Congenital Myopathy 21 With Early Respiratory Failure

Mendelian MONDO:0957224 Pathograph 38 Show in embeddings browser Congenital myopathy

Autosomal recessive protein-aggregate myopathy caused by biallelic loss-of-function variants in DNAJB4, which encodes an HSP40 (J-domain) co-chaperone that localizes to the sarcomeric Z-disc and recruits client proteins to HSP70. The defining picture is disproportionate diaphragmatic weakness with hypercapnic respiratory failure requiring ventilation, together with axial involvement (rigid spine, neck stiffness), often with little limb weakness. Onset ranges from infancy to the fifth decade. An infantile form, enriched for J-domain missense alleles, begins with neck stiffness and progresses to rigid spine, scoliosis, contractures, dysphagia and often death before adulthood; an adult form presents with abrupt respiratory failure. Muscle biopsy shows a myopathy with fiber size variation, angular fibers, protein inclusions and occasional rimmed vacuoles, and thigh MRI shows selective involvement of the semitendinosus and biceps femoris. Hypertrophic cardiomyopathy or mitral insufficiency occurs in a minority.

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1
Inheritance
10
Pathophys.
21
Phenotypes
38
Pathograph
1
Genes
4
Medical Actions
2
Models
1
Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
All reported affected individuals are homozygous for DNAJB4 variants; most families are consanguineous, and parents tested are unaffected heterozygotes.
Autosomal recessive inheritance
Show evidence (4 references)
PMID:36264506 SUPPORT Human Clinical
"This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4."
Homozygous variants in three unrelated families define the recessive disease.
PMID:39468638 SUPPORT Human Clinical
"We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds"
Five further families; the abstract states that all patients were homozygous.
PMID:39468638 SUPPORT Human Clinical
"Six of the patients were male, and one was female, with onset during the neonatal period and infancy. All the families were consanguineous"
Consanguinity in all five families is consistent with recessive inheritance.
+ 1 more reference
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Pathophysiology

10
DNAJB4 Protein Instability and Absence
Nonsense (p.Lys286Ter, p.Arg183Ter, p.Arg259Ter), frameshift (p.Gly103GlufsTer25), exon 2 and whole-gene deletion alleles, and the C-terminal missense p.Leu262Ser, produce DNAJB4 protein that is rapidly degraded or absent. DNAJB4 was absent from patient muscle and fibroblasts.
DNAJB4 hgnc:14886 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB4 (hgnc:14886). hgnc:14886 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of DNAJB4 Co-chaperone Function No DNAJB4 protein remains to engage clients and HSP70.
Show evidence (3 references)
PMID:36264506 SUPPORT Human Clinical
"DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function."
Absence of DNAJB4 protein in patient tissue.
PMID:36264506 SUPPORT In Vitro
"Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells."
Cell-based stability assays for the truncating and C-terminal missense alleles.
PMID:39468638 SUPPORT In Vitro
"Consistent with a loss of function, the nonsense variants presented decreased stability."
Extends the instability finding to p.Arg183Ter and p.Arg259Ter.
Dysfunctional J-Domain DNAJB4 Missense Proteins
The J-domain missense alleles p.Arg25Gln, p.Lys35Asn and p.Arg61Gly yield protein of normal or increased stability that still localizes to the Z-disc but fails yeast Sis1 complementation, TDP-43 disaggregation and protection from heat shock. The authors raise a possible toxic gain-of-function through altered HSP70 interaction for these alleles, which associate with earlier onset and higher mortality; this is not demonstrated.
DNAJB4 hgnc:14886 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB4 (hgnc:14886). hgnc:14886 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of DNAJB4 Co-chaperone Function The J-domain is the HSP70-interacting module, so these proteins cannot drive client handling.
Show evidence (2 references)
PMID:36264506 SUPPORT In Vitro
"In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function."
Stable but nonfunctional J-domain allele.
PMID:39468638 SUPPORT In Vitro
"In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays."
Same behaviour for p.Lys35Asn and p.Arg61Gly.
Loss of DNAJB4 Co-chaperone Function
DNAJB4 is a class B J-domain protein that binds client proteins at the Z-disc and recruits them to HSP70, stimulating its ATPase activity for folding, disaggregation or triage. Loss of DNAJB4 activity reduces this client handling; TDP-43 is the experimental client used in assays, and the disease-relevant muscle clients are not fully defined.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology. type I (slow) muscle fiber CL:0002211 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type I (slow) muscle fiber, annotated with type I muscle cell (CL:0002211). CL:0002211 is a cell type from the Cell Ontology. cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
DNAJB4 hgnc:14886 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB4 (hgnc:14886). hgnc:14886 is a gene from the HUGO Gene Nomenclature Committee.
protein folding GO:0006457 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. protein refolding GO:0042026 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein refolding (GO:0042026). GO:0042026 is a biological process from the Gene Ontology.
heat shock protein binding GO:0031072 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased heat shock protein binding (GO:0031072). GO:0031072 is a molecular function from the Gene Ontology. HSP70 ATPase activator activity GO:0001671 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased HSP70 ATPase activator activity, annotated with ATPase activator activity (GO:0001671). GO:0001671 is a molecular function from the Gene Ontology.
Experimental models
DNAJB4 variant TDP-43 disaggregation and yeast complementation assays CELL LINE Measures DNAJB4 variant chaperone activity against a model client.
Downstream
Z-Disc Protein and Chaperone Accumulation Unhandled DNAJB4 clients and stress chaperones accumulate in muscle.
Preferential Involvement of High-DNAJB4-Expressing Muscles Muscles with the highest endogenous Dnajb4 expression (soleus, diaphragm) are the most affected by its loss.
Cardiac Muscle Involvement Cardiac dysfunction occurs in a subset of patients; the cardiomyocyte mechanism has not been studied.
Show evidence (2 references)
PMID:36264506 SUPPORT BACKGROUND Other
"DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding."
Background statement of the normal co-chaperone function lost in disease.
PMID:39468638 SUPPORT In Vitro
"Following the 1-hour heat shock, cells expressing myopathy-associated DNAJB4 variants exhibited an increased percentage of cells with aggregates compared with those expressing DNAJB4-WT"
Disease variants fail to limit TDP-43 aggregation after heat shock in HeLa cells.
Z-Disc Protein and Chaperone Accumulation
DNAJB4-deficient muscle accumulates Z-disc proteins and protein chaperones, forming protein inclusions. Inclusions were seen in the founding patient biopsies but not in the limited samples of the 2024 cohort, possibly from sampling of selectively involved muscles.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
response to unfolded protein GO:0006986 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to unfolded protein (GO:0006986). GO:0006986 is a biological process from the Gene Ontology.
Animal models
Dnajb4 knockout mouse Mus musculus recapitulates Knockout muscle accumulates Z-disc proteins and chaperones with myofibrillar disorganization.
Downstream
Myofibrillar Disorganization
Muscle fiber inclusion bodies
Rimmed vacuoles
Show evidence (2 references)
PMID:36264506 SUPPORT Human Clinical
"On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
Protein inclusions in patient muscle.
PMID:39468638 SUPPORT Human Clinical
"In fact, the absence of inclusions in recessive DNAJB4 myopathy has been previously documented"
Records that inclusions are not seen in every biopsy.
Myofibrillar Disorganization
Loss of DNAJB4 disrupts sarcomeric order in knockout muscle and myotubes.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
sarcomere organization GO:0045214 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology.
Downstream
Skeletal Muscle Fiber Atrophy and Degeneration
Show evidence (1 reference)
PMID:36264506 SUPPORT Model Organism
"DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones."
Knockout muscle (and C2C12 myotubes) show myofibrillar disorganization.
Skeletal Muscle Fiber Atrophy and Degeneration
Fiber size variation, angular and atrophic fibers, endomysial fibrosis and adipose replacement in patient muscle, with prominent diaphragm involvement in the knockout mouse.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
skeletal muscle atrophy GO:0014732 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased skeletal muscle atrophy (GO:0014732). GO:0014732 is a biological process from the Gene Ontology.
Animal models
Dnajb4 knockout mouse Mus musculus recapitulates Muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis.
Downstream
Respiratory Muscle Pump Failure
Axial and Paraspinal Muscle Involvement
Increased variability in muscle fiber diameter
Angulated muscle fibers
Increased endomysial connective tissue
EMG myopathic abnormalities
Elevated circulating creatine kinase activity
Limb muscle weakness
Dysphagia Dysphagia is attributed to the myopathy clinically; involvement of oropharyngeal muscles has not been studied directly.
Show evidence (2 references)
PMID:36264506 SUPPORT Model Organism
"DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
Fiber atrophy in the knockout mouse.
PMID:39468638 SUPPORT Human Clinical
"On H&E of the muscle from P1, notable endomysial fibrosis and adipose tissue infiltration were observed, with atrophic muscle fibers occasionally clustering"
Atrophy and degenerative changes in a patient biopsy.
Preferential Involvement of High-DNAJB4-Expressing Muscles
DNAJB4 expression is highest in the soleus and diaphragm; these are the most affected muscles in Dnajb4 knockout and knock-in mice, matching disproportionate diaphragm involvement in patients and selective semitendinosus and biceps femoris involvement on thigh MRI. In the dominant allelic disorder, pathology predominates in type 1 fibers.
type I (slow) muscle fiber CL:0002211 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type I (slow) muscle fiber, annotated with type I muscle cell (CL:0002211). CL:0002211 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Animal models
Dnajb4 knockout mouse Mus musculus recapitulates Pathology concentrates in the soleus, the highest-expressing muscle.
Downstream
Respiratory Muscle Pump Failure The diaphragm is among the muscles most dependent on DNAJB4.
Show evidence (3 references)
PMID:36512060 SUPPORT Model Organism
"Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression."
Knockout mice show pathology concentrated in the highest-expressing muscle.
PMID:36512060 SUPPORT INDIRECT Human Clinical
"the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers"
Type 1 fiber predominance of pathology, shown in patients with the dominant p.Phe90Leu allelic disorder rather than the recessive form, so applying it here is an inference.
PMID:36264506 SUPPORT Human Clinical
"Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh."
Selective muscle involvement in patients.
Respiratory Muscle Pump Failure
Disproportionate diaphragm weakness reduces ventilation, producing a restrictive defect, hypercapnia and respiratory failure that can appear abruptly in adults with little limb weakness, or in infancy, where respiratory complications often lead to death before adulthood.
diaphragm contraction GO:0002086 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased diaphragm contraction (GO:0002086). GO:0002086 is a biological process from the Gene Ontology. respiratory gaseous exchange by respiratory system GO:0007585 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased respiratory gaseous exchange by respiratory system (GO:0007585). GO:0007585 is a biological process from the Gene Ontology.
Downstream
Diaphragmatic weakness
Respiratory failure
Hypercapnia
Restrictive ventilatory defect
Recurrent lower respiratory tract infections Weak ventilation and cough, plus dysphagia, predispose to infection; inferred.
Show evidence (2 references)
PMID:38127101 SUPPORT Human Clinical
"Our patient has a strikingly similar phenotype with primary diaphragmatic weakness leading to respiratory failure and clinically only subtle myopathy confirmed by muscle biopsy."
Diaphragmatic weakness as the driver of respiratory failure.
PMID:39468638 SUPPORT Human Clinical
"Patients with J-domain variants exhibit early onset and severe respiratory complications, often resulting in death before adulthood."
Respiratory complications are the cause of early death in the severe form.
Axial and Paraspinal Muscle Involvement
Axial weakness out of proportion to limb weakness with neck stiffness from infancy, rigid spine, scoliosis and ankle contractures, especially in the infantile form.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Spinal rigidity
Stiff neck
Axial muscle weakness
Scoliosis
Ankle contracture
Respiratory Muscle Pump Failure Rigid spine and scoliosis may add chest-wall restriction; inferred.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Our cohort indicates a polarization in the onset of DNAJB4 myopathy into two types: one presenting in infancy with early-onset neck stiffness, rigid spine syndrome with axial weakness out of proportion to limb weakness, and severe respiratory failure"
Axial-predominant pattern of the infantile form.
Cardiac Muscle Involvement
Hypertrophic cardiomyopathy or mitral insufficiency in a minority of patients, in the 2024 cohort only in those with truncating or deletion alleles. The cardiomyocyte mechanism is not studied.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Hypertrophic cardiomyopathy
Mitral regurgitation
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"In contrast, patients with loss-of-function variants, such as nonsense, frameshift, and exon deletions, exhibited later onset, with cardiac dysfunctions observed exclusively in these patients."
Cardiac involvement restricted to the null-allele group in this small cohort.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Myopathy 21 With Early Respiratory Failure Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Cardiovascular 2
Hypertrophic cardiomyopathy OCCASIONAL HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
Two of seven patients.
Mitral regurgitation OCCASIONAL HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral insufficiency, annotated with Mitral regurgitation (HP:0001653). HP:0001653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
One of seven patients.
Digestive 1
Dysphagia FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Three patients had dysphagia, all of whom required nasogastric or gastrostomy tubes."
Dysphagia severe enough for tube feeding in three of seven.
Head and Neck 1
Stiff neck FREQUENT HP:0025258 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neck stiffness, annotated with Stiff neck (HP:0025258), qualified as infantile onset. HP:0025258 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Three patients experienced neck stiffness from infancy."
Infantile neck stiffness in three of seven.
Immune 1
Recurrent lower respiratory tract infections FREQUENT HP:0002783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent lower respiratory tract infections (HP:0002783). HP:0002783 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Four patients had a history of recurring lower respiratory tract infections (P1, P4, P6, P7)."
Four of seven patients.
Limbs 2
Ankle contracture FREQUENT HP:0034677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle contracture (HP:0034677). HP:0034677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Ankle contractures were observed in three patients."
Three of seven.
Limb muscle weakness OCCASIONAL HP:0003690 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb muscle weakness (HP:0003690). HP:0003690 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39468638 SUPPORT Human Clinical
"Limb muscle weakness was not pronounced except in two patients: P1, who had predominantly distal weakness, and P5, who had predominantly proximal weakness."
Limb weakness in two of seven.
PMID:40769870 SUPPORT Human Clinical
"We describe the case of a 23-year-old male patient who was admitted for acute respiratory failure and motor deficit of the distal upper limbs."
Distal upper-limb weakness with acute respiratory failure.
Metabolism 1
Elevated circulating creatine kinase activity OCCASIONAL HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39468638 SUPPORT Human Clinical
"Serum creatine kinase was within the normal range in all patients except for P4."
CK elevation in one of seven.
PMID:40769870 SUPPORT Human Clinical
"Creatine kinase values were elevated (10x upper normal limit)"
Marked CK elevation in a whole-gene deletion case.
Musculoskeletal 8
Diaphragmatic weakness HP:0009113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diaphragmatic weakness (HP:0009113). HP:0009113 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38127101 SUPPORT Human Clinical
"Our patient has a strikingly similar phenotype with primary diaphragmatic weakness leading to respiratory failure and clinically only subtle myopathy confirmed by muscle biopsy."
Independent adult case with primary diaphragmatic weakness.
PMID:40769870 SUPPORT BACKGROUND Human Clinical
"Homozygous mutations in the DNAJB4 (NM_007034) gene impair HSP40 function, leading to early respiratory failure due to diaphragm involvement and rigid-spine-like characteristics."
Background summary of the disease in a later case report.
Spinal rigidity FREQUENT HP:0003306 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rigid spine, annotated with Spinal rigidity (HP:0003306). HP:0003306 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39468638 SUPPORT Human Clinical
"Spinal rigidity was observed in three patients."
Three of seven in the 2024 cohort.
PMID:36264506 SUPPORT Human Clinical
"Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life."
Axial rigidity in the founding families.
Axial muscle weakness HP:0003327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial muscle weakness (HP:0003327). HP:0003327 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness."
Axial weakness as part of rigid spine syndrome in three families.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Three patients had scoliosis, one of whom was observed at birth"
Three of seven, one congenital.
EMG myopathic abnormalities HP:0003458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic EMG, annotated with EMG: myopathic abnormalities (HP:0003458). HP:0003458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Electromyography was performed on two patients (P4 and P5), and the results indicated myopathic changes, characterized by short-duration, low-amplitude, polyphasic motor unit potentials and early recruitment patterns."
Myopathic EMG in both patients tested.
Rimmed vacuoles HP:0003805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rimmed vacuoles (HP:0003805). HP:0003805 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36264506 SUPPORT Human Clinical
"On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
Occasional rimmed vacuoles on biopsy.
Increased variability in muscle fiber diameter HP:0003557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fiber size variation, annotated with Increased variability in muscle fiber diameter (HP:0003557). HP:0003557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"H&E staining from P1 at 4 years of age, demonstrating marked variation in fiber size, prominent endomysial fibrosis, and adipose tissue infiltration."
Fiber size variation in a pediatric biopsy.
Increased endomysial connective tissue HP:0100297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Endomysial fibrosis, annotated with Increased endomysial connective tissue (HP:0100297). HP:0100297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"On H&E of the muscle from P1, notable endomysial fibrosis and adipose tissue infiltration were observed"
Endomysial fibrosis in a pediatric biopsy.
Respiratory 3
Respiratory failure VERY_FREQUENT HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36264506 SUPPORT Human Clinical
"Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life."
Respiratory failure in all four founding patients.
PMID:39468638 SUPPORT Human Clinical
"Most affected individuals experienced respiratory failure and required mechanical ventilation, except for Patient 2."
Six of seven in the second cohort.
PMID:39468638 SUPPORT Human Clinical
"Patients with J-domain variants exhibit early onset and severe respiratory complications, often resulting in death before adulthood."
Respiratory complications are fatal in childhood for many with J-domain alleles.
Hypercapnia HP:0012416 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercapnia (HP:0012416). HP:0012416 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Acute respiratory failure with life-threatening hypercapnia necessitating prolonged ventilatory support is a hallmark of DNAJB4 myopathy"
Hypercapnic failure is described as a hallmark.
Restrictive ventilatory defect HP:0002091 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive ventilatory defect (HP:0002091). HP:0002091 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40769870 SUPPORT Human Clinical
"the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values)"
Severe restrictive defect in a whole-gene deletion case.
Cellular 1
Muscle fiber inclusion bodies HP:0100299 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein inclusions in muscle fibers, annotated with Muscle fiber inclusion bodies (HP:0100299). HP:0100299 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36264506 SUPPORT Human Clinical
"On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
Protein inclusions in the founding biopsies.
Other 1
Angulated muscle fibers HP:0034045 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Angular fibers, annotated with Angulated muscle fibers (HP:0034045). HP:0034045 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36264506 SUPPORT Human Clinical
"On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
Angular fibers on biopsy.
🧬

Genetic Associations

1
DNAJB4 (Causative)
Gene: DNAJB4 hgnc:14886 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAJB4 (hgnc:14886). hgnc:14886 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:36264506 SUPPORT Human Clinical
"These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure."
Gene discovery report.
PMID:39468638 SUPPORT Human Clinical
"Compared with other variants, the J-domain variants were associated with an earlier age of onset (0.5 vs. 28 years, P = 0.035) and a higher mortality rate (75% vs. 14%, P = 0.046)."
Genotype-phenotype correlation in a small cohort.
PMID:38127101 SUPPORT Human Clinical
"Thus, our case represents the first independent replication of autosomal recessive DNAJB4-related myopathy."
Independent replication with homozygous c.308del.
💊

Medical Actions

4
Non-Invasive Ventilation
Action: non-invasive mechanical ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is non-invasive mechanical ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Platform: Device
Nocturnal non-invasive ventilation for respiratory failure from diaphragmatic weakness. No DNAJB4-specific outcome series exists.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology. Hypercapnia HP:0012416 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypercapnia (HP:0012416). HP:0012416 is a phenotype from the Human Phenotype Ontology. Diaphragmatic weakness HP:0009113 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Diaphragmatic weakness (HP:0009113). HP:0009113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38127101 SUPPORT Human Clinical
"progressive respiratory failure due to diaphragmatic weakness, necessitating nightly non-invasive ventilation"
Nightly NIV in an adult case.
Mechanical Ventilation
Action: mechanical ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mechanical ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. Ontology label: Mechanical Ventilation NCIT:C70909
Platform: Device
Invasive or prolonged ventilatory support for acute hypercapnic failure, required by most patients.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology. Hypercapnia HP:0012416 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypercapnia (HP:0012416). HP:0012416 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39468638 SUPPORT Human Clinical
"Most affected individuals experienced respiratory failure and required mechanical ventilation, except for Patient 2."
Mechanical ventilation in six of seven patients.
PMID:39468638 SUPPORT Human Clinical
"Acute respiratory failure with life-threatening hypercapnia necessitating prolonged ventilatory support is a hallmark of DNAJB4 myopathy"
Ventilatory support for hypercapnic failure.
Gastrostomy Feeding
Action: gastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy NCIT:C52006
Platform: Surgery
Nasogastric or gastrostomy tube feeding for dysphagia.
Target Phenotypes: Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39468638 SUPPORT Human Clinical
"Three patients had dysphagia, all of whom required nasogastric or gastrostomy tubes."
Tube feeding in all patients with dysphagia.
DNAJB4 Gene Replacement (proposed)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
AAV-mediated DNAJB4 replacement is proposed for the loss-of-function recessive disease; no preclinical efficacy data or trials exist.
Mechanism Target:
Loss of DNAJB4 Co-chaperone Function — Would restore the missing co-chaperone.
Show evidence (1 reference)
PMID:40696134 SUPPORT REVIEW SYNTHESIS Other
"For these conditions, gene replacement therapy using adeno-associated virus (AAV) vectors to restore functional DNAJB4 protein represents a viable option"
Proposal in a review; untested.
Show evidence (1 reference)
PMID:40696134 SUPPORT REVIEW SYNTHESIS Other
"In contrast, disorders driven primarily by LOF mechanisms, such as many cases of recessive DNAJB4 myopathy, require fundamentally different therapeutic strategies."
Frames gene replacement as the relevant strategy for the recessive form.
🔬

Diagnosis

4
Exome sequencing
Diagnosis is molecular, by exome sequencing or a neuromuscular panel including DNAJB4 with copy-number analysis, since whole-gene deletions occur. Reanalysis of earlier negative exomes has yielded diagnoses.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:36264506 SUPPORT Human Clinical
"We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis."
Exome sequencing identified the founding cases.
PMID:38127101 SUPPORT Human Clinical
"Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4)."
Reanalysis yielded a DNAJB4 diagnosis.
PMID:40769870 SUPPORT Human Clinical
"Genetic analysis by NGS panel sequencing identified a homozygous deletion c.(?_1)_(1014_?)del, p.? (HGVS nomenclature) of the entire DNAJB4 gene, confirmed by qPCR."
Whole-gene deletion detected by panel copy-number analysis.
Muscle biopsy
Myopathic changes with angular fibers, protein inclusions, occasional rimmed vacuoles and myofibrillar myopathy features; DNAJB4 protein is absent with null alleles.
muscle biopsy NCIT:C51895 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36264506 SUPPORT Human Clinical
"On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
Biopsy findings in the founding families.
PMID:40769870 SUPPORT Human Clinical
"The deltoid muscle biopsy findings were consistent with myofibrillar myopathy."
Myofibrillar myopathy pattern in a later case.
Muscle MRI
Thigh MRI shows selective involvement of the semitendinosus and biceps femoris.
magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:36264506 SUPPORT Human Clinical
"Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh."
Selective muscle pattern on MRI.
Pulmonary function testing
Spirometry shows a restrictive defect. Regular respiratory screening is recommended.
pulmonary function test NCIT:C38081 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:40769870 SUPPORT Human Clinical
"the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values)"
Restrictive physiology on pulmonary function testing.
PMID:39468638 SUPPORT Human Clinical
"It is prudent to screen patients with DNAJB4 myopathy regularly for early cardiac and respiratory manifestations and dysphagia and proactively institute life-saving supportive measures."
Authors recommend regular respiratory screening.
🧫

Experimental Models

1
DNAJB4 variant TDP-43 disaggregation and yeast complementation assays CELL_LINE
HeLa cells co-expressing TDP-43 and DNAJB4 variants under heat shock, and sis1-deleted Saccharomyces cerevisiae complemented with DNAJB variants, used to classify stable missense alleles as loss of function.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:39468638
Pathograph links
Loss of DNAJB4 Co-chaperone Function measures fidelity: moderate observes: molecular Measures DNAJB4 variant chaperone activity against a model client.
Limitations: TDP-43 is an experimental client, not an established disease substrate in muscle, and HeLa cells and yeast lack sarcomeres.
Show evidence (1 reference)
PMID:39468638 SUPPORT In Vitro
"In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays."
Assay results for the missense variants.
🐁

Animal Models

1
Dnajb4 knockout mouse
Species
Mus musculus
Genotype
Dnajb4-/-
Publication
PMID:36264506
Pathograph links
Skeletal Muscle Fiber Atrophy and Degeneration recapitulates fidelity: moderate observes: tissue Muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis.
Limitations: The knockout is a complete null and so does not model the stable J-domain missense alleles, and the cited abstract reports no lethal respiratory failure in the mice.
Show evidence (1 reference)
PMID:36264506 SUPPORT Model Organism
"DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
Phenotype of the knockout.
Z-Disc Protein and Chaperone Accumulation recapitulates fidelity: high observes: cellular Knockout muscle accumulates Z-disc proteins and chaperones with myofibrillar disorganization.
Show evidence (1 reference)
PMID:36264506 SUPPORT Model Organism
"DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones."
Proteostasis lesion reproduced in knockout muscle.
Preferential Involvement of High-DNAJB4-Expressing Muscles recapitulates fidelity: moderate observes: tissue Pathology concentrates in the soleus, the highest-expressing muscle.
Limitations: Mouse fiber-type composition differs from human, so the muscle pattern is not directly comparable.
Show evidence (1 reference)
PMID:36512060 SUPPORT Model Organism
"Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression."
Soleus-selective pathology in knockout mice.
{ }

Source YAML

click to show 
name: Congenital Myopathy 21 With Early Respiratory Failure
creation_date: "2026-10-15T12:30:00Z"
category: Mendelian
synonyms:
- CMYO21
- recessive DNAJB4 myopathy
- DNAJB4-related myopathy with early respiratory failure
description: >-
  Autosomal recessive protein-aggregate myopathy caused by biallelic
  loss-of-function variants in DNAJB4, which encodes an HSP40 (J-domain)
  co-chaperone that localizes to the sarcomeric Z-disc and recruits client
  proteins to HSP70. The defining picture is disproportionate diaphragmatic
  weakness with hypercapnic respiratory failure requiring ventilation, together
  with axial involvement (rigid spine, neck stiffness), often with little limb
  weakness. Onset ranges from infancy to the fifth decade. An infantile form,
  enriched for J-domain missense alleles, begins with neck stiffness and
  progresses to rigid spine, scoliosis, contractures, dysphagia and often death
  before adulthood; an adult form presents with abrupt respiratory failure.
  Muscle biopsy shows a myopathy with fiber size variation, angular fibers,
  protein inclusions and occasional rimmed vacuoles, and thigh MRI shows
  selective involvement of the semitendinosus and biceps femoris. Hypertrophic
  cardiomyopathy or mitral insufficiency occurs in a minority.
disease_term:
  preferred_term: congenital myopathy 21 with early respiratory failure
  term:
    id: MONDO:0957224
    label: congenital myopathy 21 with early respiratory failure
parents:
- Congenital myopathy
inheritance:
- name: Autosomal Recessive
  description: >-
    All reported affected individuals are homozygous for DNAJB4 variants; most
    families are consanguineous, and parents tested are unaffected
    heterozygotes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4."
    explanation: Homozygous variants in three unrelated families define the recessive disease.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds"
    explanation: Five further families; the abstract states that all patients were homozygous.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six of the patients were male, and one was female, with onset during the neonatal period and infancy. All the families were consanguineous"
    explanation: Consanguinity in all five families is consistent with recessive inheritance.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both healthy parents exhibited the variant at the heterozygous state."
    explanation: Unaffected heterozygous parents of a homozygous whole-gene deletion case.
pathophysiology:
- name: DNAJB4 Protein Instability and Absence
  biological_scale: MOLECULAR
  description: >-
    Nonsense (p.Lys286Ter, p.Arg183Ter, p.Arg259Ter), frameshift
    (p.Gly103GlufsTer25), exon 2 and whole-gene deletion alleles, and the
    C-terminal missense p.Leu262Ser, produce DNAJB4 protein that is rapidly
    degraded or absent. DNAJB4 was absent from patient muscle and fibroblasts.
  genes:
  - preferred_term: DNAJB4
    term:
      id: hgnc:14886
      label: DNAJB4
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function."
    explanation: Absence of DNAJB4 protein in patient tissue.
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells."
    explanation: Cell-based stability assays for the truncating and C-terminal missense alleles.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistent with a loss of function, the nonsense variants presented decreased stability."
    explanation: Extends the instability finding to p.Arg183Ter and p.Arg259Ter.
  downstream:
  - target: Loss of DNAJB4 Co-chaperone Function
    causal_link_type: DIRECT
    description: No DNAJB4 protein remains to engage clients and HSP70.
    evidence:
    - reference: PMID:40696134
      reference_title: "Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "These typically lead to diminished protein stability or the absence of functional DNAJB4 protein."
      explanation: Review synthesis of the recessive alleles as loss of functional protein.
- name: Dysfunctional J-Domain DNAJB4 Missense Proteins
  biological_scale: MOLECULAR
  description: >-
    The J-domain missense alleles p.Arg25Gln, p.Lys35Asn and p.Arg61Gly yield
    protein of normal or increased stability that still localizes to the
    Z-disc but fails yeast Sis1 complementation, TDP-43 disaggregation and
    protection from heat shock. The authors raise a possible toxic
    gain-of-function through altered HSP70 interaction for these alleles, which
    associate with earlier onset and higher mortality; this is not demonstrated.
  genes:
  - preferred_term: DNAJB4
    term:
      id: hgnc:14886
      label: DNAJB4
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function."
    explanation: Stable but nonfunctional J-domain allele.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays."
    explanation: Same behaviour for p.Lys35Asn and p.Arg61Gly.
  downstream:
  - target: Loss of DNAJB4 Co-chaperone Function
    causal_link_type: DIRECT
    description: The J-domain is the HSP70-interacting module, so these proteins cannot drive client handling.
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "While loss-of-function variants presented decreased protein stability, J-domain variants maintained normal stability but were dysfunctional in TDP-43 disaggregation and yeast viability assays."
      explanation: Both allele classes converge on loss of chaperone activity.
- name: Loss of DNAJB4 Co-chaperone Function
  biological_scale: MOLECULAR
  description: >-
    DNAJB4 is a class B J-domain protein that binds client proteins at the
    Z-disc and recruits them to HSP70, stimulating its ATPase activity for
    folding, disaggregation or triage. Loss of DNAJB4 activity reduces this
    client handling; TDP-43 is the experimental client used in assays, and the
    disease-relevant muscle clients are not fully defined.
  genes:
  - preferred_term: DNAJB4
    term:
      id: hgnc:14886
      label: DNAJB4
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: type I (slow) muscle fiber
    term:
      id: CL:0002211
      label: type I muscle cell
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: heat shock protein binding
    term:
      id: GO:0031072
      label: heat shock protein binding
    modifier: DECREASED
  - preferred_term: HSP70 ATPase activator activity
    term:
      id: GO:0001671
      label: ATPase activator activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  - preferred_term: protein refolding
    term:
      id: GO:0042026
      label: protein refolding
    modifier: DECREASED
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding."
    explanation: Background statement of the normal co-chaperone function lost in disease.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Following the 1-hour heat shock, cells expressing myopathy-associated DNAJB4 variants exhibited an increased percentage of cells with aggregates compared with those expressing DNAJB4-WT"
    explanation: Disease variants fail to limit TDP-43 aggregation after heat shock in HeLa cells.
  downstream:
  - target: Z-Disc Protein and Chaperone Accumulation
    causal_link_type: DIRECT
    description: Unhandled DNAJB4 clients and stress chaperones accumulate in muscle.
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration."
      explanation: The authors' model linking chaperone loss to client accumulation, stated as a hypothesis.
  - target: Preferential Involvement of High-DNAJB4-Expressing Muscles
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Muscles with the highest endogenous Dnajb4 expression (soleus,
      diaphragm) are the most affected by its loss.
    evidence:
    - reference: PMID:40696134
      reference_title: "Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "The models revealed that the soleus and diaphragm muscles, which have the highest endogenous Dnajb4 expression, were the most severely affected, providing a compelling explanation for the selective muscle involvement seen in the human disease"
      explanation: Review summary of the knockout and knock-in mouse findings on muscle selectivity.
  - target: Cardiac Muscle Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cardiac dysfunction occurs in a subset of patients; the cardiomyocyte
      mechanism has not been studied.
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "reinforces the understanding that neck stiffness and cardiac dysfunction are indeed manifestations of DNAJB4 myopathy"
      explanation: Clinical attribution of cardiac involvement to the DNAJB4 disease; mechanism inferred.
- name: Z-Disc Protein and Chaperone Accumulation
  biological_scale: CELLULAR
  conforms_to: loss_of_proteostasis#Misfolded-Protein Aggregation
  description: >-
    DNAJB4-deficient muscle accumulates Z-disc proteins and protein
    chaperones, forming protein inclusions. Inclusions were seen in the
    founding patient biopsies but not in the limited samples of the 2024
    cohort, possibly from sampling of selectively involved muscles.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: response to unfolded protein
    term:
      id: GO:0006986
      label: response to unfolded protein
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
    explanation: Protein inclusions in patient muscle.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In fact, the absence of inclusions in recessive DNAJB4 myopathy has been previously documented"
    explanation: Records that inclusions are not seen in every biopsy.
  downstream:
  - target: Myofibrillar Disorganization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones."
      explanation: >-
        Knockout mouse muscle shows Z-disc protein accumulation together with
        myofibrillar disorganization; the sentence also covers C2C12 knockout
        myotubes.
  - target: Muscle fiber inclusion bodies
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
      explanation: Accumulated proteins are seen as inclusions on patient biopsy.
  - target: Rimmed vacuoles
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
      explanation: Rimmed vacuoles accompany the inclusions; the link between them is inferred.
- name: Myofibrillar Disorganization
  biological_scale: CELLULAR
  description: >-
    Loss of DNAJB4 disrupts sarcomeric order in knockout muscle and myotubes.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones."
    explanation: Knockout muscle (and C2C12 myotubes) show myofibrillar disorganization.
  downstream:
  - target: Skeletal Muscle Fiber Atrophy and Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40769870
      reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The deltoid muscle biopsy findings were consistent with myofibrillar myopathy."
      explanation: Myofibrillar myopathy pathology in a homozygous whole-gene deletion patient with weakness.
- name: Skeletal Muscle Fiber Atrophy and Degeneration
  biological_scale: TISSUE
  description: >-
    Fiber size variation, angular and atrophic fibers, endomysial fibrosis and
    adipose replacement in patient muscle, with prominent diaphragm involvement
    in the knockout mouse.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: skeletal muscle atrophy
    term:
      id: GO:0014732
      label: skeletal muscle atrophy
    modifier: INCREASED
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
    explanation: Fiber atrophy in the knockout mouse.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On H&E of the muscle from P1, notable endomysial fibrosis and adipose tissue infiltration were observed, with atrophic muscle fibers occasionally clustering"
    explanation: Atrophy and degenerative changes in a patient biopsy.
  downstream:
  - target: Respiratory Muscle Pump Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
      explanation: Atrophy prominently involves the diaphragm in the knockout; the step to ventilatory failure is inferred for humans.
  - target: Axial and Paraspinal Muscle Involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
      explanation: Kyphosis in the knockout is the mouse counterpart of axial involvement.
  - target: Increased variability in muscle fiber diameter
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "H&E staining from P1 at 4 years of age, demonstrating marked variation in fiber size, prominent endomysial fibrosis, and adipose tissue infiltration."
      explanation: Fiber size variation as a biopsy readout of atrophy.
  - target: Angulated muscle fibers
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
      explanation: Angular atrophic fibers on biopsy.
  - target: Increased endomysial connective tissue
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On H&E of the muscle from P1, notable endomysial fibrosis and adipose tissue infiltration were observed, with atrophic muscle fibers occasionally clustering"
      explanation: Endomysial fibrosis accompanies fiber atrophy.
  - target: EMG myopathic abnormalities
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electromyography was performed on two patients (P4 and P5), and the results indicated myopathic changes, characterized by short-duration, low-amplitude, polyphasic motor unit potentials and early recruitment patterns."
      explanation: Myopathic motor units reflect the fiber-level myopathy.
  - target: Elevated circulating creatine kinase activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40769870
      reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Creatine kinase values were elevated (10x upper normal limit)"
      explanation: CK leak from degenerating muscle in one case; usually normal.
  - target: Limb muscle weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Limb muscle weakness was not pronounced except in two patients: P1, who had predominantly distal weakness, and P5, who had predominantly proximal weakness."
      explanation: Limb weakness from the myopathy in a minority.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysphagia is attributed to the myopathy clinically; involvement of
      oropharyngeal muscles has not been studied directly.
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The detection of these clinical features in several new cases in the present study not only reveals that dysphagia, ankle contracture, and scoliosis are manifestations of DNAJB4 myopathy"
      explanation: Clinical attribution of dysphagia to the myopathy; muscle-level mechanism inferred.
- name: Preferential Involvement of High-DNAJB4-Expressing Muscles
  biological_scale: TISSUE
  description: >-
    DNAJB4 expression is highest in the soleus and diaphragm; these are the
    most affected muscles in Dnajb4 knockout and knock-in mice, matching
    disproportionate diaphragm involvement in patients and selective
    semitendinosus and biceps femoris involvement on thigh MRI. In the
    dominant allelic disorder, pathology predominates in type 1 fibers.
  cell_types:
  - preferred_term: type I (slow) muscle fiber
    term:
      id: CL:0002211
      label: type I muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:36512060
    reference_title: "Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression."
    explanation: Knockout mice show pathology concentrated in the highest-expressing muscle.
  - reference: PMID:36512060
    reference_title: "Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers"
    explanation: >-
      Type 1 fiber predominance of pathology, shown in patients with the
      dominant p.Phe90Leu allelic disorder rather than the recessive form, so
      applying it here is an inference.
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh."
    explanation: Selective muscle involvement in patients.
  downstream:
  - target: Respiratory Muscle Pump Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The diaphragm is among the muscles most dependent on DNAJB4.
    evidence:
    - reference: PMID:40696134
      reference_title: "Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "The Dnajb4 KO mouse exhibits kyphosis, muscle weakness, and significant diaphragm atrophy, effectively modeling the early respiratory failure seen in patients with recessive LOF mutations"
      explanation: Review links diaphragm atrophy in the knockout to the human respiratory phenotype.
- name: Respiratory Muscle Pump Failure
  biological_scale: ORGANISM
  description: >-
    Disproportionate diaphragm weakness reduces ventilation, producing a
    restrictive defect, hypercapnia and respiratory failure that can appear
    abruptly in adults with little limb weakness, or in infancy, where
    respiratory complications often lead to death before adulthood.
  biological_processes:
  - preferred_term: diaphragm contraction
    term:
      id: GO:0002086
      label: diaphragm contraction
    modifier: DECREASED
  - preferred_term: respiratory gaseous exchange by respiratory system
    term:
      id: GO:0007585
      label: respiratory gaseous exchange by respiratory system
    modifier: DECREASED
  evidence:
  - reference: PMID:38127101
    reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient has a strikingly similar phenotype with primary diaphragmatic weakness leading to respiratory failure and clinically only subtle myopathy confirmed by muscle biopsy."
    explanation: Diaphragmatic weakness as the driver of respiratory failure.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with J-domain variants exhibit early onset and severe respiratory complications, often resulting in death before adulthood."
    explanation: Respiratory complications are the cause of early death in the severe form.
  downstream:
  - target: Diaphragmatic weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38127101
      reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our patient has a strikingly similar phenotype with primary diaphragmatic weakness leading to respiratory failure and clinically only subtle myopathy confirmed by muscle biopsy."
      explanation: Primary diaphragmatic weakness in an adult case.
  - target: Respiratory failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38127101
      reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "found through reanalysis in a patient initially presenting with severe weight loss at the age of 32 followed by progressive respiratory failure due to diaphragmatic weakness"
      explanation: Respiratory failure attributed to diaphragmatic weakness.
  - target: Hypercapnia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Acute respiratory failure with life-threatening hypercapnia necessitating prolonged ventilatory support is a hallmark of DNAJB4 myopathy"
      explanation: Hypoventilatory failure is hypercapnic.
  - target: Restrictive ventilatory defect
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40769870
      reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values)"
      explanation: Restrictive physiology accompanying respiratory muscle failure.
  - target: Recurrent lower respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Weak ventilation and cough, plus dysphagia, predispose to infection; inferred.
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Four patients had a history of recurring lower respiratory tract infections (P1, P4, P6, P7)."
      explanation: Infections occur in patients with respiratory muscle failure; the causal link is inferred.
- name: Axial and Paraspinal Muscle Involvement
  biological_scale: TISSUE
  description: >-
    Axial weakness out of proportion to limb weakness with neck stiffness from
    infancy, rigid spine, scoliosis and ankle contractures, especially in the
    infantile form.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our cohort indicates a polarization in the onset of DNAJB4 myopathy into two types: one presenting in infancy with early-onset neck stiffness, rigid spine syndrome with axial weakness out of proportion to limb weakness, and severe respiratory failure"
    explanation: Axial-predominant pattern of the infantile form.
  downstream:
  - target: Spinal rigidity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Spinal rigidity was observed in three patients."
      explanation: Rigid spine as the axial phenotype.
  - target: Stiff neck
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three patients experienced neck stiffness from infancy."
      explanation: Neck stiffness as an early axial sign.
  - target: Axial muscle weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness."
      explanation: Axial weakness within rigid spine syndrome.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Three patients had scoliosis, one of whom was observed at birth"
      explanation: Scoliosis co-occurs with axial involvement; the causal step is inferred.
  - target: Ankle contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Ankle contractures were observed in three patients."
      explanation: Contractures accompany the rigid spine presentation; mechanism inferred.
  - target: Respiratory Muscle Pump Failure
    causal_link_type: UNKNOWN
    description: Rigid spine and scoliosis may add chest-wall restriction; inferred.
- name: Cardiac Muscle Involvement
  biological_scale: TISSUE
  description: >-
    Hypertrophic cardiomyopathy or mitral insufficiency in a minority of
    patients, in the 2024 cohort only in those with truncating or deletion
    alleles. The cardiomyocyte mechanism is not studied.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, patients with loss-of-function variants, such as nonsense, frameshift, and exon deletions, exhibited later onset, with cardiac dysfunctions observed exclusively in these patients."
    explanation: Cardiac involvement restricted to the null-allele group in this small cohort.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
      explanation: Hypertrophic cardiomyopathy as a form of cardiac involvement.
  - target: Mitral regurgitation
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
      explanation: Mitral insufficiency as a form of cardiac involvement; mechanism unknown.
phenotypes:
- category: Respiratory
  name: Respiratory failure
  frequency: VERY_FREQUENT
  description: >-
    Respiratory failure requiring ventilator support, from infancy to the
    fifth decade; present in all followed patients except one lost to
    follow-up at age two. In the infantile J-domain form, respiratory
    complications often lead to death before adulthood.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life."
    explanation: Respiratory failure in all four founding patients.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals experienced respiratory failure and required mechanical ventilation, except for Patient 2."
    explanation: Six of seven in the second cohort.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with J-domain variants exhibit early onset and severe respiratory complications, often resulting in death before adulthood."
    explanation: Respiratory complications are fatal in childhood for many with J-domain alleles.
- category: Respiratory
  name: Diaphragmatic weakness
  phenotype_term:
    preferred_term: Diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: PMID:38127101
    reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient has a strikingly similar phenotype with primary diaphragmatic weakness leading to respiratory failure and clinically only subtle myopathy confirmed by muscle biopsy."
    explanation: Independent adult case with primary diaphragmatic weakness.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Homozygous mutations in the DNAJB4 (NM_007034) gene impair HSP40 function, leading to early respiratory failure due to diaphragm involvement and rigid-spine-like characteristics."
    explanation: Background summary of the disease in a later case report.
- category: Respiratory
  name: Hypercapnia
  phenotype_term:
    preferred_term: Hypercapnia
    term:
      id: HP:0012416
      label: Hypercapnia
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute respiratory failure with life-threatening hypercapnia necessitating prolonged ventilatory support is a hallmark of DNAJB4 myopathy"
    explanation: Hypercapnic failure is described as a hallmark.
- category: Respiratory
  name: Restrictive ventilatory defect
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values)"
    explanation: Severe restrictive defect in a whole-gene deletion case.
- category: Respiratory
  name: Recurrent lower respiratory tract infections
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent lower respiratory tract infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients had a history of recurring lower respiratory tract infections (P1, P4, P6, P7)."
    explanation: Four of seven patients.
- category: Musculoskeletal
  name: Spinal rigidity
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rigid spine
    term:
      id: HP:0003306
      label: Spinal rigidity
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinal rigidity was observed in three patients."
    explanation: Three of seven in the 2024 cohort.
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life."
    explanation: Axial rigidity in the founding families.
- category: Musculoskeletal
  name: Stiff neck
  frequency: FREQUENT
  description: Neck stiffness beginning in infancy.
  phenotype_term:
    preferred_term: Neck stiffness
    term:
      id: HP:0025258
      label: Stiff neck
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients experienced neck stiffness from infancy."
    explanation: Infantile neck stiffness in three of seven.
- category: Musculoskeletal
  name: Axial muscle weakness
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness."
    explanation: Axial weakness as part of rigid spine syndrome in three families.
- category: Musculoskeletal
  name: Scoliosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had scoliosis, one of whom was observed at birth"
    explanation: Three of seven, one congenital.
- category: Musculoskeletal
  name: Ankle contracture
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ankle contracture
    term:
      id: HP:0034677
      label: Ankle contracture
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ankle contractures were observed in three patients."
    explanation: Three of seven.
- category: Musculoskeletal
  name: Limb muscle weakness
  frequency: OCCASIONAL
  description: >-
    Limb weakness is often mild or absent despite severe respiratory failure;
    when present it may be distal or proximal.
  phenotype_term:
    preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb muscle weakness was not pronounced except in two patients: P1, who had predominantly distal weakness, and P5, who had predominantly proximal weakness."
    explanation: Limb weakness in two of seven.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the case of a 23-year-old male patient who was admitted for acute respiratory failure and motor deficit of the distal upper limbs."
    explanation: Distal upper-limb weakness with acute respiratory failure.
- category: Gastrointestinal
  name: Dysphagia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had dysphagia, all of whom required nasogastric or gastrostomy tubes."
    explanation: Dysphagia severe enough for tube feeding in three of seven.
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
    explanation: Two of seven patients.
- category: Cardiovascular
  name: Mitral regurgitation
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mitral insufficiency
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac dysfunction was observed in three patients—two with hypertrophic cardiomyopathy and one with mitral insufficiency."
    explanation: One of seven patients.
- category: Laboratory
  name: Elevated circulating creatine kinase activity
  frequency: OCCASIONAL
  description: CK is usually normal; one child and one adult had raised values, the adult tenfold.
  phenotype_term:
    preferred_term: Elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum creatine kinase was within the normal range in all patients except for P4."
    explanation: CK elevation in one of seven.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine kinase values were elevated (10x upper normal limit)"
    explanation: Marked CK elevation in a whole-gene deletion case.
- category: Neuromuscular
  name: EMG myopathic abnormalities
  phenotype_term:
    preferred_term: Myopathic EMG
    term:
      id: HP:0003458
      label: "EMG: myopathic abnormalities"
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electromyography was performed on two patients (P4 and P5), and the results indicated myopathic changes, characterized by short-duration, low-amplitude, polyphasic motor unit potentials and early recruitment patterns."
    explanation: Myopathic EMG in both patients tested.
- category: Histopathology
  name: Muscle fiber inclusion bodies
  phenotype_term:
    preferred_term: Protein inclusions in muscle fibers
    term:
      id: HP:0100299
      label: Muscle fiber inclusion bodies
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
    explanation: Protein inclusions in the founding biopsies.
- category: Histopathology
  name: Rimmed vacuoles
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
    explanation: Occasional rimmed vacuoles on biopsy.
- category: Histopathology
  name: Angulated muscle fibers
  phenotype_term:
    preferred_term: Angular fibers
    term:
      id: HP:0034045
      label: Angulated muscle fibers
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
    explanation: Angular fibers on biopsy.
- category: Histopathology
  name: Increased variability in muscle fiber diameter
  phenotype_term:
    preferred_term: Fiber size variation
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "H&E staining from P1 at 4 years of age, demonstrating marked variation in fiber size, prominent endomysial fibrosis, and adipose tissue infiltration."
    explanation: Fiber size variation in a pediatric biopsy.
- category: Histopathology
  name: Increased endomysial connective tissue
  phenotype_term:
    preferred_term: Endomysial fibrosis
    term:
      id: HP:0100297
      label: Increased endomysial connective tissue
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On H&E of the muscle from P1, notable endomysial fibrosis and adipose tissue infiltration were observed"
    explanation: Endomysial fibrosis in a pediatric biopsy.
genetic:
- name: DNAJB4
  gene_term:
    preferred_term: DNAJB4
    term:
      id: hgnc:14886
      label: DNAJB4
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Reported biallelic alleles (NM_007034.5), all homozygous: J-domain
    missense c.74G>A p.(Arg25Gln), c.105G>C p.(Lys35Asn), c.181A>G
    p.(Arg61Gly); C-terminal missense c.785T>C p.(Leu262Ser); nonsense
    c.547C>T p.(Arg183*), c.775C>T p.(Arg259*), c.856A>T p.(Lys286*);
    frameshift c.308del p.(Gly103Glufs*25); an exon 2 deletion; and a
    whole-gene deletion. In a small cohort, J-domain missense alleles were
    associated with earlier onset (median 0.5 vs 28 years) and higher
    mortality (75% vs 14%). The heterozygous c.270T>A p.(Phe90Leu) variant in
    the G/F-rich domain causes a separate autosomal dominant distal myopathy
    with a proposed gain-of-function mechanism and is not part of this entry.
    The homozygous p.(Arg61Gly) family was first reported in an intellectual
    disability cohort (PMID:36344539); cognition was normal in the 2024
    cohort. No ClinGen gene-disease validity record for this pair was found in
    the local cache.
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure."
    explanation: Gene discovery report.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with other variants, the J-domain variants were associated with an earlier age of onset (0.5 vs. 28 years, P = 0.035) and a higher mortality rate (75% vs. 14%, P = 0.046)."
    explanation: Genotype-phenotype correlation in a small cohort.
  - reference: PMID:38127101
    reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, our case represents the first independent replication of autosomal recessive DNAJB4-related myopathy."
    explanation: Independent replication with homozygous c.308del.
animal_models:
- name: Dnajb4 knockout mouse
  species: Mus musculus
  genotype: Dnajb4-/-
  publication: PMID:36264506
  modeled_mechanisms:
  - target: Skeletal Muscle Fiber Atrophy and Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis.
    limitations: >-
      The knockout is a complete null and so does not model the stable
      J-domain missense alleles, and the cited abstract reports no lethal
      respiratory failure in the mice.
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis."
      explanation: Phenotype of the knockout.
  - target: Z-Disc Protein and Chaperone Accumulation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Knockout muscle accumulates Z-disc proteins and chaperones with myofibrillar disorganization.
    evidence:
    - reference: PMID:36264506
      reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones."
      explanation: Proteostasis lesion reproduced in knockout muscle.
  - target: Preferential Involvement of High-DNAJB4-Expressing Muscles
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Pathology concentrates in the soleus, the highest-expressing muscle.
    limitations: Mouse fiber-type composition differs from human, so the muscle pattern is not directly comparable.
    evidence:
    - reference: PMID:36512060
      reference_title: "Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression."
      explanation: Soleus-selective pathology in knockout mice.
experimental_models:
- name: DNAJB4 variant TDP-43 disaggregation and yeast complementation assays
  experimental_model_type: CELL_LINE
  description: >-
    HeLa cells co-expressing TDP-43 and DNAJB4 variants under heat shock, and
    sis1-deleted Saccharomyces cerevisiae complemented with DNAJB variants,
    used to classify stable missense alleles as loss of function.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:39468638
  modeled_mechanisms:
  - target: Loss of DNAJB4 Co-chaperone Function
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Measures DNAJB4 variant chaperone activity against a model client.
    limitations: >-
      TDP-43 is an experimental client, not an established disease substrate
      in muscle, and HeLa cells and yeast lack sarcomeres.
    evidence:
    - reference: PMID:39468638
      reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays."
      explanation: Assay results for the missense variants.
diagnosis:
- name: Exome sequencing
  description: >-
    Diagnosis is molecular, by exome sequencing or a neuromuscular panel
    including DNAJB4 with copy-number analysis, since whole-gene deletions
    occur. Reanalysis of earlier negative exomes has yielded diagnoses.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis."
    explanation: Exome sequencing identified the founding cases.
  - reference: PMID:38127101
    reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4)."
    explanation: Reanalysis yielded a DNAJB4 diagnosis.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis by NGS panel sequencing identified a homozygous deletion c.(?_1)_(1014_?)del, p.? (HGVS nomenclature) of the entire DNAJB4 gene, confirmed by qPCR."
    explanation: Whole-gene deletion detected by panel copy-number analysis.
- name: Muscle biopsy
  description: >-
    Myopathic changes with angular fibers, protein inclusions, occasional
    rimmed vacuoles and myofibrillar myopathy features; DNAJB4 protein is
    absent with null alleles.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles."
    explanation: Biopsy findings in the founding families.
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deltoid muscle biopsy findings were consistent with myofibrillar myopathy."
    explanation: Myofibrillar myopathy pattern in a later case.
- name: Muscle MRI
  description: Thigh MRI shows selective involvement of the semitendinosus and biceps femoris.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:36264506
    reference_title: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh."
    explanation: Selective muscle pattern on MRI.
- name: Pulmonary function testing
  description: >-
    Spirometry shows a restrictive defect. Regular respiratory screening is
    recommended.
  diagnosis_term:
    preferred_term: pulmonary function test
    term:
      id: NCIT:C38081
      label: Pulmonary Function Test
  evidence:
  - reference: PMID:40769870
    reference_title: "Homozygous DNAJB4 deletion revealing myopathy with acute respiratory failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values)"
    explanation: Restrictive physiology on pulmonary function testing.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is prudent to screen patients with DNAJB4 myopathy regularly for early cardiac and respiratory manifestations and dysphagia and proactively institute life-saving supportive measures."
    explanation: Authors recommend regular respiratory screening.
treatments:
- name: Non-Invasive Ventilation
  description: >-
    Nocturnal non-invasive ventilation for respiratory failure from
    diaphragmatic weakness. No DNAJB4-specific outcome series exists.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: non-invasive mechanical ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  - preferred_term: Hypercapnia
    term:
      id: HP:0012416
      label: Hypercapnia
  - preferred_term: Diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: PMID:38127101
    reference_title: "Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive respiratory failure due to diaphragmatic weakness, necessitating nightly non-invasive ventilation"
    explanation: Nightly NIV in an adult case.
- name: Mechanical Ventilation
  description: >-
    Invasive or prolonged ventilatory support for acute hypercapnic failure,
    required by most patients.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  - preferred_term: Hypercapnia
    term:
      id: HP:0012416
      label: Hypercapnia
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals experienced respiratory failure and required mechanical ventilation, except for Patient 2."
    explanation: Mechanical ventilation in six of seven patients.
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute respiratory failure with life-threatening hypercapnia necessitating prolonged ventilatory support is a hallmark of DNAJB4 myopathy"
    explanation: Ventilatory support for hypercapnic failure.
- name: Gastrostomy Feeding
  description: Nasogastric or gastrostomy tube feeding for dysphagia.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:39468638
    reference_title: "Genotype‒phenotype correlation in recessive DNAJB4 myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had dysphagia, all of whom required nasogastric or gastrostomy tubes."
    explanation: Tube feeding in all patients with dysphagia.
- name: DNAJB4 Gene Replacement (proposed)
  description: >-
    AAV-mediated DNAJB4 replacement is proposed for the loss-of-function
    recessive disease; no preclinical efficacy data or trials exist.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Loss of DNAJB4 Co-chaperone Function
    description: Would restore the missing co-chaperone.
    evidence:
    - reference: PMID:40696134
      reference_title: "Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "For these conditions, gene replacement therapy using adeno-associated virus (AAV) vectors to restore functional DNAJB4 protein represents a viable option"
      explanation: Proposal in a review; untested.
  evidence:
  - reference: PMID:40696134
    reference_title: "Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In contrast, disorders driven primarily by LOF mechanisms, such as many cases of recessive DNAJB4 myopathy, require fundamentally different therapeutic strategies."
    explanation: Frames gene replacement as the relevant strategy for the recessive form.
notes: >-
  No prevalence estimate exists; about a dozen affected individuals from
  roughly ten families were reported through 2025. MONDO places this term
  among the congenital myopathies although onset extends into the fifth
  decade. The dominant DNAJB4 p.(Phe90Leu) distal myopathy (PMID:36512060) is
  a distinct allelic disorder. Frontal atrophy and a thin corpus callosum were
  each seen in one patient and are not annotated because their relation to
  DNAJB4 is uncertain. Death in childhood is recorded in the respiratory
  failure phenotype description because HP:0003819 lies outside the
  phenotypic-abnormality branch that the phenotype slot accepts.
📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Congenital_Myopathy_21_With_Early_Respiratory_Failure · 2026-10-15T13:17:39Z · View source

New entry for MONDO:0957224 (recessive DNAJB4 myopathy). Inputs: the Perplexity deep-research report research/Congenital_Myopathy_21_With_Early_Respiratory_Failure-deep-research-perplexity.md, used as a lead list only, plus a PubMed search for DNAJB4 myopathy. Cited sources: Weihl 2023 gene discovery (PMID:36264506), Inoue 2024 cohort (PMID:39468638, full text), independent adult replication (PMID:38127101), homozygous whole-gene deletion case (PMID:40769870), J-domain protein myopathy review (PMID:40696134), and the dominant p.Phe90Leu paper for knockout-mouse soleus selectivity (PMID:36512060). The pathograph runs from two allele classes (unstable/absent protein; stable but nonfunctional J-domain missense) to loss of co-chaperone function, Z-disc protein accumulation (conforms to loss_of_proteostasis#Misfolded-Protein Aggregation), myofibrillar disorganization, fiber atrophy, preferential involvement of high-DNAJB4 muscles, respiratory pump failure, axial involvement and a cardiac branch; all 21 phenotypes are causally connected. The dominant DNAJB4 distal myopathy is excluded as a distinct allelic disorder. Death in childhood could not be bound because HP:0003819 is outside the PhenotypeTerm enum; it is described under respiratory failure. Validation: just validate, validate-terms, validate-disorders, count-verified-snippets (102/102), check-entity-refs, check-causal-targets, list-disconnected-phenotypes (0 disconnected), check-snippet-length, check-folded-hyphens all pass; check-genereviews reports no GeneReviews chapter.

Perplexity ▸
Congenital Myopathy 21 With Early Respiratory Failure
sonar-deep-research 55 citations 2026-10-15T12:34:21.743564

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

Publication Date and evidence type Key contribution PMID / DOI / URL
Weihl et al., “Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure” Online 20 October 2022; issue January 2023; primary human, cellular, yeast and mouse study Established recessive DNAJB4 myopathy in four patients from three families and demonstrated loss of chaperone function PMID 36264506; DOI 10.1007/s00401-022-02510-8; https://pmc.ncbi.nlm.nih.gov/articles/PMC9812937/ [54]
Inoue et al., “Genotype–phenotype correlation in recessive DNAJB4 myopathy” 28 October 2024; peer-reviewed human cohort plus functional assays Added seven affected persons/five families, five variants and preliminary genotype–phenotype statistics PMID 39468638; DOI 10.1186/s40478-024-01878-w; https://pmc.ncbi.nlm.nih.gov/articles/PMC11514740/ [47]
Al-Kasbi et al., “The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 Middle Eastern families” 7 November 2022; human WES cohort First report of homozygous DNAJB4 p.Arg61Gly in a ventilator-dependent child; subsequently incorporated into the disease spectrum PMID 36344539; DOI 10.1038/s41598-022-22036-z; https://pmc.ncbi.nlm.nih.gov/articles/PMC9640568/ [88]
Schoser et al., adult neuromuscular NGS reassessment Online 21 December 2023; human diagnostic cohort Independent replication with homozygous c.308del, identified on exome reanalysis https://pmc.ncbi.nlm.nih.gov/articles/PMC10972933/ [318]
Wang et al., congenital-myopathy standard-of-care consensus 2012; expert consensus Pulmonary, nutritional, orthopedic and rehabilitation management framework PMID 22431881; https://pmc.ncbi.nlm.nih.gov/articles/PMC5234865/ [106][109]

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

Identifier system Identifier / name
MONDO MONDO:0957224, congenital myopathy 21 with early respiratory failure
OMIM phenotype 620326
MedGen C5830424, UID 1841060
Causal gene OMIM DNAJB4: 611327
HGNC DNAJB4: HGNC:14886
NCBI Gene 11080
Ensembl ENSG00000162616
UniProt Q9UDY4
Cytogenetic location 1p31.1
Common abbreviation CMYO21
Common alternative descriptions DNAJB4-related myopathy with early respiratory failure; recessive DNAJB4 myopathy; DNAJB4-related rigid-spine myopathy; DNAJB4 chaperonopathy
ICD-10 No dedicated code; parent congenital-myopathy category G71.2 is the closest disease-class code
ICD-11 No dedicated code; congenital myopathies 8C72
MeSH No disease-specific descriptor identified; broader descriptors include congenital myopathies and muscle diseases
Orphanet No clearly established disease-specific recessive CMYO21 record was located. ORPHA:97245 is the parent “congenital myopathy” group. ORPHA:700170 refers instead to DNAJB4-related dominant distal myopathy, a distinct allelic disorder.

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.

Phenotype type Manifestation and suggested HPO term Onset, severity and progression Observed frequency/evidence Functional and quality-of-life effect
Clinical sign Respiratory failure — HP:0002878 Infancy to adulthood; often severe, progressive or abrupt; generally hypercapnic 6/7 developed failure in the 2024 cohort; the seventh was lost to follow-up at age two. All four foundational patients developed failure. [47][54] Hospitalization, syncope/arrest, long-term ventilation, tracheostomy and death
Clinical sign Diaphragmatic weakness — HP:0009113 May be isolated or disproportionate to limb weakness; chronic/progressive Defining feature in the original four cases; adult FVC was 38% and pCO₂ 70 mmHg in one patient. [54] Orthopnea/dyspnea, impaired sleep, dependence on assisted ventilation
Physiologic abnormality Nocturnal hypoventilation — HP:0002877; hypercapnia Often precedes daytime or acute respiratory failure Documented in an adult before syncope and respiratory failure; likely underdetected without CO₂ monitoring. [54] Morning symptoms, sleep fragmentation, daytime fatigue and sudden decompensation risk
Symptom Dyspnea — HP:0002094 Variable; may appear acutely in adults Both Spanish adult cases presented with dyspnea/hypercapnic insufficiency. [54] Exercise and sleep limitation
Musculoskeletal sign Spinal rigidity — HP:0003306 Infancy or adulthood; persistent/progressive 3/7 in the 2024 cohort and 3/4 foundational patients Reduced neck/trunk flexion, dressing and mobility difficulties; worsens chest-wall restriction
Musculoskeletal sign Axial muscle weakness — HP:0003327 Early or adult; often exceeds appendicular weakness Common component of rigid-spine presentation Impaired posture, head control and chest expansion
Musculoskeletal sign Neck stiffness / limited cervical motion Usually infancy in severe J-domain disease 3/7 in 2024 series Difficulty turning or bending the head
Musculoskeletal sign Scoliosis — HP:0002650 Congenital or progressive childhood/adolescent 3/7 in 2024 cohort Further restrictive physiology, seating and pain burden
Musculoskeletal sign Ankle/joint contractures — HP:0001371 Childhood, generally progressive 3/7 in 2024 cohort Reduced range of motion and walking efficiency
Symptom/sign Limb weakness — HP:0001324; distal weakness HP:0002460 or proximal weakness HP:0003701 Often absent or mild; can be adult progressive Pronounced in only two of seven recent patients—one distal, one proximal Gait and hand-function limitations when present
Feeding sign Dysphagia — HP:0002015 Severe pediatric form; chronic 3/7; all three required nasogastric or gastrostomy feeding. [47] Aspiration, malnutrition and caregiver burden
Infectious complication Recurrent lower respiratory infection — HP:0002783 Usually secondary to weak cough/dysphagia 4/7 in 2024 cohort Admissions, antibiotic use and accelerated respiratory decline
Cardiac sign Hypertrophic cardiomyopathy — HP:0001639 Variable; not universal Two recent patients plus one original patient; mitral insufficiency occurred in another Arrhythmia/heart-failure surveillance and treatment burden
Laboratory abnormality Elevated CK — HP:0003236 Normal to mildly/moderately elevated; nonspecific Original range normal to 500–700 U/L; recent cohort mostly normal, one 1,226 U/L Diagnostic clue only; not a severity biomarker
Electrophysiology Myopathic EMG — HP:0003458 Short-duration, low-amplitude, polyphasic units and early recruitment Present in most tested cases but not obligatory Supports muscle rather than neuropathic localization
Pathology Rimmed vacuoles — HP:0003805; fiber-size variation, angular fibers, inclusions Variable between muscles and disease stages Rimmed vacuoles and inclusions occurred in the foundational biopsies; inclusions were not evident in limited recent samples. [54][47] Diagnostic tissue evidence; not directly patient-reported
Imaging Selective hamstring involvement Semitendinosus/biceps femoris in initial study; semimembranosus and adductor longus in later cases Reproduced across small independent cohorts Can direct biopsy and support differential diagnosis
Neurologic/imaging Brain atrophy or thin corpus callosum Rare; uncertain direct causality Frontal atrophy in one patient; thin corpus callosum/mild atrophy in another Potential neurodevelopmental burden, but cognition was generally normal
Developmental Developmental/intellectual impairment Rare and attribution uncertain Reported in the original p.Arg61Gly candidate-gene family; not apparent in the 2024 cohort May require developmental support, but is not a core phenotype
Other Inguinal hernia, fetal growth restriction, lipoid pneumonia Isolated reports Seen in the p.Arg61Gly family Case-specific burden; insufficient evidence for core annotation

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

Field Information
Gene DNAJB4
Full name DnaJ heat shock protein family (Hsp40) member B4
HGNC HGNC:14886
NCBI Gene 11080
OMIM gene 611327
Ensembl ENSG00000162616
UniProt Q9UDY4
Locus 1p31.1; GRCh38 approximately chr1:77,979,175–78,017,964
Disease inheritance Autosomal recessive for CMYO21
Protein role HSP40/DNAJ co-chaperone; client recognition and recruitment to HSP70, stimulating HSP70 ATPase activity and protein folding/triage
Important localization Cytosol and skeletal-muscle Z-disc

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.

Variant Class/domain Population evidence Clinical/functional interpretation
c.74G>A, p.Arg25Gln Missense, J-domain Absent from gnomAD in foundational report ClinVar pathogenic; stable and Z-disc-localized but failed yeast complementation, TDP-43 disaggregation and heat-stress protection
c.105G>C, p.Lys35Asn Missense, J-domain gnomAD v4 AF 0.000003181, no homozygotes Called pathogenic by 2024 authors; increased stability but loss of function in yeast/disaggregation assays
c.181A>G, p.Arg61Gly Missense, J-domain Absent from gnomAD ClinVar pathogenic; segregated recessively; normal stability but defective functional assays
c.308del, p.Gly103GlufsTer25 Frameshift Rare; no population homozygotes reported Pathogenic homozygous variant identified on exome reanalysis in an adult with diaphragmatic respiratory failure
c.547C>T, p.Arg183Ter Nonsense gnomAD v4 AF 0.000008893, no homozygotes Pathogenic in 2024 study; rapidly degraded
c.775C>T, p.Arg259Ter Nonsense gnomAD v4 AF 0.000002813, no homozygotes Pathogenic in 2024 study; rapidly degraded
c.785T>C, p.Leu262Ser Missense, C-terminal substrate-binding region Absent from gnomAD in foundational report ClinVar pathogenic; unstable and rapidly degraded
c.856A>T, p.Lys286Ter Nonsense, last exon/C-terminal region Absent from gnomAD in foundational report ClinVar pathogenic; truncated protein absent/rapidly degraded
Exon 2 deletion, hg38 chr1:78,013,051–78,013,619 Exonic structural deletion Absent from gnomAD; no homozygotes Pathogenic loss-of-function allele in adult-onset disease

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

Category Current evidence
Toxins, radiation, pollution or occupational exposures No causal association
Smoking or alcohol No CMYO21-specific association; smoking would reasonably reduce respiratory reserve but has not been studied
Diet No preventive or causal diet identified
Exercise No evidence that exercise prevents disease. Individually prescribed submaximal activity may preserve function; exhaustive exercise has not been evaluated
Infection No pathogen causes CMYO21. Respiratory infection can cause acute deterioration because cough and ventilation are weak
Aspiration Secondary to dysphagia; contributes to pneumonia rather than primary disease
Heat/proteotoxic stress Mutant cells perform poorly under experimental heat shock, but a clinical environmental interaction is unproven

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:

Category Suggested ontology term
Biological process GO:0006457 — protein folding
Biological process GO:0051085 — chaperone cofactor-dependent protein refolding
Biological process Response to unfolded protein
Biological process Protein disaggregation
Biological process Sarcomere organization / myofibril organization
Molecular function GO:0031072 — heat-shock-protein binding
Molecular function GO:0051082 — unfolded-protein binding
Molecular function ATPase-activator activity
Cellular component Z-disc
Cellular component Myofibril / sarcomere
Cellular component Cytosol
Cell type CL:0000188 — cell of skeletal muscle
Cell type CL:0000594 — skeletal muscle fiber
Experimental cell CL:0000515 — skeletal muscle myoblast
Experimental cell CL:0002372 — myotube
Probable secondary cell Cardiomyocyte

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

Technology Disease-specific findings
Exome sequencing Main discovery and diagnostic technology
Genome sequencing No published CMYO21-specific systematic cohort; useful for unresolved CNVs/intronic variants
RNA sequencing No CMYO21-specific diagnostic series or transcriptomic signature
Proteomics No unbiased human proteomic dataset; targeted immunoblotting showed changes in Z-disc and chaperone proteins
Metabolomics/lipidomics No disease-specific data
Single-cell or spatial transcriptomics None reported
CRISPR screen No genome-wide screen; CRISPR was used to generate C2C12 knockout cells and knockout mice
Multi-omics None reported

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

Level Structure and suggested ontology Evidence
Primary organ Skeletal muscle — UBERON:0001134 / general skeletal-muscle tissue UBERON:0002036 Primary disease tissue
Primary muscle Diaphragm — UBERON:0001103 Disproportionate clinical weakness and severe knockout-mouse atrophy [245]
Axial sites Paraspinal, neck and chest-wall musculature Rigid spine, neck stiffness and limited chest expansion
Limb muscles Semitendinosus, biceps femoris; semimembranosus and adductor longus; sometimes soleus and gluteus maximus Selective MRI/CT abnormalities [321]
Secondary respiratory organs Lungs/airways Structurally secondary; affected by hypoventilation, weak cough, pneumonia and aspiration
Secondary skeleton Vertebral column Rigidity, kyphosis and scoliosis
Secondary cardiac site Myocardium and mitral valve apparatus HCM or mitral insufficiency in a subset
Tissue Striated skeletal-muscle tissue Fiber atrophy, fibrosis, fatty replacement and aggregates
Cell Multinucleated skeletal myofiber Principal target
Subcellular Z-disc, sarcomere, myofibril and cytosol DNAJB4 localization and aggregate pathology
Lateralization Generally bilateral/systemic No consistent unilateral pattern; selective muscles can be asymmetrically affected, but this is not defining

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

Investigation Expected/useful finding
Upright and supine spirometry Reduced FVC; a disproportionate supine decline supports diaphragm weakness
Maximal inspiratory/expiratory pressures Reduced respiratory-muscle strength
Peak cough flow Detects inadequate cough and need for cough assistance
Overnight oximetry with CO₂ measurement Sleep-related hypoventilation; oximetry alone may miss hypercapnia
Polysomnography Distinguishes hypoventilation from obstructive apnea
Arterial/capillary blood gas Elevated pCO₂; one index adult had pCO₂ 70 mmHg
Serum bicarbonate Chronic CO₂-retention clue
CK Often normal or mildly elevated; occasionally about 1,200 U/L
ECG and echocardiogram HCM, valvular disease or rhythm complications
Swallow study Dysphagia and aspiration
EMG/NCS Myopathic motor units; nerve conduction usually not the primary abnormality
Muscle MRI Selective posterior-thigh/hamstring involvement
Muscle biopsy Fiber-size variation, angular fibers, fibrosis, fatty replacement, rubbed-out/core-like regions, aggregates, Z-disc disruption and occasional rimmed vacuoles
Electron microscopy Z-disc streaming and granulofilamentous material

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

Differential Distinguishing considerations
SELENON-related rigid-spine muscular dystrophy/multiminicore disease Similar axial rigidity and disproportionate respiratory weakness; test SELENON and assess characteristic pathology
TTN-related hereditary myopathy with early respiratory failure Usually dominant/adult, often distal weakness; cytoplasmic bodies and TTN A-band variants
Late-onset Pompe disease Acid α-glucosidase deficiency; elevated biomarkers and enzyme assay; treatable
Nemaline myopathy, including NEB, ACTA1, TNNT1 Nemaline rods and gene-specific pattern
Myofibrillar myopathies—DES, CRYAB, FLNC, BAG3, FHL1 Overlapping aggregates and hamstring MRI; often different inheritance and cardiac/neuropathic patterns
Congenital muscular dystrophy due to LMNA or LAMA2 Dystrophic biopsy, contractures and gene-specific imaging
Spinal muscular atrophy Neurogenic EMG, areflexia and SMN1 testing
Congenital myasthenic syndrome Fatigability, decrement and neuromuscular-junction gene findings
Congenital myotonic dystrophy Maternal myotonia and DMPK expansion
Mitochondrial myopathy Multisystem features, lactate/respiratory-chain or mtDNA findings
Dominant DNAJB4 distal myopathy Heterozygous p.Phe90Leu, distal hand onset, later respiratory disease

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

Intervention Indication and practical role Suggested NCIT-style intervention term
Bilevel non-invasive positive-pressure ventilation with backup rate Nocturnal hypoventilation, hypercapnia or respiratory-muscle failure; preferred to CPAP because CPAP does not provide ventilation Noninvasive Positive Pressure Ventilation
Invasive mechanical ventilation/tracheostomy Severe acute failure, inability to protect airway or inadequate NIV Mechanical Ventilation; Tracheostomy
Mechanical insufflation–exsufflation and assisted cough Low peak cough flow, secretion retention or respiratory infection Cough Assist Therapy; Airway Clearance Therapy
Chest physiotherapy/suction Mobilization and removal of secretions Respiratory Therapy
Prompt antibiotics for bacterial infection Pneumonia or other bacterial respiratory infection; not chronic disease modification Antibiotic Therapy
Swallow evaluation and feeding modification Dysphagia or aspiration risk Swallowing Therapy; Nutritional Support
Nasogastric or gastrostomy feeding Unsafe swallow, aspiration or inadequate nutrition Enteral Nutrition; Gastrostomy
Physical and occupational therapy Preserve range, function and participation; prevent secondary contractures Physical Therapy; Occupational Therapy
Stretching, orthoses and seating support Contracture and scoliosis management Orthopedic Device; Rehabilitation Therapy
Scoliosis surgery Selected progressive deformity after respiratory/anesthetic planning Spinal Fusion
Cardiomyopathy-directed medication HCM, mitral disease, arrhythmia or heart failure according to cardiology standards Cardiovascular Therapy
Vaccination Reduce respiratory infectious complications Vaccination

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

Species Taxonomy identifier Ortholog / identifier Natural disease evidence
Human, Homo sapiens NCBI Taxon 9606 DNAJB4, NCBI Gene 11080 CMYO21
House mouse, Mus musculus NCBI Taxon 10090 Dnajb4, NCBI Gene 67035, MGI:1914285 Engineered models; no established analogous spontaneous breed disease
Rat, Rattus norvegicus NCBI Taxon 10116 Dnajb4, NCBI Gene 295549 No natural homologous disease established
Zebrafish, Danio rerio NCBI Taxon 7955 dnajb4, NCBI Gene 445061 No published CMYO21-like natural disease
Budding yeast, Saccharomyces cerevisiae NCBI Taxon 4932 SIS1 is a functional class-B DNAJ homolog, not a one-to-one vertebrate ortholog Used for complementation assays

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

Model Type/resource Recapitulated findings Applications Limitations
Dnajb4 knockout mouse Mammalian CRISPR knockout; C57BL/6NJ-Dnajb4^em1(IMPC)J/Mmjax; MMRRC_046155-JAX Kyphosis by four to eight months, reduced hanging-grid endurance, lower muscle mass, marked diaphragm thinning/atrophy, core-like fibers and accumulation of Z-disc/chaperone proteins Causal proof of loss of function; diaphragm biology; pathology; preclinical gene replacement Did not reproduce acute lethal respiratory failure within the reported period; forelimb grip was preserved through eight months
Dnajb4 p.Phe90Leu knock-in mouse Mammalian knock-in model of dominant allelic disease Weakness and type-1-fiber protein inclusions Distinguishes dominant toxic/dominant-negative disease from recessive CMYO21 Models a separate dominant distal myopathy, not CMYO21
C2C12 Dnajb4-knockout cells CRISPR skeletal-myoblast/myotube model Normal differentiation but excess fusion, larger myotubes, insoluble desmin/DNAJB6/CRYAB and myofibrillar aggregates Cell-autonomous proteostasis and rescue assays Murine immortalized cells do not model ventilation or systemic progression
Patient fibroblasts Human primary in-vitro model Reduced/absent DNAJB4 for destabilizing variants Protein stability and variant validation Fibroblasts are not mature skeletal myofibers
HEK293/Flp-In expression systems Human-cell overexpression model Variant-specific degradation kinetics Protein half-life and rescue experiments Artificial expression and non-muscle context
HeLa TDP-43 heat-shock assay Human-cell stress model Persistent TDP-43 aggregates with mutant DNAJB4 Functional classification of missense variants TDP-43’s role as the decisive disease client remains unproven
S. cerevisiae sis1 complementation Invertebrate/fungal functional system J-domain-equivalent variants failed to rescue essential Sis1 function Tests conserved DNAJ activity Yeast lacks vertebrate sarcomeres, diaphragm and clinical phenotype

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.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 17
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 34
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 5
Terms whose name was checked 8
Terms named correctly 5
Terms named as a different term 0
Terms whose name is worth a second look 3

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.