specific defibrillator threshold can be supported.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  frequency: UNKNOWN
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias"
    explanation: >-
      Establishes life-threatening arrhythmia as a recognized risk of this
      disease class. Indirect because no CRYAB-specific arrhythmia incidence has
      been reported.
diagnosis:
- name: Echocardiography
  description: >-
    First-line and usually sufficient to establish the phenotype: left
    ventricular internal dimensions and ejection fraction identify the dilated,
    hypocontractile chamber. The diagnosis is a clinical one and requires
    excluding loading conditions and coronary disease adequate to explain the
    findings, so the study is necessary but not sufficient on its own. Nothing
    about the imaging is CRYAB-specific.
  diagnosis_term:
    preferred_term: transthoracic echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling"
    explanation: >-
      Names echocardiography as the required modality for assessing the
      ventricular dysfunction that defines this disease class.
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the exclusions that make the imaging finding necessary but not
      sufficient for the diagnosis.
- name: Cardiac Magnetic Resonance Imaging with Late Gadolinium Enhancement
  description: >-
    CMR adds tissue characterisation to the chamber measurements, and with it the
    risk stratification that drives management in nonischemic dilated
    cardiomyopathy. In a meta-analysis of 103 studies and 29,687 patients, both
    the presence and the extent of late gadolinium enhancement predicted
    all-cause mortality and arrhythmic events, while ejection fraction — the
    number echocardiography gives you — did not predict either. No CMR finding
    from a CRYAB carrier is quotable from any source this entry cites, so this
    entry can say what the study would be for without saying what it shows in
    this genotype; see the `Myocardial fibrosis` phenotype, which is unmeasured
    here for the same reason, and which records the one CRYAB-specific case
    report that this entry cannot read past the abstract of.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Late gadolinium enhancement (LGE) presence and extent (per 1%) were associated with higher all-cause mortality"
    explanation: >-
      Establishes late gadolinium enhancement as the prognostic signal CMR adds
      beyond echocardiography. Indirect because the pooled cohorts are
      unselected nonischemic dilated cardiomyopathy, not CRYAB carriers.
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"
    explanation: >-
      The negative result that makes CMR worth curating separately from
      echocardiography: the echo-derived measure does not carry the mortality
      signal that late gadolinium enhancement does. Indirect for the same reason
      as the item above.
- name: Natriuretic Peptide Measurement
  description: >-
    Plasma BNP or NT-proBNP supports detection and staging of heart failure in a
    carrier with symptoms or borderline imaging, and is the practical serum
    marker for longitudinal follow-up. Its strength is exclusion rather than
    confirmation — a normal value rules heart failure out well, a raised one does
    not rule it in, which is why imaging remains the confirmatory step.
    High-sensitivity troponin and the routine metabolic, thyroid and iron studies
    that accompany a first cardiomyopathy workup are part of the same panel but
    are not separately evidenced in this entry. No CRYAB-specific threshold or
    distribution exists.
  diagnosis_term:
    preferred_term: NT-proBNP measurement
    term:
      id: NCIT:C96610
      label: N-Terminal ProB-type Natriuretic Peptide Measurement
  evidence:
  - reference: PMID:25740799
    reference_title: "The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      At the rule-out thresholds recommended in the 2012 European Society of
      Cardiology guidelines for heart failure, plasma B type natriuretic peptide,
      NTproBNP, and MRproANP have excellent ability to exclude acute heart
      failure.
    explanation: >-
      Quantified basis for using natriuretic peptides as the rule-out test in
      suspected heart failure. Indirect twice over: the setting is acute care
      rather than the chronic surveillance this entry describes, and the cohorts
      are unselected for genotype.
  - reference: PMID:25740799
    reference_title: "The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required."
    explanation: >-
      States the limit of the biomarker directly, which is why this entry orders
      the workup imaging-first and treats the peptide as an adjunct.
- name: Cardiomyopathy Multigene Panel Sequencing
  description: >-
    The confirmatory test is molecular. A curated cardiomyopathy panel that
    includes CRYAB is the appropriate first-line test, because dilated
    cardiomyopathy is genetically heterogeneous and the CRYAB phenotypes overlap
    other cardiomyopathies and the myofibrillar myopathies; both reported CMD1II
    ascertainments came through sequencing rather than through a clinical
    suspicion of alpha-B crystallinopathy. Exome or genome sequencing is the
    fallback for panel-negative familial disease. Interpretation is the hard
    part here, not detection: the number of reported CRYAB cardiac probands is
    very small, no ClinGen Gene-Disease Validity classification exists for the
    CRYAB-dilated cardiomyopathy relationship, and a novel CRYAB missense variant
    in a DCM proband will often be a variant of uncertain significance. Once a
    variant is established in a family, targeted cascade testing directs
    surveillance of relatives.
  diagnosis_term:
    preferred_term: cardiomyopathy multigene panel sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews chapter states the proband evaluation strategy that a
      gene-specific entry such as this one sits inside. Evidence source is OTHER
      because GeneReviews is an expert-authored review resource; note that the
      cached PubMed record for this chapter carries only its stated purpose, so
      no clinical-characteristics text could be mined from it.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome
    explanation: >-
      The GeneReviews purpose statement for relatives of a DCM proband: genetic
      risk assessment driving cardiac surveillance. This is the basis for the
      cascade-testing treatment recorded in this entry.
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant"
    explanation: >-
      Documents the sequencing route by which a CRYAB variant actually reached a
      dilated cardiomyopathy proband, and the diagnostic yield it sat in.
differential_diagnoses:
- name: CRYAB-related myofibrillar myopathy (alpha-B crystallinopathy with skeletal muscle disease)
  description: >-
    This is the differential this entry exists to draw. The same gene produces a
    myofibrillar myopathy in which skeletal muscle, not the heart, is the
    presenting problem, and in which cardiac involvement — when present — sits
    alongside distal and proximal weakness, cataract and respiratory failure. The
    boundary is allelic rather than clinical: p.Arg120Gly loses binding to both
    the heart-specific titin N2B domain and the striated-muscle-specific I26/I27
    domains and forms intracellular aggregates, whereas the founding CMD1II allele
    p.Arg157His loses only the N2B interaction and leaves the protein's
    distribution in cardiomyocytes unchanged. The boundary is also porous:
    p.Gly154Ser was reported first in isolated cardiomyopathy and later in a
    family with late-onset distal vacuolar myopathy and no cardiac dysfunction at
    all, so allele alone does not settle it. Curated in this knowledge base as
    `Myofibrillar_Myopathy`, subtype MFM2.
  disease_term:
    preferred_term: myofibrillar myopathy 2
    term:
      id: MONDO:0012130
      label: myofibrillar myopathy 2
  distinguishing_features:
  - Distal and later proximal skeletal-muscle weakness, dysphagia and respiratory
    muscle involvement, with elevated creatine kinase; absent in the reported
    cardiac-restricted CRYAB probands.
  - Protein aggregates containing alpha-B crystallin and desmin on skeletal muscle
    biopsy, which the founding CMD1II allele does not produce.
  - A neurological examination and a creatine kinase measurement separate the two
    at the bedside before any molecular result is available.
  evidence:
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein."
    explanation: >-
      The allele-versus-allele comparison that distinguishes the two entities at
      the molecular level.
  - reference: PMID:20171888
    reference_title: "The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction"
    explanation: >-
      Recorded as REFUTE against the claim that the differential is cleanly
      allelic: one allele appears on both sides of the line, which is exactly the
      uncertainty the `cmd1ii_entity_boundary` discussion carries.
- name: Syndromic alpha-B crystallinopathy with congenital cataract
  description: >-
    A CRYAB stop-loss allele, p.(Ter176TrpextTer19), produced dilated
    cardiomyopathy together with bilateral congenital cataracts and no myopathy —
    a third pattern that is neither the cardiac-restricted presentation nor
    myofibrillar myopathy. It matters diagnostically because the lens finding may
    be the first and, in a young relative, the only manifestation: the proband's
    ten-year-old child carried the same variant, had congenital cataracts, and was
    cardiologically unremarkable. A cataract in a CRYAB carrier is therefore an
    indication for cardiac surveillance rather than a reason to reclassify the
    family.
  distinguishing_features:
  - Bilateral congenital cataract accompanying dilated cardiomyopathy, with no
    skeletal myopathy.
  - The cardiac-restricted p.Arg157His presentation has no reported ocular
    finding; myofibrillar myopathy pairs cataract with muscle weakness.
  evidence:
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms"
    explanation: >-
      Documents the combination — cataract plus dilated cardiomyopathy, without
      myopathy — that defines this presentation and separates it from the
      myofibrillar entity.
- name: Dilated cardiomyopathy caused by another gene
  description: >-
    CRYAB is a minor contributor to a genetically crowded phenotype. Sarcomeric
    and desmosomal genes, and TTN and LMNA above all, account for far more
    familial dilated cardiomyopathy than CRYAB does, and several of them carry
    management consequences that CRYAB does not — LMNA in particular changes the
    defibrillator threshold. A CRYAB variant found on a panel should not close the
    analysis of the rest of the panel.
  distinguishing_features:
  - Conduction disease or early ventricular arrhythmia points to LMNA or FLNC
    rather than CRYAB.
  - Skeletal-muscle or ocular findings point back toward the CRYAB spectrum.
  - Segregation and gene-level validity evidence, not the variant call alone,
    should settle attribution.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome."
    explanation: >-
      Establishes the genetic heterogeneity that makes gene-level attribution the
      diagnostic problem. Indirect because it is a class-level statement that does
      not mention CRYAB.
- name: Acquired (nongenetic) dilated cardiomyopathy
  description: >-
    Myocarditis, toxic exposure, endocrine and autoimmune disease, tachycardia
    mediation, peripartum onset and ischemic disease all produce the same chamber
    phenotype. Because CMD1II presents in adulthood in a small number of families
    and has no distinguishing cardiac feature of its own, these are the causes
    that must be excluded before a CRYAB variant is treated as explanatory.
  distinguishing_features:
  - A history of toxic exposure, recent infection or pregnancy, or a regional
    rather than global wall motion abnormality.
  - Coronary imaging, and endomyocardial biopsy where inflammation or infiltration
    remains plausible.
  - A three-generation pedigree is the cheapest discriminator; its absence should
    raise the bar for calling a CRYAB variant causal.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Nongenetic forms of DCM can result from different aetiologies, including
      inflammation of the myocardium due to an infection (mostly viral); exposure
      to drugs, toxins or allergens; and systemic endocrine or autoimmune
      diseases.
    explanation: >-
      Enumerates the acquired causes that share the phenotype. Indirect because it
      is a class-level statement rather than a differential drawn against CRYAB.
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected"
    explanation: >-
      Names the test that adjudicates the inflammatory arm of this differential.
      Indirect because it is a class-level recommendation.
treatments:
- name: Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction
  description: >-
    There is no genotype-directed therapy for CRYAB-related dilated
    cardiomyopathy. Management is the standard heart-failure regimen — an
    angiotensin receptor-neprilysin inhibitor or ACE inhibitor, an evidence-based
    beta-blocker, a mineralocorticoid receptor antagonist, an SGLT2 inhibitor, and
    diuretics for congestion. The supporting trials enrolled unselected patients
    with reduced ejection fraction; none was CRYAB-stratified, and the benefit is
    recorded here as class-level rather than disease-specific.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan)
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: dapagliflozin
      term:
        id: CHEBI:85078
        label: dapagliflozin
    - preferred_term: carvedilol
      term:
        id: CHEBI:3441
        label: carvedilol
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  target_mechanisms:
  - target: Adverse Ventricular Remodeling and Myocardial Fibrosis
    description: >-
      Neurohormonal blockade and SGLT2 inhibition act on the shared remodeling
      stage of the pathograph rather than on the CRYAB lesion upstream of it.
    evidence:
    - reference: PMID:25176015
      reference_title: "Angiotensin-neprilysin inhibition versus enalapril in heart failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure."
      explanation: >-
        Establishes the benefit of neprilysin inhibition in heart failure with
        reduced ejection fraction. Indirect for this entry because the trial
        population was unselected for genotype.
  evidence:
  - reference: PMID:25176015
    reference_title: "Angiotensin-neprilysin inhibition versus enalapril in heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less"
    explanation: >-
      Defines the trial population whose results are being extended to CRYAB
      carriers, making the extrapolation explicit.
  - reference: PMID:31535829
    reference_title: "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      the risk of worsening heart failure or death from cardiovascular causes was
      lower among those who received dapagliflozin than among those who received
      placebo, regardless of the presence or absence of diabetes.
    explanation: >-
      Supports SGLT2 inhibition as a component of the regimen. Indirect because
      the trial was not genotype-stratified.
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for prevention of sudden cardiac death, indicated by general
    cardiomyopathy and arrhythmia guidelines. Noted here because a family history
    of sudden cardiac death accompanied the founding p.Arg157His report; no
    CRYAB-specific risk-stratification rule exists, so the standard
    ejection-fraction-based indication applies.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    description: >-
      The device does not modify the myocardial disease; it intercepts the
      arrhythmic outcome of the established organ-level lesion.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias"
      explanation: >-
        Supports defibrillator use in this disease class. Indirect because it is
        a class-level recommendation with no CRYAB-specific threshold.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."
    explanation: >-
      States the device indication for dilated cardiomyopathy generally.
- name: Cardiac Resynchronization Therapy
  description: >-
    Biventricular pacing for a dilated, dyssynchronous ventricle with systolic
    dysfunction and conduction delay. The indication follows general heart-failure
    criteria and not genotype; no reported CRYAB carrier has been described as
    receiving it, and no CRYAB-specific conduction phenotype has been established
    that would change the threshold.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    treatment_effect: MODULATES
    description: >-
      Resynchronizing contraction improves the mechanical efficiency of an
      already-dilated ventricle. It does not act on the chaperone lesion upstream.
    evidence:
    - reference: PMID:31073128
      reference_title: "Dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."
      explanation: >-
        Establishes resynchronization as part of standard management of this
        disease class. Indirect because the quoted sentence frames both devices in
        terms of arrhythmia prevention, whereas resynchronization's action on this
        node is mechanical.
  evidence:
  - reference: PMID:42475150
    reference_title: "Heart Failure With Reduced Ejection Fraction Update: A Review Of Clinical Trials and New Therapeutic Considerations."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Device therapies, such as implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT), and left ventricular assist devices (LVADs), are critical for advanced cases."
    explanation: >-
      Names resynchronization among the device therapies used in advanced heart
      failure with reduced ejection fraction. Indirect because the population is
      unselected for genotype.
- name: Advanced Heart Failure Therapy (mechanical circulatory support and transplantation)
  description: >-
    For disease refractory to medical and device therapy the remaining options are
    durable mechanical circulatory support and heart transplantation. This is
    curated as the endpoint of the generic dilated-cardiomyopathy pathway: no
    CRYAB carrier has been reported to have received either, and nothing in the
    titin-interaction or aggregation routes predicts a different response, so no
    genotype-specific claim is made. Note that both the cardiac and the
    myofibrillar CRYAB presentations can involve respiratory muscle weakness in
    the syndromic alleles, which is a candidate-selection consideration rather
    than a contraindication.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  notes: >-
    Mechanical circulatory support is named in the cited evidence alongside
    transplantation and is covered by this entry's description; `treatment_term`
    binds to transplantation because NCIT's device terms and the surgical modality
    cannot both be carried on one record.
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    treatment_effect: MODULATES
    description: >-
      Both options replace or unload the failing chamber rather than treating the
      myocardial disease that produced it.
    evidence:
    - reference: PMID:42475150
      reference_title: "Heart Failure With Reduced Ejection Fraction Update: A Review Of Clinical Trials and New Therapeutic Considerations."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "left ventricular assist devices (LVADs), are critical for advanced cases"
      explanation: >-
        Establishes mechanical circulatory support as part of the management of
        advanced heart failure with reduced ejection fraction, which is the state
        this node describes at its worst. Indirect because the population is
        unselected for genotype.
- name: Genetic Counseling and Cascade Testing of First-Degree Relatives
  description: >-
    Once a pathogenic CRYAB variant is established in a proband, targeted testing
    of first-degree relatives identifies carriers for cardiac surveillance. The
    stop-loss family makes the case concretely: the proband's child carried the
    same variant and had already declared the ocular phenotype while remaining
    cardiologically unremarkable, which is exactly the situation surveillance
    exists for.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant."
    explanation: >-
      Demonstrates that familial variant testing identifies at-risk relatives
      before cardiac disease appears. Indirect because the report describes the
      finding rather than evaluating a surveillance programme.
animal_models:
- name: CryAB R120G cardiomyocyte-targeted transgenic mouse
  species: Mouse
  genotype: Cardiomyocyte-restricted transgenic overexpression of CryAB p.Arg120Gly
  publication: PMID:11440982
  description: >-
    The reference model of cardiac alpha-B crystallinopathy. It is included here
    because it is the only in vivo evidence for the aggregation route, and it is
    explicitly NOT a model of CMD1II: the allele causes desmin-related myopathy
    rather than isolated dilated cardiomyopathy, the phenotype reported is
    hypertrophic rather than dilated, and the effect is dose-dependent on a
    transgene rather than produced at endogenous expression.
  modeled_mechanisms:
  - target: Alpha-B Crystallin and Desmin Aggregate Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces alpha-B crystallin and desmin aggregation with desmin filament
      disruption and myofibrillar misalignment in cardiomyocytes in vivo.
    limitations: >-
      p.Arg120Gly is a desmin-related myopathy allele and is not a reported cause
      of isolated dilated cardiomyopathy, and the phenotype is produced by
      transgenic overexpression, with a high-expressing line reaching 100%
      mortality by early adulthood. Severity is therefore an expression artefact
      as much as an allele effect.
    readouts:
    - name: Cardiomyocyte desmin filament integrity and myofibril alignment
      target: Alpha-B Crystallin and Desmin Aggregate Accumulation
      direction: DECREASED
      interpretation: >-
        Structural correlate of the aggregation node in this model.
      evidence:
      - reference: PMID:11440982
        reference_title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The desmin filaments in the cardiomyocytes were overtly affected, myofibril alignment was significantly impaired"
        explanation: >-
          Reports the histological measurement that grounds this readout.
    evidence:
    - reference: PMID:11440982
      reference_title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The data show that the R120G mutation causes a desminopathy, is dominant negative, and results in cardiac hypertrophy."
      explanation: >-
        Supports treating this model as informative for the aggregation node,
        while naming the hypertrophic phenotype that limits its relevance to
        dilated cardiomyopathy.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model does not reproduce the dilated phenotype that defines this entry.
    limitations: >-
      The reported cardiac response in this transgenic line is hypertrophic, at
      both the molecular and the cellular level, rather than dilated. Curating it
      as a model of dilated cardiomyopathy would misrepresent the published
      result.
    evidence:
    - reference: PMID:11440982
      reference_title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "a hypertrophic response occurred at both the molecular and cellular levels"
      explanation: >-
        States the phenotype the model produces, which is not the dilated
        phenotype of this disease.
- name: CryAB R120G Drosophila heart model
  species: Drosophila melanogaster
  genotype: Cardiac expression of human CryAB p.Arg120Gly
  publication: PMID:23818860
  description: >-
    An invertebrate model in which cardiac expression of the mutant chaperone
    impairs contractile function and enlarges the heart tube, and in which the
    phenotype is suppressed by reducing NADPH-generating enzyme activity —
    evidence that reductive stress is part of the downstream pathology.
  modeled_mechanisms:
  - target: Cardiomyocyte Sarcomeric Stress-Protection Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Cardiac expression of the mutant chaperone is sufficient to impair
      contractile function and increase chamber dimensions.
    limitations: >-
      The allele is p.Arg120Gly rather than a CMD1II allele, the organ is a
      Drosophila heart tube rather than a four-chambered mammalian heart, and the
      protein is expressed heterologously.
    readouts:
    - name: Cardiac function and heart tube dimension
      target: Cardiomyocyte Sarcomeric Stress-Protection Deficit
      direction: ALTERED
      interpretation: >-
        Functional correlate of the cardiomyocyte insult node in this model.
      evidence:
      - reference: PMID:23818860
        reference_title: "The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions"
        explanation: >-
          Reports the functional and dimensional measurements behind this readout.
    evidence:
    - reference: PMID:23818860
      reference_title: "The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it"
      explanation: >-
        Supports treating the model as informative for the cardiomyocyte insult
        node, since the phenotype is modifiable in the direction the redox
        hypothesis predicts.
discussions:
- discussion_id: cmd1ii_model_allele_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the p.Arg120Gly proteotoxic model of cardiac alpha-B crystallinopathy
    describe the mechanism of the alleles that actually cause isolated dilated
    cardiomyopathy?
  attaches_to:
  - "pathophysiology#Alpha-B Crystallin and Desmin Aggregate Accumulation"
  - "pathophysiology#Cardiomyocyte Sarcomeric Stress-Protection Deficit"
  rationale: >-
    Evidence for the aggregation route is not absent — it is abundant, detailed
    and in the wrong allele. Every in vivo and cell system cited for cardiac
    alpha-B crystallinopathy uses p.Arg120Gly, which causes desmin-related
    myopathy and which the founding CMD1II paper singles out as behaving
    differently: p.Arg120Gly loses binding to both the heart-specific N2B domain
    and the striated-muscle-specific I26/I27 domains and forms intracellular
    aggregates, while p.Arg157His loses only the N2B interaction and does not
    redistribute. The mouse model compounds the mismatch by producing a
    hypertrophic rather than a dilated phenotype, and by producing it from a
    transgene whose expression level sets the severity. So the well-supported
    mechanism belongs to a neighbouring disease, and the disease curated here has
    a binding measurement and no allele-matched model at all. This is the reason
    the two routes are separated into hypothesis groups instead of being merged
    into one chain.
  proposed_experiments:
  - experiment_id: exp_cmd1ii_r157h_knockin_mouse
    name: Knock-in mouse carrying the CRYAB p.Arg157His allele at endogenous expression
    description: >-
      Generate a heterozygous knock-in of p.Arg157His or its murine equivalent
      and phenotype the heart for chamber dimensions, ejection fraction, fibrosis
      and aggregate burden. This is the experiment that would show whether the
      titin N2B binding defect is sufficient to cause dilated cardiomyopathy, and
      whether it does so without the aggregation that defines the neighbouring
      myofibrillar disease.
    would_support:
    - "pathophysiology#Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain"
    supporting_outcome:
    - >-
        Progressive left ventricular dilation with reduced ejection fraction in
        heterozygous knock-in animals, with no alpha-B crystallin or desmin
        aggregates on immunohistochemistry.
    would_refute:
    - "pathophysiology#Loss of Alpha-B Crystallin Binding to the Cardiac Titin N2B Domain"
    refuting_outcome:
    - >-
        Normal cardiac dimensions and function through the animals' lifespan,
        indicating that the measured binding defect is not by itself sufficient to
        produce disease.
  - experiment_id: exp_cmd1ii_ipsc_cardiomyocyte_titin_strain
    name: Patient-derived iPSC cardiomyocytes under mechanical load
    description: >-
      Differentiate cardiomyocytes from a p.Arg157His carrier and an isogenic
      corrected control, and measure titin-based passive stiffness, sarcomere
      integrity and contractile function under increasing mechanical and thermal
      stress. This tests the stress-protection step directly in human cells, which
      is the step currently carried as inference.
    would_support:
    - "pathophysiology#Cardiomyocyte Sarcomeric Stress-Protection Deficit"
    supporting_outcome:
    - >-
        Variant cardiomyocytes show sarcomere disorganization and contractile
        failure at stress levels the isogenic control tolerates.
- discussion_id: cmd1ii_entity_boundary
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do CRYAB alleles partition cleanly enough into cardiac-restricted and
    myofibrillar groups to justify two knowledge-base entries rather than one?
  attaches_to:
  - "disease#Dilated Cardiomyopathy 1II"
  - "genetic#CRYAB"
  rationale: >-
    This entry is curated as a sibling of the alpha-B crystallinopathy subtype of
    `Myofibrillar_Myopathy` rather than as a subtype of it, on the strength of a
    single allele-versus-allele biochemical comparison and a small number of
    cardiac-restricted patients. The counter-evidence is real and is recorded
    rather than argued away: p.Gly154Ser was first reported in isolated
    cardiomyopathy and later found in a family with late-onset distal vacuolar
    myopathy and no cardiac dysfunction, so at least one allele sits on both
    sides of the boundary. What would settle it is a systematic
    genotype-phenotype study across reported CRYAB carriers, and a ClinGen
    Gene-Disease Validity curation of the CRYAB-dilated cardiomyopathy
    relationship, which the ClinGen release cached in this repository does not
    contain. Until then the split is a mechanistic judgement, not a demonstrated
    partition, and a future curator with better data should feel free to reverse
    it.
  proposed_experiments:
  - experiment_id: exp_cmd1ii_genotype_phenotype_survey
    name: Systematic genotype-phenotype survey of reported CRYAB variant carriers
    description: >-
      Assemble every published CRYAB carrier with allele, cardiac imaging,
      skeletal-muscle assessment and ophthalmic examination, and test whether
      cardiac-restricted disease associates with alleles that spare the
      striated-muscle-specific titin domains. This is the analysis that would turn
      the present mechanistic argument into an empirical one.
  evidence:
  - reference: PMID:20171888
    reference_title: "The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction"
    explanation: >-
      Counts against a clean allelic partition: an allele reported in isolated
      cardiomyopathy also produces aggregate-positive distal myopathy with no
      cardiac involvement, which is the myofibrillar phenotype in a supposedly
      cardiac allele.
  - reference: PMID:16483541
    reference_title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "its disease-causing mechanism is different from the mutation found in desmin-related myopathy"
    explanation: >-
      The primary statement that the founding CMD1II allele acts by a different
      mechanism from the myofibrillar myopathy allele, which is the basis for
      curating the two as separate entities.
notes: >-
  Relationship to other entries. `Myofibrillar_Myopathy` curates the
  alpha-B crystallinopathy that presents with skeletal-muscle disease, including
  the dominant p.Arg120Gly adult-onset form and the recessive fatal infantile
  hypertonic form; its MFM2 subtype is bound to MONDO:0012130. This entry curates
  the cardiac-restricted presentation bound to MONDO:0014073. The two are
  siblings under alpha-B crystallinopathy. A `kb/groupings/` entry uniting the
  CRYAB-related phenotypes would be a reasonable follow-up and is deliberately
  not created here, since it would need the DES, BAG3 and other chaperone
  entries considered alongside it rather than being assembled around one gene in
  passing.


  Gene identifier. Issue #10634 and the stub give the causal gene as
  `hgnc:2388`. That CURIE is CRYAA (alpha-A crystallin). CRYAB is `hgnc:2389`,
  which is what this entry and the pre-existing `Myofibrillar_Myopathy` entry
  both use.


  Deep-research provenance. The Edison/falcon report
  `research/Dilated_Cardiomyopathy_1II-deep-research-falcon.md` was read as a
  lead. Its prose is not quoted, because its substantive claims are attributed
  to page ranges in unnamed sources rather than to identifiable statements. Its
  reference list was screened individually: one reference is specific to this
  disease, the Orlando et al. 2025 CRYAB case report (DOI:10.1002/ccr3.70213),
  and it is cited above for restrictive physiology; the others are
  general-cardiology or myofibrillar-myopathy background and are not used. Its
  most useful contribution was negative: it
  flags clearly that R120G findings are supporting biology rather than proof of
  the mechanism of every CMD1II allele, and that framing survives into this
  entry. Every reference cited above was fetched independently.


  Datasets. `just discover-datasets Dilated_Cardiomyopathy_1II` was run and
  returned six candidates, all of them GENE_ONLY matches on CRYAB and none of them
  about this disease. The two human hits are an ovarian-carcinoma expression study
  and a Wnt/lncRNA study that happen to mention CRYAB; the four mouse hits are the
  p.Arg120Gly heart and lens models, which belong to the neighbouring myofibrillar
  entity this entry is deliberately separate from. This is the Named Entity
  Confusion pattern reached through dataset search — every accession resolves, and
  none of them is evidence about CMD1II — so `datasets:` is left empty rather than
  filled with accessions that would have to be discounted on the page. Recorded
  here so the search is not repeated.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:16483541
  title: "Alpha B-crystallin mutation in dilated cardiomyopathy."
  findings: []
- reference: DOI:10.1002/ccr3.70213
  title: "An Unusual Case of <scp>11αB</scp> ‐Crystallin ( <scp>CRYAB</scp> ) Mutation as a Cause of Dilated Cardiomyopathy With Restrictive Physiology: A Case Report and Focused Review of the Literature"
  findings: []
- reference: PMID:9731540
  title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
  findings: []
- reference: PMID:20171888
  title: "The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy."
  findings: []
- reference: PMID:38212463
  title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
  findings: []
- reference: PMID:11440982
  title: "Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice."
  findings: []
- reference: PMID:23818860
  title: "The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster."
  findings: []
- reference: PMID:31073128
  title: "Dilated cardiomyopathy."
  findings: []
- reference: PMID:29323059
  title: "Histological and morphometric analysis of dilated cardiomyopathy with special reference to collagen IV expression."
  findings: []
- reference: PMID:33928704
  title: "The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy."
  findings: []
- reference: PMID:39298146
  title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
  findings: []
- reference: PMID:25740799
  title: "The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting."
  findings: []
- reference: PMID:25176015
  title: "Angiotensin-neprilysin inhibition versus enalapril in heart failure."
  findings: []
- reference: PMID:31535829
  title: "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction."
  findings: []
- reference: PMID:42475150
  title: "Heart Failure With Reduced Ejection Fraction Update: A Review Of Clinical Trials and New Therapeutic Considerations."
  findings: []

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References & Deep Research