Congenital Myopathy 21 With Early Respiratory Failure

Disease knowledge-base research report — evidence reviewed through 15 October 2026

Executive summary

Congenital myopathy 21 with early respiratory failure (CMYO21) is an ultra-rare, autosomal-recessive protein-aggregate/myofibrillar myopathy caused by biallelic pathogenic variants in DNAJB4. Its defining clinical combination is disproportionate diaphragmatic/respiratory-muscle weakness, often producing nocturnal hypoventilation or abrupt hypercapnic respiratory failure, together with axial rigidity or rigid-spine syndrome. Limb strength can remain nearly normal despite life-threatening respiratory disease. Onset ranges from infancy to the fifth decade, with J-domain missense variants associated in a small cohort with substantially earlier onset and higher mortality. [54][47]

The principal mechanism is failure of the DNAJB4 HSP40 co-chaperone at the myofibrillar Z-disc. This disrupts HSP70-assisted protein quality control, permits accumulation of myofibrillar/Z-disc proteins, and produces sarcomeric disorganization, protein inclusions, muscle-fiber atrophy and particularly severe diaphragm involvement. This causal interpretation is supported by human genetics, patient tissue, cultured cells, yeast complementation, CRISPR-knockout myotubes and knockout mice. [54]

No disease-modifying treatment is approved. Current practice is proactive respiratory surveillance, bilevel non-invasive ventilation, cough assistance and airway clearance, plus cardiac, swallowing, nutritional, orthopedic and rehabilitation care. Gene replacement is a plausible but preclinical concept, not a clinical intervention. [106][191]

Evidence limitation: CMYO21 was defined only in 2022–2023, and published cohorts remain very small. Frequencies and genotype–phenotype associations should therefore be treated as provisional rather than population estimates.

Key evidence sources

Two particularly informative abstract statements are:

“Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life.” [54]

“Missense variants in the J-domain may predict a more severe phenotype.” [47]

1. Disease information

1.1 Definition

CMYO21 is a Mendelian, autosomal-recessive skeletal-muscle chaperonopathy due to biallelic DNAJB4 variants. It is characterized primarily by:

• Diaphragmatic weakness and restrictive/hypercapnic respiratory failure;
• Nocturnal hypoventilation or sudden respiratory decompensation;
• Rigid spine, neck stiffness and axial weakness;
• Relatively mild or absent appendicular weakness in many patients;
• Myofibrillar disorganization, protein aggregates and sometimes rimmed vacuoles on biopsy.

The label “congenital” refers to its classification among congenital myopathies, but symptoms are not necessarily present at birth: documented onset extends from approximately three months to 45 years. [47][154]

1.2 Identifiers and synonyms

The MONDO, OMIM, MedGen and gene-location assignments are reported in MedGen and OMIM. [1][144] The parent Orphanet/ICD mappings are ORPHA:97245, ICD-10 G71.2 and ICD-11 8C72. [149]

1.3 Data provenance

This report is aggregated disease-level evidence, not an extraction from a single EHR. It synthesizes:

• Published individual-patient and pedigree data;
• Disease resources such as OMIM, MedGen, MONDO and ClinVar;
• Cohort-level functional experiments;
• General congenital-myopathy care guidance.

Because cohorts are tiny, much of the phenotype evidence ultimately traces to identifiable case-series participants rather than registry-scale epidemiology.

2. Etiology

2.1 Causal factor

The primary cause is biallelic germline pathogenic or likely pathogenic variation in DNAJB4, encoding DNAJ/HSP40 family member B4. The disease mechanism is predominantly loss of function:

• Truncating variants produce absent or rapidly degraded protein;
• p.Leu262Ser destabilizes the protein;
• J-domain variants such as p.Arg25Gln, p.Lys35Asn and p.Arg61Gly can be stable but functionally defective in chaperone assays. [54][47]

No infectious, toxic, nutritional or environmental cause is established.

2.2 Risk factors

Genetic

• Homozygosity or compound heterozygosity for deleterious DNAJB4 alleles;
• Parental consanguinity, which increases the probability of homozygosity for rare recessive alleles;
• Positive family history of compatible respiratory/rigid-spine myopathy;
• Preliminary evidence suggests J-domain missense variants confer more severe disease than truncating or C-terminal variants: median onset 0.5 versus 28 years and mortality 75% versus 14% in the small comparison, respectively. [47]

Environmental and acquired

No environmental exposure is known to cause CMYO21. Respiratory infections, aspiration, surgery, anesthesia or sedative medications may precipitate decompensation in someone who already has respiratory-muscle weakness, but they are complications or stressors, not proven etiologic factors.

Age is not a causal risk factor, although expression is age-dependent in adult-onset cases. No credible sex-specific biological risk has been established; the male predominance in one recent series—six males and one female—is likely vulnerable to ascertainment and family-size effects. [47]

2.3 Protective factors

No protective allele, modifier gene, diet or lifestyle exposure has been demonstrated. Potentially protective clinical practices include early detection of nocturnal hypoventilation, vaccination, infection avoidance, cough augmentation and timely ventilation, but these prevent complications rather than prevent the genotype or underlying myopathy.

2.4 Gene–environment interactions

No formal gene–environment interaction study exists. Heat-shock experiments showed that mutant DNAJB4 impaired clearance of TDP-43 aggregates and protection from heat-induced cell death, suggesting that cellular proteotoxic stress can expose deficient chaperone reserve. Extrapolation from this in-vitro result to environmental heat exposure in patients is not established. [54]

3. Phenotypes

3.1 Phenotype summary and suggested HPO annotations

Frequencies below refer where possible to the seven affected individuals in the 2024 cohort, not to a population registry. Patient ascertainment specifically for early respiratory disease inflates respiratory-feature frequencies.

Established HPO identifiers for spinal rigidity, diaphragmatic weakness and respiratory failure are HP:0003306, HP:0009113 and HP:0002878. [284] Axial weakness is HP:0003327. [273]

3.2 Negative or uncommon findings

Several affected persons retained normal gait, limb strength, motor milestones, facial movement, ocular movement, bulbar function and cognition despite severe respiratory disease. Absence of conspicuous appendicular weakness therefore does not exclude CMYO21. [54]

No disease-specific EQ-5D, SF-36, PROMIS or other formal quality-of-life study has been published. Expected major burdens are ventilator dependence, restricted spine movement, repeated respiratory admission, feeding-tube dependence and caregiver requirements.

4. Genetic and molecular information

4.1 Causal gene

NCBI lists ATPase-activator activity and Z-disc localization for DNAJB4. [91] OMIM places CMYO21 at 1p31.1 with recessive inheritance. [144]

4.2 Reported recessive disease variants

Reference transcript: NM_007034.5.

Four variants—p.Lys286Ter, p.Leu262Ser, p.Arg25Gln and p.Arg61Gly—had disease-specific ClinVar pathogenic records in the retrieved dataset. [166] The 2024 cohort reported the remaining variants as pathogenic but did not give variant-specific formal ACMG evidence codes. Frequencies and functional results are from that peer-reviewed study. [47]

All disease-causing variants are constitutional/germline, not somatic.

Important allelic distinction

Heterozygous DNAJB4 c.270T>A, p.Phe90Leu causes a separate autosomal-dominant distal myopathy, not recessive CMYO21. It produces late-onset hand/distal weakness with protein inclusions and later respiratory involvement. [90] It should not be merged into the CMYO21 variant set.

4.3 Functional consequence

The best-supported overarching mechanism is loss of DNAJB4 co-chaperone function. A purely haploinsufficient mechanism is unlikely for CMYO21 because heterozygous carriers are clinically unaffected. Stable J-domain mutants may also acquire abnormal interactions with HSP70, but a toxic component remains speculative. [47]

4.4 Modifier genes, epigenetics and chromosomal abnormalities

• Modifier genes: none established.
• Protective alleles: none established.
• Disease-specific epigenetic signature: none reported.
• Large cytogenetic abnormality: no recurrent aneuploidy, translocation or inversion is associated.
• A homozygous single-exon deletion is known, so exon-level CNV analysis is diagnostically relevant.
• No pathogenic repeat expansion or mitochondrial-DNA mechanism is known.

5. Environmental information

6. Mechanism and pathophysiology

6.1 Ordered causal chain

1. Biallelic pathogenic DNAJB4 variation leads to absent, unstable or functionally defective DNAJB4 co-chaperone in skeletal myofibers.
2. Defective DNAJB4 leads to impaired recognition/handling of unfolded or damaged client proteins and impaired recruitment of those clients to HSP70 at or near the myofibrillar Z-disc.
3. Impaired DNAJB4–HSP70 proteostasis leads to deficient protein refolding/disaggregation and accumulation of client, Z-disc and stress-chaperone proteins; the exact disease-driving client proteins remain incompletely identified.
4. Protein accumulation leads to desmin-, myotilin- and related protein-positive inclusions, insoluble aggregates, Z-disc streaming and sarcomeric/myofibrillar disorganization.
5. Myofibrillar disruption leads to reduced muscle-fiber integrity, fiber-size variation, angular/atrophic fibers, core-like areas, occasional rimmed vacuoles and progressive loss of contractile capacity.
6. Preferential injury or limited reserve in diaphragm and axial muscles leads to diaphragmatic weakness, reduced chest expansion, axial weakness, neck stiffness and rigid spine. Why the diaphragm is disproportionately affected is strongly demonstrated phenotypically but mechanistically inferred, not fully resolved.
7. Diaphragm/chest-wall weakness leads to reduced tidal volume, restrictive ventilatory physiology and sleep-first alveolar hypoventilation.
8. Progressive hypoventilation leads to hypercapnia, dyspnea, morning/sleep symptoms and eventually acute or chronic respiratory failure, ventilator dependence or death.
9. Branch A: axial weakness and contracture lead to scoliosis and further mechanical restriction, which can compound respiratory failure.
10. Branch B: bulbar weakness/dysphagia leads to aspiration, recurrent lower respiratory infection and feeding-tube dependence.
11. Branch C: cardiac-muscle involvement in a subset leads to hypertrophic cardiomyopathy or valvular dysfunction; this branch is clinically observed, but the precise cardiomyocyte mechanism is not specifically demonstrated.

6.2 Molecular and cellular detail

DNAJB4 is a type-II DNAJ/HSP40 co-chaperone. DNAJ proteins bind selected clients and stimulate HSP70 ATP hydrolysis, thereby promoting folding, disaggregation or degradation. In muscle, wild-type DNAJB4 co-localizes with α-actinin at the Z-disc. [54][95]

Human evidence

Patient muscle showed:

• Loss or marked reduction of DNAJB4;
• Z-disc streaming and sarcomeric disorganization;
• Dense granulofilamentous material;
• Desmin- and myotilin-positive inclusions;
• Fiber atrophy and occasional rimmed vacuoles.

The p.Lys286Ter and p.Leu262Ser proteins were rapidly degraded. p.Arg25Gln retained Z-disc localization but failed functional tests, separating localization from chaperone competence. [54]

In-vitro evidence

CRISPR Dnajb4-knockout C2C12 cells differentiated into myotubes but showed:

• Increased myoblast fusion/myonuclei per myotube;
• Increased desmin and α-actinin;
• Insoluble DNAJB6, CRYAB and desmin;
• Desmin, actin and myotilin aggregates.

HeLa-cell heat-shock assays showed persistent nuclear TDP-43 aggregates with disease variants. TDP-43 was an experimental client/readout; it is not yet proven to be the principal human muscle disease substrate. [54][47]

Model-organism evidence

Dnajb4-null mice developed kyphosis, reduced hanging-grid endurance, lower hindlimb muscle weights, diaphragm thinning and marked diaphragm-fiber atrophy. Knockout muscle accumulated desmin, myotilin, α-actinin, HSPA1 and CRYAB. [54]

Pathways and processes

No canonical oncogenic-style pathway such as Wnt, MAPK or PI3K–AKT has been shown to drive CMYO21. The central pathway is the DNAJ–HSP70 proteostasis network.

Suggested ontology annotations:

GO:0006457 denotes protein folding and GO:0051085 cofactor-dependent protein refolding. [252][254] Relevant cell-ontology identifiers include skeletal-muscle myoblast CL:0000515 and myotube CL:0002372. [241]

6.3 Metabolism, immunity and tissue injury

• No reproducible metabolomic or lipidomic disease signature exists.
• Core-like regions and diminished oxidative-enzyme staining occur, but there is no established primary mitochondrial enzyme deficiency.
• No primary autoimmune or inflammatory mechanism has been demonstrated.
• Rare necrotic fibers, fibrosis and fatty replacement are downstream tissue injury, not the initiating lesion.
• Autophagic involvement is suggested by rimmed vacuoles/protein aggregates, but a disease-specific autophagy defect has not been proven.

6.4 Molecular profiling and advanced technologies

In broader neuromuscular diagnostics, integrated genome/RNA/protein analysis increased family-level diagnostic yield from approximately 40% to over 60%, but this is general evidence rather than a CMYO21-specific validation. [301]

7. Anatomical structures affected

8. Temporal development

8.1 Onset patterns

Two provisional clinical patterns emerge:

1. Infantile/childhood pattern: neck stiffness or respiratory disease in the first year, followed by rigid spine, contractures, dysphagia and severe respiratory failure. This is enriched for J-domain missense variants.
2. Adult pattern: insidious weight loss or mild weakness followed by abrupt dyspnea, syncope, respiratory arrest or hypercapnic failure, sometimes with little limb weakness.

Reported first symptoms range from approximately three months to 45 years. [47]

8.2 Progression

• Chronic, lifelong and generally progressive;
• No established relapsing-remitting course;
• Respiratory symptoms may appear suddenly after a clinically silent period;
• Infantile J-domain disease can progress to death before adulthood;
• Adult cases may remain ambulant while requiring nocturnal ventilation;
• No spontaneous molecular remission is reported.

Practical stages are:

1. Presymptomatic/genetic stage;
2. Early axial or sleep-related stage—neck stiffness, reduced chest expansion or nocturnal symptoms;
3. Established respiratory stage—reduced FVC, nocturnal hypercapnia, recurrent infection;
4. Advanced stage—daytime hypercapnia, prolonged ventilation, tracheostomy, dysphagia and cardiopulmonary complications.

The key intervention window is before daytime respiratory failure, when sleep CO₂ abnormalities, supine FVC decline or weak cough may first be detectable.

9. Inheritance and population

9.1 Inheritance

• Autosomal recessive;
• Parents of affected persons are usually clinically unaffected heterozygotes;
• For two confirmed carrier parents, each pregnancy has a theoretical:
• 25% affected risk;
• 50% carrier risk;
• 25% non-carrier/unaffected probability.
• Penetrance for clearly pathogenic biallelic genotypes appears high but has not been quantified.
• Expressivity is markedly variable, from infantile fatal respiratory disease to adult-onset respiratory failure.
• No genetic anticipation is established.
• Germline mosaicism has not been reported but cannot be excluded as a general counseling consideration.
• Consanguinity is prominent in severe pediatric families, although unrelated non-consanguineous Spanish patients demonstrate that it is not required. [54][47]

9.2 Epidemiology

No population prevalence, birth prevalence or annual incidence has been calculated for CMYO21. Published evidence through 2024 comprised only a small number of families, so it is appropriately considered ultra-rare.

For context—not a CMYO21 estimate—the pooled prevalence of all congenital myopathies was 1.62 per 100,000 overall and 2.76 per 100,000 children in a systematic review. [151]

No founder variant is established. Families have been reported from Spain, Saudi Arabia, Oman, Turkey, Colombia and an adult European diagnostic cohort, arguing for broad geographic distribution. [47][54]

Carrier frequency cannot be reliably computed from current data. All individually enumerated pathogenic alleles are absent or extremely rare in gnomAD and were not observed homozygously in population controls. [47]

9.3 Demographics

• Both sexes are affected.
• No valid male:female ratio can be inferred.
• Age distribution spans infancy through at least the seventh decade.
• No ethnicity-specific susceptibility is established beyond ascertainment in consanguineous populations.

10. Diagnostics

10.1 When to suspect CMYO21

Strong diagnostic clues are:

• Unexplained hypercapnic or restrictive respiratory failure;
• Diaphragm weakness out of proportion to limb weakness;
• Infantile neck stiffness or rigid-spine syndrome;
• Preserved ambulation despite severe respiratory impairment;
• Normal or mildly increased CK;
• Selective hamstring abnormalities on muscle MRI;
• Myofibrillar protein inclusions, Z-disc streaming or rimmed vacuoles;
• Recessive family history or consanguinity.

The 2024 authors specifically recommend considering DNAJB4 when an infant has neck stiffness or an adult develops respiratory failure without prominent limb weakness. [188]

10.2 Clinical investigations

10.3 Genetic-testing strategy

1. First line: a comprehensive congenital-myopathy, rigid-spine or neuromuscular panel that includes DNAJB4 and exon-level deletion/duplication analysis.
2. Alternative first line: trio WES or genome sequencing, especially with atypical, multisystem or nonspecific respiratory presentations.
3. Confirmatory testing: Sanger confirmation and parental segregation for SNVs/indels; orthogonal CNV confirmation for exon deletion.
4. If negative: reanalyse exome data as gene–disease knowledge evolves. The c.308del diagnosis was found through reanalysis after the DNAJB4 association became known. [318]
5. If still unresolved: WGS for structural/deep-intronic variants and muscle/fibroblast RNA studies for aberrant splicing or expression.
6. Single-gene testing: reasonable in a highly specific phenotype or known familial variant.
7. CMA/karyotype/FISH: low yield for isolated CMYO21; CMA may identify broad CNVs but is not the preferred test for small DNAJB4 variants.
8. Mitochondrial DNA and repeat-expansion testing: not CMYO21 tests; use only when the differential suggests another disease.

DNAJB4 is a green/high-evidence gene on the NHS congenital-myopathy panel, which uses WES or medium-panel testing with exon-level CNV analysis. [288][296]

10.4 Diagnostic criteria

No validated scoring system or formal society criteria exist. A molecular diagnosis requires:

• A compatible phenotype;
• Two pathogenic/likely pathogenic DNAJB4 alleles in trans or a confirmed homozygous allele;
• Appropriate segregation;
• Exclusion of the separate dominant p.Phe90Leu distal-myopathy phenotype.

A VUS should not be considered diagnostic without segregation, population, functional and phenotype evidence.

10.5 Differential diagnosis

These pediatric and adult differentials are explicitly discussed in the 2023 and 2024 primary studies. [316][321]

10.6 Screening

• No population or newborn screening program exists.
• Cascade genetic testing is appropriate for adult relatives after a familial variant is identified.
• Test symptomatic relatives promptly even when limb strength is normal.
• Asymptomatic biallelic relatives should receive baseline pulmonary, sleep, cardiac and swallowing assessment.
• Carrier testing is appropriate for reproductive partners in families where the familial allele is known.

11. Outcome and prognosis

11.1 Survival and mortality

No valid five-year, ten-year or median-survival estimate exists. Outcomes range from preserved ambulation into adulthood to death in infancy or childhood from respiratory disease.

In the small genotype comparison:

• J-domain variants: 75% mortality;
• Other variants: 14% mortality;
• P = 0.046.

The corresponding onset ages were 0.5 versus 28 years, P = 0.035. These are hypothesis-generating results from very small groups, not stable prognostic percentages. [47]

Documented severe outcomes include:

• Death at 11 months;
• Death at ages seven, nine and 11 years;
• Tracheostomy and near-continuous ventilation;
• Adult respiratory arrest and syncope;
• Long-term nocturnal non-invasive ventilation.

11.2 Morbidity

Major morbidity arises from:

• Chronic ventilatory insufficiency;
• Recurrent pneumonia and weak secretion clearance;
• Dysphagia, aspiration and feeding-tube dependence;
• Rigid spine, scoliosis and contractures;
• Cardiomyopathy in a subset;
• Reduced independence and caregiver burden.

No standardized disease-specific quality-of-life instrument has been validated.

11.3 Prognostic factors

Probable adverse factors are:

• J-domain missense genotype;
• Infantile onset;
• Early neck stiffness or rigid spine;
• Declining FVC, especially supine;
• Sleep or daytime hypercapnia;
• Recurrent lower respiratory infection;
• Dysphagia/aspiration;
• Cardiac involvement.

No molecular or circulating prognostic biomarker has been validated. CK does not reliably track severity.

Recovery of lost muscle function is not documented. Ventilation can correct hypoventilation and substantially improve safety and symptoms, but it does not reverse the underlying chaperonopathy.

12. Treatment

12.1 Current strategy

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy or cell therapy for CMYO21. Treatment is supportive and should be coordinated by neuromuscular, respiratory, cardiology, nutrition/swallowing, rehabilitation and orthopedic teams. A 2025 mechanistic review confirmed that no mechanism-based therapy is approved for any J-domain-protein myopathy. [191]

12.2 Interventions

Congenital-myopathy consensus guidance recommends at least annual spirometry, inspiratory/expiratory pressures, peak cough flow and oximetry in low-risk patients, with more frequent testing in high-risk patients. Bilevel ventilation is recommended for hypoventilation, while CPAP alone is insufficient. [106]

Practical respiratory algorithm

1. Obtain sitting and supine spirometry, inspiratory/expiratory pressures and peak cough flow.
2. Perform overnight oximetry with transcutaneous or end-tidal CO₂, or full polysomnography.
3. Start nocturnal bilevel ventilation when hypoventilation/hypercapnia or clinically significant respiratory-muscle weakness appears.
4. Add cough augmentation and secretion clearance early.
5. During infection, increase airway clearance and ventilation and avoid treating hypoventilation with oxygen alone.
6. Escalate to invasive support for severe failure or when NIV cannot maintain ventilation/airway protection.

12.3 Pharmacotherapy and pharmacogenomics

No drug has demonstrated a CMYO21-specific response rate. Bronchodilators, antibiotics, analgesics and cardiology medications should be used for standard indications, not as treatment of DNAJB4 deficiency.

No CMYO21-specific CPIC, PharmGKB or FDA pharmacogenomic guidance exists.

12.4 Experimental treatment

Conceptual strategies include:

• AAV-mediated DNAJB4 gene replacement for recessive loss of function;
• Enhancement of HSP70/proteostasis capacity;
• Substrate reduction for aggregation-prone clients;
• Manipulation of DNAJ–HSP70 interactions.

Gene replacement remains preclinical and faces skeletal-muscle/diaphragm delivery, immune and durability challenges. [191] No CMYO21-specific interventional ClinicalTrials.gov study or NCT identifier was found.

13. Prevention

13.1 Primary prevention

The genotype cannot be prevented by lifestyle change or vaccination. Reproductive options after identifying familial variants include:

• Preconception carrier testing;
• Partner testing;
• Prenatal diagnosis by chorionic-villus sampling or amniocentesis;
• IVF with preimplantation genetic testing for monogenic disease;
• Donor gametes or other family-planning options.

13.2 Secondary prevention

• Cascade testing of siblings and relatives;
• Pulmonary and sleep evaluation before symptoms;
• Early echocardiography and swallow assessment;
• Periodic reanalysis of negative genomic results in strongly suggestive families;
• Early institution of ventilation before daytime respiratory failure.

13.3 Tertiary prevention

• NIV and cough assistance to reduce hypoventilation and secretion retention;
• Vaccination against influenza, COVID-19 and pneumococcal disease according to age/risk schedules;
• Aspiration precautions and enteral feeding where required;
• Contracture prevention, orthopedic surveillance and bone-health support;
• Cardiac surveillance;
• Respiratory/anesthetic planning before surgery;
• Avoid unnecessary respiratory depressants and carefully monitor opioids, sedatives and anesthesia.

No public-health sanitation or vector-control intervention is applicable because the disorder is neither infectious nor environmentally transmitted.

14. Other species and naturally occurring disease

14.1 Orthologs and taxonomy

Mouse, rat and zebrafish stringent orthology is listed by MGI, and the zebrafish Gene ID is 445061. [196][197]

14.2 Natural veterinary disease and transmission

No naturally occurring DNAJB4-related myopathy was identified in OMIA or veterinary case literature, and no breed-specific VBO annotation is established. Consequently:

• Veterinary prevalence and breed risk are unknown;
• There is no zoonotic potential;
• There is no horizontal or cross-species transmission;
• Conservation is relevant to comparative muscle proteostasis, not infectious susceptibility.

15. Model organisms and experimental systems

The knockout mouse was viable at Mendelian ratios but developed kyphosis, weakness and particularly severe diaphragm atrophy, closely matching the anatomical selectivity of human disease. [230] MGI identifies mouse Dnajb4 as MGI:1914285/NCBI Gene 67035. [227]

Knowledge-base conclusions

1. Definitive disease–gene relationship: CMYO21 is caused by biallelic DNAJB4 variants and follows autosomal-recessive inheritance.
2. Core phenotype: early or disproportionate respiratory failure plus axial rigidity/rigid spine, often with preserved limb strength.
3. Mechanistic class: HSP40/HSP70-associated chaperonopathy and protein-aggregate myopathy centered on Z-disc/myofibrillar proteostasis.
4. Most useful diagnostic test: genomic testing that includes DNAJB4 sequence and exon-level CNV analysis, followed by segregation; WES/WGS reanalysis is important.
5. Best-supported management: proactive sleep/CO₂ and pulmonary surveillance, bilevel ventilation, assisted cough and multidisciplinary complication management.
6. Major evidence gaps: true prevalence, natural history, penetrance, disease-specific patient-reported outcomes, definitive client proteins, modifiers, biomarkers and clinical therapeutic trials.
7. Most important recent development: the October 2024 cohort broadened the variant and phenotype spectrum and provided preliminary evidence that J-domain missense variants predict earlier onset and greater mortality. [47]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0051085 (obsolete chaperone cofactor-dependent protein refolding) (2 mentions) - replaced by GO:0006457
• GO:0051082 (obsolete unfolded protein binding) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• GO:0051085 (2 mentions) - the report calls it "chaperone cofactor-dependent protein refolding"; GO calls it obsolete chaperone cofactor-dependent protein refolding, and lists "chaperone co-factor-dependent protein refolding" among its other names
• GO:0051082 (1 mention) - the report calls it "unfolded-protein binding"; GO calls it obsolete unfolded protein binding
• CL:0000594 (1 mention) - the report calls it "skeletal muscle fiber"; CL calls it skeletal muscle satellite cell

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

27 of 34 terms resolved to a current term; the rest could not be looked up either way.