Bailey-Bloch Congenital Myopathy

Mendelian MONDO:0009722 Pathograph 22 Show in embeddings browser Congenital myopathy

Bailey-Bloch congenital myopathy is an autosomal recessive congenital myopathy caused by biallelic loss-of-function variants in STAC3, the muscle-specific adaptor that assembles the skeletal-muscle excitation-contraction (EC) coupling apparatus. STAC3 is not itself a channel: it is the scaffold that gets the CaV1.1 voltage sensor properly expressed at the triad and tunes its conformational coupling to the sarcoplasmic-reticulum calcium release channel RyR1. When that scaffold fails, depolarization of the T-tubule no longer releases calcium efficiently, and the disorder that results is congenital and structural rather than progressive and degenerative — hypotonia and weakness from birth, arthrogryposis and talipes, myopathic facies with ptosis, palatal anomalies including cleft palate, short stature, and progressive kyphoscoliosis, with intellect typically spared. The feature that makes the diagnosis anaesthetically load-bearing is a substantial risk of malignant hyperthermia on exposure to volatile anaesthetics or succinylcholine, arising from the same triad lesion rather than from RYR1 or CACNA1S variants of the patient's own. Two things about this entry are worth flagging up front. First, the eponym has actively harmed diagnosis: the disorder was first described in the Lumbee Native American tribe of North Carolina and named accordingly, and the label "Native American myopathy" then biased clinical suspicion away from patients of other ancestry for two decades. The recurrent c.851G>C (p.Trp284Ser) allele has since turned out to be a common cause of congenital hypotonia in Southern Africa, and the evidence now points to an African rather than an Amerindian origin for it. Second, the mechanism is not fully closed: functional work on patient muscle found EC coupling clearly impaired while the STAC3-CaV1.1 interaction itself was not measurably disrupted, which is recorded here as an open question rather than smoothed over.

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1
Inheritance
7
Pathophys.
1
Histopath.
15
Phenotypes
2
Gaps
22
Pathograph
2
Genes
7
Medical Actions
5
Differentials
3
Models
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic (homozygous or compound heterozygous) pathogenic STAC3 variants. Heterozygous carriers are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31219695 SUPPORT Human Clinical
"STAC3 disorder is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance directly.
PMID:23736855 SUPPORT Human Clinical
"As expected for an autosomal recessive disorder, all affected individuals were homozygous for a G>C missense mutation of base pair 1046 in exon 10 of the STAC3 gene"
Segregation in the five original Lumbee families established recessive inheritance of the founder allele.
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Discussions and Knowledge Gaps

2
If excitation-contraction coupling is clearly impaired in STAC3-patient muscle, but the STAC3-CaV1.1 interaction and CaV1.1 sarcolemmal localization are not measurably disrupted in that same tissue, what is the proximate lesion?
OPEN QUESTION stac3_cav11_interaction_paradox
Attached to
pathophysiology#Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
The intuitive model — patient variant disrupts STAC3 binding to CaV1.1, therefore coupling fails — is supported by biophysical work on the isolated W284S SH3 domain and by reduced DHPR levels in zebrafish, but the study that looked in human patient muscle found the interaction preserved. Compounding this, the SH3/II-III loop contact that W284S disrupts has since been shown to be facilitating rather than strictly required for coupling, while the essential contact is the one made by the N-terminal region. Curating a single clean chain here would paper over a genuine discrepancy between model systems and patient tissue.
Proposed experiments
Quantify CaV1.1 charge movement and STAC3 occupancy in patient-derived myotubes
stac3_patient_myotube_charge_movement
Measure gating charge, calcium release and STAC3-CaV1.1 stoichiometry side by side in myotubes carrying p.Trp284Ser, to determine whether the deficit lies in channel voltage sensing, in coupling efficiency, or in a step downstream of a normally assembled complex.
Show evidence (2 references)
PMID:30168660 SUPPORT Human Clinical
"Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants."
The patient-tissue result that creates the discrepancy.
PMID:30168660 SUPPORT Human Clinical
"While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction."
The authors state the open pathomechanism explicitly.
By what mechanism does loss of STAC3 confer susceptibility to anaesthetic-triggered malignant hyperthermia, given that affected patients do not carry pathogenic RYR1 or CACNA1S variants?
KNOWLEDGE GAP stac3_mh_trigger_mechanism
Attached to
pathophysiology#Anesthetic-Triggered Malignant Hyperthermia Susceptibility
Malignant hyperthermia susceptibility is one of the clinically decisive features of this disorder, yet the causal chain from an adaptor-protein loss to triggered uncontrolled calcium release is not worked out. It is not simply a more severe version of the coupling defect: the coupling defect reduces calcium release, while the crisis is an excess of it. The zebrafish knock-in does show increased caffeine-induced release and elevated store calcium, which is suggestive, but that has not been connected to volatile-anaesthetic triggering in patients.
Proposed experiments
Halothane and caffeine response in STAC3-null and W284S myotubes
stac3_halothane_contracture_myotubes
Compare halothane- and caffeine-evoked contracture and calcium release in myotubes reconstituted with wild-type STAC3, W284S STAC3, and no STAC3, on an otherwise wild-type RYR1 background, to test whether STAC3 loss is sufficient to produce a trigger-sensitive phenotype.
Show evidence (1 reference)
PMID:28003463 SUPPORT Model Organism
"Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+"
The suggestive model-organism observation, recorded as partial support because it has not been tied to anaesthetic triggering in patients.
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Pathophysiology

7
Biallelic STAC3 Loss of Function
STAC3 encodes a muscle-specific adaptor protein with an N-terminal C1 (cysteine-rich) domain, a linker region, and two tandem SH3 domains. Nearly all reported disease alleles are biallelic loss-of-function changes, and the overwhelming majority of patients worldwide are homozygous for the recurrent missense change c.851G>C (p.Trp284Ser), which substitutes a conserved tryptophan in the first SH3 domain. Nonsense, frameshift and splice-site alleles have also been reported, and a patient has been described carrying a deletion of the SH3 domains entirely.
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.
STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context functional_impact_category: LOSS_OF_FUNCTION
Downstream
Failure of STAC3-Dependent CaV1.1 Assembly at the Triad Loss of functional STAC3 removes the adaptor that positions and stabilizes the CaV1.1 voltage sensor in the triad junction.
Show evidence (3 references)
PMID:23736855 SUPPORT Human Clinical
"This mutation resulted in a tryptophan (W) to serine (S) substitution at amino acid 284 in the first SH3 domain"
Identifies the founder allele and locates it in the SH3-1 domain of STAC3.
PMID:23736855 SUPPORT Human Clinical
"we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM)"
Establishes STAC3 as the causal gene for this disorder.
PMID:40779452 SUPPORT In Vitro
"the most common mutation associated with STAC3 disorder, W284S in the SH3-1 domain, impairs the binding ability of STAC3"
Gives the biophysical consequence of the founder substitution.
Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
STAC3 is required for the functional expression of CaV1.1 (the dihydropyridine receptor, the skeletal-muscle L-type calcium channel that acts as the T-tubule voltage sensor) and for its conformational coupling to RyR1. Two distinct STAC3-CaV1.1 contacts have been resolved: the C1/linker region binds the proximal C-terminus of CaV1.1 and is necessary and sufficient for functional channel expression, while the SH3-1 domain binds the CaV1.1 II-III loop and, contrary to the long-standing assumption, is not strictly required for coupling but enhances calcium release. In zebrafish stac3 mutants, DHPR levels, functionality and stability are all reduced.
CACNA1S hgnc:1397 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CACNA1S (hgnc:1397). hgnc:1397 is a gene from the HUGO Gene Nomenclature Committee. RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee.
voltage-gated calcium channel activity GO:0005245 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased voltage-gated calcium channel activity (GO:0005245). GO:0005245 is a molecular function from the Gene Ontology. ↓ DECREASED
sarcoplasmic reticulum GO:0016529 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcoplasmic reticulum (GO:0016529). GO:0016529 is a cellular component from the Gene Ontology.
Animal models
stac3 NAM knock-in zebrafish Zebrafish recapitulates Reduced DHPR/CaV1.1 levels, functionality and stability in the presence of the patient-equivalent substitution.
Downstream
Defective Skeletal Muscle Excitation-Contraction Coupling Without a properly assembled and voltage-competent CaV1.1, T-tubule depolarization fails to trigger RyR1-mediated calcium release.
Show evidence (3 references)
PMID:40779452 SUPPORT In Vitro
"A key regulator of this process is STAC3, a protein essential for both the functional expression of CaV1.1 and its conformational coupling with RyR1."
States the two roles of STAC3 that this node represents.
PMID:40779452 SUPPORT In Vitro
"we demonstrated that the interaction between STAC3 and the proximal C-terminus is necessary and sufficient for CaV1.1 functional expression and minimal EC coupling"
Assigns the essential channel-expression role to the N-terminal contact rather than to the SH3/II-III loop contact.
PMID:28003463 SUPPORT Model Organism
"we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants"
Direct measurement of the CaV1.1/DHPR deficit caused by loss of Stac3.
Defective Skeletal Muscle Excitation-Contraction Coupling
The functional core of the disease. Depolarization of the T-tubule membrane no longer efficiently triggers release of calcium from the sarcoplasmic reticulum, so the myofibre generates less force for a given electrical stimulus. The contractile machinery itself and gross triad architecture are comparatively preserved, which is why this is a coupling failure rather than a structural myopathy in the usual sense. In patient muscle, KCl-induced depolarization produced significantly reduced sarcoplasmic-reticulum calcium release.
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.
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808). GO:0014808 is a biological process from the Gene Ontology. ↓ DECREASED skeletal muscle contraction GO:0003009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased skeletal muscle contraction (GO:0003009). GO:0003009 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
stac3 mi34 null zebrafish Zebrafish recapitulates Mutant muscle shows greatly reduced calcium transients with intact contractile machinery and grossly normal triad anatomy, isolating the defect to coupling itself.
Downstream
Congenital Muscle Weakness Less calcium released per depolarization means less force per stimulus, from fetal life onward.
Anesthetic-Triggered Malignant Hyperthermia Susceptibility The same triad lesion confers susceptibility to pharmacologically triggered uncontrolled calcium release, but the steps connecting STAC3 loss to the MH trigger cascade are not established.
Show evidence (2 references)
PMID:30168660 SUPPORT Human Clinical
"In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release."
Demonstrates the coupling defect in muscle from patients rather than only in model systems.
PMID:23736855 SUPPORT Model Organism
"Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling."
Shows the patient allele itself, not just a null, reduces EC coupling.
Congenital Muscle Weakness
Reduced force generation produces generalized hypotonia and weakness present at birth, with the characteristic myopathic facies and ptosis reflecting involvement of facial and levator musculature. Bulbar weakness gives feeding difficulty and aspiration risk; respiratory and paraspinal weakness gives restrictive lung disease and, over time, progressive kyphoscoliosis and short stature. Palatal anomalies including cleft palate are part of the same congenital pattern. Curated separately from the contracture node below because the two have different proximate causes — weakness is the direct consequence of reduced force, whereas contractures come from the reduced fetal movement that weakness produces.
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
Reduced Fetal Movement and Congenital Joint Contracture Weak fetal muscle moves the joints less, and joints that do not move in utero form fixed contractures.
Show evidence (2 references)
PMID:31219695 SUPPORT Human Clinical
"Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures."
GeneReviews summary of the core musculoskeletal phenotype.
PMID:36030003 SUPPORT Human Clinical
"characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia"
Independent statement of the same clinical constellation in a non-Lumbee cohort.
Reduced Fetal Movement and Congenital Joint Contracture
The fetal-akinesia arm. Weak intrauterine movement leaves joints fixed in position, producing the contracture spectrum seen at birth — isolated talipes equinovarus at the mild end through arthrogryposis multiplex congenita at the severe end. Decreased fetal movement is directly documented in the majority of STAC3 patients in a cohort that recorded it, which is what makes this a separate mechanistic step rather than a restatement of weakness.
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.
Show evidence (2 references)
PMID:39966651 SUPPORT Human Clinical
"Notably, cleft palate (40%), talipes equinovarus (50%), and cryptorchidism (16%) were frequently observed, with a higher incidence than in some other cohorts, reinforcing the unique phenotypic characteristics of KDS-like presentations in African patients."
Quantifies the contracture-spectrum burden in a cohort whose STAC3 arm is the larger of the two genotype groups.
PMID:36030003 SUPPORT Human Clinical
"characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia"
Places arthrogryposis and talipes among the defining congenital features.
Anesthetic-Triggered Malignant Hyperthermia Susceptibility
Exposure to halogenated volatile anaesthetics or succinylcholine can precipitate a hypermetabolic malignant hyperthermia crisis. This is a genuinely separate consequence of the triad lesion rather than a severity marker of the myopathy: it is incompletely penetrant, patients may have had several uneventful anaesthetics before a crisis, and in reported STAC3 patients it occurs without pathogenic RYR1 or CACNA1S variants. The mechanistic route from STAC3 loss to triggered uncontrolled calcium release is not established, and this entry does not assert one.
STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808). GO:0014808 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (3 references)
PMID:40262809 SUPPORT Human Clinical
"We report three MH crises, in two boys and one girl, 2 to 15 years old. All of them received halogenated agents and one additionally received succinylcholine."
Documents the triggering agents in confirmed STAC3 patients.
PMID:40262809 SUPPORT Human Clinical
"Two patients presented two to four previous uneventful general anesthesia."
Supports the statement that an uneventful prior anaesthetic does not exclude risk.
PMID:40262809 SUPPORT Human Clinical
"The MH crises in this series of patients with STAC3 gene mutations demonstrated variable clinical characteristics (expressivity) and occurrence (penetrance)."
Supports incomplete penetrance and variable expressivity of the MH trait.
Skeletal Muscle Lipid Accumulation
An emerging and deliberately hedged branch. Increased lipid content in skeletal muscle has been noted in patients, and a CRISPR stac3-knockout zebrafish reproduces it, with elevated neutral lipid levels appearing alongside cytoskeletal and myogenic-regulator changes. Whether the lipid accumulation is a driver of weakness or a downstream consequence of it is explicitly unresolved, and the supporting measurements are in zebrafish, not human muscle.
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
stac3 CRISPR knockout zebrafish (lipid phenotype) Zebrafish partially recapitulates Reproduces the increased muscle lipid noted clinically in patients, with a developmental time course.
Show evidence (2 references)
PMID:39592070 SUPPORT Model Organism
"These muscle alterations were associated with elevated neutral lipid levels starting at 5 dpf and persisting beyond 7 dpf."
Reports the lipid finding in the zebrafish knockout that motivates this node.
PMID:39592070 SUPPORT Human Clinical
"Clinically, NAM patients demonstrated increased lipids in skeletal muscle, but it is unclear if neutral lipids are associated with altered muscle function in NAM."
States both the human observation and the explicit uncertainty about its functional significance, which is why this node is curated at low confidence.
✶

Histopathology

1
Non-Specific Myopathic Muscle Biopsy FREQUENT
Muscle biopsy is abnormal in most patients who undergo it, but the findings are non-specific: type 1 fibre predominance is the commonest single pattern, followed by generic myopathic features, mild atrophic fibres, and type 2 fibre predominance. There is no defining structural lesion of the kind that names other congenital myopathies (no cores, no rods, no central nuclei as a defining feature), which is precisely why biopsy cannot make this diagnosis and molecular testing must. Increased lipid droplets and subsarcolemmal mitochondrial accumulation have also been described on electron microscopy and are the human counterpart of the lipid finding modelled in zebrafish.
Show evidence (2 references)
PMID:38824262 SUPPORT Human Clinical
"Abnormal muscle biopsy histology results were reported in 11/16 patients (69%). and included documented type 1 muscle fibre predominance (5/11 (45%)), features of non-specific myopathy (3/11 (27%)), mild atrophic fibres (2/11 (18%)), and type 2 muscle fibre predominance (1/11 (9%))."
Quantifies both the yield and the pattern distribution of muscle biopsy in a genotype-confirmed cohort.
PMID:38824262 SUPPORT Human Clinical
"Muscle biopsy histology was abnormal in most patients who underwent the procedure (69%), with non-specific myopathy features being most common, consistent with previous reports"
States the non-specificity that limits the diagnostic value of biopsy here.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Bailey-Bloch Congenital Myopathy 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

15
Digestive 1
Feeding Difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones."
GeneReviews names feeding difficulties as a defining feature.
Ear 1
Sensorineural Hearing Impairment VERY_RARE HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"Additionally, he had bilateral hearing loss (threshold of 50 dB in the right ear and 70 dB in the left), and polysomnography revealed an obstructive sleep apnea syndrome."
Single-patient report; supports the observation but not a frequency estimate.
Eye 1
Ptosis VERY_FREQUENT HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature."
GeneReviews lists ptosis as a common finding.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39966651 SUPPORT Human Clinical
"These patients exhibit a range of KDS characteristics, including myopathy, ptosis, malar hypoplasia, skeletal and other dysmorphic features, cryptorchidism, and, in some cases, documented episodes of MH following surgery."
Lists cryptorchidism among the features of the cohort in which STAC3 was one of the two causal genes; PARTIAL because the description covers the mixed RYR1/STAC3 cohort rather than STAC3 patients alone.
Head and Neck 2
Myopathic Facies VERY_FREQUENT HP:0002058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic facies (HP:0002058). HP:0002058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures."
GeneReviews lists myopathic facies among the near-universal features.
Cleft Palate VERY_FREQUENT HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia."
Quantifies palatal involvement at 93%, supporting the VERY_FREQUENT band.
Limbs 1
Talipes Equinovarus FREQUENT HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia."
Gives the 59% figure underlying the FREQUENT band.
Metabolism 1
Malignant Hyperthermia Susceptibility OCCASIONAL HP:0002047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malignant hyperthermia (HP:0002047). HP:0002047 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:39966651 SUPPORT Human Clinical
"Eighteen (41%) participants had undergone surgery. Among this subset, MH was observed in eight (18%) participants from the STAC3 group."
Second cohort figure underlying the OCCASIONAL band.
PMID:39966651 SUPPORT Human Clinical
"Reliable data on MH are challenging to collect since this is only expected to develop upon administration of volatile anaesthetic gasses (isoflurane) or succinylcholine"
States the ascertainment problem that makes any cohort rate a floor, which is why the band is set conservatively rather than from the highest reported series.
PMID:31219695 SUPPORT Human Clinical
"Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased."
GeneReviews states the increased malignant hyperthermia risk.
+ 1 more reference
Musculoskeletal 2
Congenital Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia."
Names congenital hypotonia as a defining feature; the cohort was ascertained through hypotonia referrals.
Kyphoscoliosis FREQUENT HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751), qualified as course progressive. HP:0002751 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia."
Gives the 52% spinal-anomaly figure underlying the FREQUENT band.
Nervous System 1
Delayed Motor Milestones FREQUENT Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones."
GeneReviews names delayed motor milestones as a defining feature.
Respiratory 1
Restrictive Respiratory Insufficiency FREQUENT 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 (2 references)
PMID:31219695 SUPPORT Human Clinical
"Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased."
GeneReviews explicitly flags increased risk of restrictive lung disease.
PMID:37626540 SUPPORT Human Clinical
"Pulmonary function tests (PFTs) revealed a moderate restrictive lung disease."
Documents the restrictive pattern on formal pulmonary function testing.
Growth 1
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature."
GeneReviews lists short stature among the common findings.
Other 2
Arthrogryposis Multiplex Congenita FREQUENT HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia."
Gives the 38% figure underlying the FREQUENT band.
Normal Intellect
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal."
GeneReviews states that intellect is typically spared. The quote carries the preceding sentence so it states a finding rather than a bare clause.
🧬

Genetic Associations

2
STAC3 (Genetic Mutation)
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:23736855 SUPPORT Human Clinical
"we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM)"
Original identification of STAC3 as the causal gene.
PMID:37626540 SUPPORT Human Clinical
"Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is a condition caused by biallelic missense pathogenic variants in STAC3, which encodes an important protein necessary for the excitation-relaxation coupling machinery in the muscle."
Confirms the gene-disease relationship and the biallelic requirement under the CMYP13 designation.
STAC3 c.851G>C recurrent allele (Genetic Mutation)
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:38824262 SUPPORT Human Clinical
"The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks."
States the revised origin hypothesis for the recurrent allele.
PMID:36030003 SUPPORT Human Clinical
"Local history and geography may explain the overrepresentation of NAM in the Comorian Archipelago with a founder effect."
Documents a second, independent founder population for the same allele.
💊

Medical Actions

7
Avoidance of Malignant Hyperthermia Triggering Anaesthetics
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
The single most consequential intervention in this disorder. Halogenated volatile anaesthetics and depolarizing neuromuscular blockers are avoided outright; total intravenous anaesthesia is used instead, with dantrolene immediately available. A previous uneventful general anaesthetic does not establish safety.
Mechanism Target:
INHIBITS Anesthetic-Triggered Malignant Hyperthermia Susceptibility — Removing the pharmacologic trigger prevents the crisis; it does not modify the underlying triad lesion.
Show evidence (2 references)
PMID:31219695 SUPPORT Human Clinical
"Agents/circumstances to avoid: Anesthetic agents with a high risk of triggering malignant hyperthermia."
GeneReviews management guidance naming trigger avoidance.
PMID:40262809 SUPPORT Human Clinical
"Neuromuscular patients with findings suggestive of STAC3 myopathy should increase diagnostic suspicion regarding the risk of MH."
Supports pre-emptive recognition as the basis for anaesthetic planning.
Physical and Occupational Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Range-of-motion work, stretching, splinting and adaptive devices to maintain mobility and limit contracture progression.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Occupational and physical therapy needs regarding range of motion and mobility."
GeneReviews management guidance for the musculoskeletal manifestations.
Orthopaedic Management of Spinal and Limb Deformity
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Bracing and surgical correction for progressive scoliosis and for talipes deformity.
Target Phenotypes: Kyphoscoliosis HP:0002751 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Kyphoscoliosis (HP:0002751). HP:0002751 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Surveillance: Routine monitoring of growth, musculoskeletal complications (e.g., scoliosis and/or joint contractures), speech development, swallowing function, respiratory function, and educational needs."
Establishes scoliosis and contractures as monitored, managed complications.
Cleft Palate Repair by a Multidisciplinary Craniofacial Team
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Timing and technique of palatal surgery are decided by a craniofacial team because the anaesthetic and respiratory comorbidities of this disorder change the risk calculus relative to isolated cleft palate.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Due to the medical comorbidities in STAC3 disorder, decisions regarding type and timing of cleft palate surgery should be determined by a multidisciplinary craniofacial team."
GeneReviews guidance, including the reason the decision is team-based.
Ptosis Repair
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Surgical correction of ptosis (levator resection or frontalis sling) to prevent deprivation amblyopia and improve the visual field. Whether it is delivered by an ophthalmologist within the craniofacial team or as a separate intervention depends on how that team is organised — and either way it inherits the anaesthetic constraint that governs every procedure in this disorder.
Target Phenotypes: Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Depending on the structure of the managing craniofacial team, interventions for ptosis may be undertaken by an ophthalmologist as part of team care, or as an insertion intervention."
GeneReviews management guidance for ptosis, including who delivers it.
Nutritional and Feeding Support
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Speech-language pathology and nutrition assessment, specialized feeding equipment, and nasogastric or gastrostomy feeding when oral intake is unsafe or inadequate.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Surveillance: Routine monitoring of growth, musculoskeletal complications (e.g., scoliosis and/or joint contractures), speech development, swallowing function, respiratory function, and educational needs."
Establishes swallowing function and growth as monitored domains driving feeding intervention.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive recurrence risk of 25% per pregnancy for carrier couples; carrier and prenatal testing are available once the familial variants are known. Relevant well beyond the Lumbee population given the worldwide distribution of the recurrent allele.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
Provides the recurrence risk that genetic counselling communicates.
🌍

Environmental Factors

1
Exposure to halogenated volatile anaesthetics or succinylcholine
The only established environmental determinant in this disorder. It does not cause or modify the underlying myopathy; it converts a latent triad susceptibility into an acute, potentially fatal hypermetabolic crisis.
Show evidence (1 reference)
PMID:31219695 SUPPORT Human Clinical
"Agents/circumstances to avoid: Anesthetic agents with a high risk of triggering malignant hyperthermia."
GeneReviews records the exposure as the disorder's designated agent to avoid.
Mechanism Target:
TRIGGERS Anesthetic-Triggered Malignant Hyperthermia Susceptibility — Halogenated agents and depolarizing neuromuscular blockers are the documented triggers of malignant hyperthermia crises in patients with biallelic STAC3 variants.
Show evidence (1 reference)
PMID:40262809 SUPPORT Human Clinical
"We report three MH crises, in two boys and one girl, 2 to 15 years old. All of them received halogenated agents and one additionally received succinylcholine."
Directly links the exposure to crises in STAC3 patients.
🔬

Diagnosis

4
Molecular Genetic Testing of STAC3
Diagnosis rests on biallelic pathogenic STAC3 variants in a proband with a compatible phenotype. Targeted testing for c.851G>C is a reasonable first step in populations where the allele is common; otherwise a congenital myopathy panel or exome sequencing is used. The key practice point is that ancestry must not gate the test.
Show evidence (2 references)
PMID:31219695 SUPPORT Human Clinical
"The diagnosis of STAC3 disorder is established in a proband with suggestive clinical findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing."
States the diagnostic standard.
PMID:30168660 SUPPORT Human Clinical
"This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported."
Explicit recommendation that testing not be restricted by ancestry.
Genetics-Before-Biopsy Testing Strategy
A sequencing decision that is specific to this disorder rather than generic good practice: because muscle biopsy requires anaesthesia and this disorder carries malignant hyperthermia risk, the biopsy is itself a hazard, and its yield is non-specific anyway. Genetic testing should therefore come first. The same logic applies to the diagnostic yield of targeted testing: 25 of 127 (20%) samples referred for congenital hypotonia in one Southern African laboratory cohort were homozygous for the founder allele, so in that setting a single targeted test resolves a fifth of the referral population without any procedure.
Show evidence (2 references)
PMID:38824262 SUPPORT Human Clinical
"In a patient with suspected STAC3 disorder, genetic testing should be performed as the first line investigation, instead of a muscle biopsy which could pose a risk for MH."
States the testing-order recommendation and the reason for it.
PMID:38824262 SUPPORT Human Clinical
"In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C."
Quantifies the diagnostic yield of targeted testing in a congenital-hypotonia referral population.
Electromyography
Shows a myopathic pattern. Supportive rather than diagnostic, and it does not distinguish this disorder from other congenital myopathies.
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"Electromyography (EMG) revealed a myopathic pattern-polyphasic, short-duration, low-amplitude motor unit action potentials, and early recruitment."
Describes the electrophysiological findings.
Serum Creatine Kinase
Normal or only mildly elevated, so a normal CK does not argue against the diagnosis. Recorded because a normal CK is a common reason congenital myopathy is dismissed.
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"Creatine phosphokinase (CK) levels were normal."
Documents a normal CK in a genetically confirmed patient.
📊

Prevalence

2
Lumbee Native American tribe, North Carolina
Point Prevalence 20.0 per 100,000 1–9 per 10,000
Founder-population estimate of approximately 1 in 5,000 among enrolled Lumbee tribal members, reported by GeneReviews. Recorded as a class-level estimate; the numeric rate is the arithmetic conversion of 1 in 5,000.
Southern African population (derived from healthy-cohort carrier rate)
Birth Prevalence 8.0 per 100,000 1–9 per 100,000
Predicted birth rate of 1 in 12,500 derived from an observed carrier rate of 1 in 56 in a healthy Southern African cohort.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort."
Source of both the carrier frequency and the derived birth prevalence.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Bailey-Bloch Congenital Myopathy:

King-Denborough syndrome
Overlapping Features Congenital myopathy with dysmorphic features and malignant hyperthermia susceptibility. The relationship is one of overlap rather than exclusion: in a South African cohort of 44 patients diagnosed clinically with King-Denborough syndrome, biallelic STAC3 and RYR1 variants were the two predominant causes, so a King-Denborough phenotype is a reason to test STAC3, not to stop.
Distinguishing Features
  • Genotype rather than phenotype discriminates the two labels
  • RYR1 is the alternative causal gene in this presentation
Show evidence (1 reference)
PMID:39966651 SUPPORT Human Clinical
"The study identified RYR1 and STAC3 mutations as the predominant genetic causes of KDS in this cohort, with mutations in both genes exhibiting autosomal recessive inheritance."
Establishes the genetic overlap between the two clinical labels.
Central core myopathy MONDO:0007294
Overlapping Features RYR1-related congenital myopathy that also features contractures, respiratory insufficiency and malignant hyperthermia susceptibility.
Distinguishing Features
  • Characteristic central cores on muscle biopsy
  • RYR1 rather than STAC3 genotype
  • Frequently autosomal dominant rather than recessive
Carey-Fineman-Ziter syndrome Not Yet Curated MONDO:0031415
Overlapping Features Congenital myopathy sharing the upturned nasal tip, micrognathia, generalized muscle hypoplasia and delayed motor milestones. Clinically the most useful differential in this entry, because the discriminating feature is exactly the one that changes management. Bound to the phenotypic-series parent rather than to Carey-Fineman-Ziter syndrome 1 (MONDO:0800437, the MYMK-related form), because the differential holds across the series and type 2 has a different causal gene.
Distinguishing Features
  • No malignant hyperthermia susceptibility, so anaesthetic precautions differ
  • A different causal gene — MYMK in Carey-Fineman-Ziter syndrome 1
Moebius syndrome Not Yet Curated MONDO:0008006
Overlapping Features Overlaps through cleft palate, talipes, short stature, scoliosis and contractures, and is genetically heterogeneous.
Distinguishing Features
  • Obligatory impairment of ocular abduction and other cranial nerve findings
  • No malignant hyperthermia susceptibility
X-linked myotubular myopathy
Overlapping Features A severe congenital myopathy that is mechanistically unrelated — X-linked, caused by loss of the MTM1 lipid phosphatase, without malignant hyperthermia susceptibility. Listed here specifically because it is the entity a name-based search for this disorder is most likely to be confused with.
Distinguishing Features
  • X-linked rather than autosomal recessive inheritance
  • MTM1 genotype
  • No malignant hyperthermia susceptibility
🐁

Animal Models

3
stac3 mi34 null zebrafish
The founding model. An unbiased forward genetic screen for zebrafish locomotor mutants isolated mi34, mapped it to stac3, and thereby identified the human disease gene — the model preceded and produced the gene-disease association rather than following it.
Species
Zebrafish
Genotype
stac3 mi34 splice-donor mutation (functionally null)
Publication
PMID:23736855
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling recapitulates fidelity: high Mutant muscle shows greatly reduced calcium transients with intact contractile machinery and grossly normal triad anatomy, isolating the defect to coupling itself.
Limitations: A functional null, so it models the severe end of the human allelic spectrum rather than the hypomorphic missense biology of most patients; larvae die and the model cannot address the progressive musculoskeletal deformity or the malignant hyperthermia trait.
Show evidence (1 reference)
PMID:23736855 SUPPORT Model Organism
"Ca2+ transients were greatly reduced in both mutant slow and fast twitch fibers (Fig. 2b,c). Thus EC coupling in skeletal muscles was defective in the mi34 mutants."
Reports the calcium-release measurement that grounds the coupling claim.
stac3 NAM knock-in zebrafish
Knock-in of the patient allele rather than a null, making it the closer model of human founder-variant biology.
Species
Zebrafish
Genotype
stac3 encoding the W-to-S substitution equivalent to human p.Trp284Ser
Publication
PMID:28003463
Pathograph links
Failure of STAC3-Dependent CaV1.1 Assembly at the Triad recapitulates fidelity: moderate Reduced DHPR/CaV1.1 levels, functionality and stability in the presence of the patient-equivalent substitution.
Limitations: The knock-in also shows increased caffeine-induced calcium release and increased internal store calcium, a gain-of-release phenotype whose relation to the human malignant hyperthermia trait has not been established; reading it as an MH mechanism would overstate the evidence.
Show evidence (1 reference)
PMID:28003463 SUPPORT Model Organism
"Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants."
The measurement behind the channel-assembly claim.
stac3 CRISPR knockout zebrafish (lipid phenotype)
A CRISPR knockout used to follow early skeletal muscle development, which surfaced neutral lipid accumulation alongside the expected weakness.
Species
Zebrafish
Genotype
stac3-/- CRISPR/Cas9 knockout
Publication
PMID:39592070
Pathograph links
Skeletal Muscle Lipid Accumulation partially recapitulates fidelity: low Reproduces the increased muscle lipid noted clinically in patients, with a developmental time course.
Limitations: Whether lipid accumulation contributes to weakness or merely accompanies it is unresolved in both the model and patients; the knockout does not survive past 11 days post-fertilization, so no chronic or adult phenotype can be assessed.
Show evidence (1 reference)
PMID:39592070 SUPPORT Model Organism
"we determined that loss of stac3 leads to delayed larval hatching which corresponds with muscle weakness and decreased whole-body Ca2+ level during early skeletal development"
Reports the model's core muscle phenotype in which the lipid finding was observed.
{ }

Source YAML

click to show 
name: Bailey-Bloch Congenital Myopathy
creation_date: "2026-08-15T00:00:00Z"
category: Mendelian
parents:
- Congenital myopathy
synonyms:
- Native American myopathy
- NAM
- STAC3 disorder
- STAC3-related congenital myopathy
- Congenital myopathy 13
- CMYP13
- congenital myopathy - cleft palate - malignant hyperthermia
disease_term:
  preferred_term: Bailey-Bloch Congenital Myopathy
  term:
    id: MONDO:0009722
    label: Bailey-Bloch congenital myopathy
description: >-
  Bailey-Bloch congenital myopathy is an autosomal recessive congenital myopathy
  caused by biallelic loss-of-function variants in STAC3, the muscle-specific
  adaptor that assembles the skeletal-muscle excitation-contraction (EC) coupling
  apparatus. STAC3 is not itself a channel: it is the scaffold that gets the
  CaV1.1 voltage sensor properly expressed at the triad and tunes its
  conformational coupling to the sarcoplasmic-reticulum calcium release channel
  RyR1. When that scaffold fails, depolarization of the T-tubule no longer
  releases calcium efficiently, and the disorder that results is congenital and
  structural rather than progressive and degenerative — hypotonia and weakness
  from birth, arthrogryposis and talipes, myopathic facies with ptosis, palatal
  anomalies including cleft palate, short stature, and progressive
  kyphoscoliosis, with intellect typically spared. The feature that makes the
  diagnosis anaesthetically load-bearing is a substantial risk of malignant
  hyperthermia on exposure to volatile anaesthetics or succinylcholine, arising
  from the same triad lesion rather than from RYR1 or CACNA1S variants of the
  patient's own.

  Two things about this entry are worth flagging up front. First, the eponym has
  actively harmed diagnosis: the disorder was first described in the Lumbee
  Native American tribe of North Carolina and named accordingly, and the label
  "Native American myopathy" then biased clinical suspicion away from patients of
  other ancestry for two decades. The recurrent c.851G>C (p.Trp284Ser) allele has
  since turned out to be a common cause of congenital hypotonia in Southern
  Africa, and the evidence now points to an African rather than an Amerindian
  origin for it. Second, the mechanism is not fully closed: functional work on
  patient muscle found EC coupling clearly impaired while the STAC3-CaV1.1
  interaction itself was not measurably disrupted, which is recorded here as an
  open question rather than smoothed over.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic (homozygous or compound heterozygous) pathogenic
    STAC3 variants. Heterozygous carriers are unaffected.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAC3 disorder is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews states the mode of inheritance directly.
  - reference: PMID:23736855
    reference_title: >-
      Stac3 is a component of the excitation-contraction coupling machinery and
      mutated in Native American myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As expected for an autosomal recessive disorder, all affected individuals
      were homozygous for a G>C missense mutation of base pair 1046 in exon 10 of
      the STAC3 gene
    explanation: >-
      Segregation in the five original Lumbee families established recessive
      inheritance of the founder allele.
prevalence:
- population: Lumbee Native American tribe, North Carolina
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 20.0
  notes: >-
    Founder-population estimate of approximately 1 in 5,000 among enrolled Lumbee
    tribal members, reported by GeneReviews. Recorded as a class-level estimate;
    the numeric rate is the arithmetic conversion of 1 in 5,000.
- population: Southern African population (derived from healthy-cohort carrier rate)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 8.0
  notes: >-
    Predicted birth rate of 1 in 12,500 derived from an observed carrier rate of
    1 in 56 in a healthy Southern African cohort.
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated
      from a healthy cohort.
    explanation: >-
      Source of both the carrier frequency and the derived birth prevalence.
pathophysiology:
- name: Biallelic STAC3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    STAC3 encodes a muscle-specific adaptor protein with an N-terminal C1
    (cysteine-rich) domain, a linker region, and two tandem SH3 domains. Nearly
    all reported disease alleles are biallelic loss-of-function changes, and the
    overwhelming majority of patients worldwide are homozygous for the recurrent
    missense change c.851G>C (p.Trp284Ser), which substitutes a conserved
    tryptophan in the first SH3 domain. Nonsense, frameshift and splice-site
    alleles have also been reported, and a patient has been described carrying a
    deletion of the SH3 domains entirely.
  genes:
  - preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
    causal_link_type: DIRECT
    description: >-
      Loss of functional STAC3 removes the adaptor that positions and stabilizes
      the CaV1.1 voltage sensor in the triad junction.
  evidence:
  - reference: PMID:23736855
    reference_title: >-
      Stac3 is a component of the excitation-contraction coupling machinery and
      mutated in Native American myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation resulted in a tryptophan (W) to serine (S) substitution at
      amino acid 284 in the first SH3 domain
    explanation: >-
      Identifies the founder allele and locates it in the SH3-1 domain of STAC3.
  - reference: PMID:23736855
    reference_title: >-
      Stac3 is a component of the excitation-contraction coupling machinery and
      mutated in Native American myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reveal that a mutation in human STAC3 is the genetic basis of the
      debilitating Native American myopathy (NAM)
    explanation: >-
      Establishes STAC3 as the causal gene for this disorder.
  - reference: PMID:40779452
    reference_title: >-
      STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports
      skeletal muscle excitation-contraction coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the most common mutation associated with STAC3 disorder, W284S in the SH3-1
      domain, impairs the binding ability of STAC3
    explanation: >-
      Gives the biophysical consequence of the founder substitution.
- name: Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
  biological_scale: MOLECULAR
  description: >-
    STAC3 is required for the functional expression of CaV1.1 (the dihydropyridine
    receptor, the skeletal-muscle L-type calcium channel that acts as the T-tubule
    voltage sensor) and for its conformational coupling to RyR1. Two distinct
    STAC3-CaV1.1 contacts have been resolved: the C1/linker region binds the
    proximal C-terminus of CaV1.1 and is necessary and sufficient for functional
    channel expression, while the SH3-1 domain binds the CaV1.1 II-III loop and,
    contrary to the long-standing assumption, is not strictly required for coupling
    but enhances calcium release. In zebrafish stac3 mutants, DHPR levels,
    functionality and stability are all reduced.
  genes:
  - preferred_term: CACNA1S
    term:
      id: hgnc:1397
      label: CACNA1S
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  molecular_functions:
  - preferred_term: voltage-gated calcium channel activity
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: sarcoplasmic reticulum
    term:
      id: GO:0016529
      label: sarcoplasmic reticulum
  downstream:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    causal_link_type: DIRECT
    description: >-
      Without a properly assembled and voltage-competent CaV1.1, T-tubule
      depolarization fails to trigger RyR1-mediated calcium release.
  evidence:
  - reference: PMID:40779452
    reference_title: >-
      STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports
      skeletal muscle excitation-contraction coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A key regulator of this process is STAC3, a protein essential for both the
      functional expression of CaV1.1 and its conformational coupling with RyR1.
    explanation: >-
      States the two roles of STAC3 that this node represents.
  - reference: PMID:40779452
    reference_title: >-
      STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports
      skeletal muscle excitation-contraction coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that the interaction between STAC3 and the proximal
      C-terminus is necessary and sufficient for CaV1.1 functional expression and
      minimal EC coupling
    explanation: >-
      Assigns the essential channel-expression role to the N-terminal contact
      rather than to the SH3/II-III loop contact.
  - reference: PMID:28003463
    reference_title: >-
      Congenital myopathy results from misregulation of a muscle Ca2+ channel by
      mutant Stac3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we find significantly reduced DHPR levels, functionality, and stability in
      stac3 mutants
    explanation: >-
      Direct measurement of the CaV1.1/DHPR deficit caused by loss of Stac3.
- name: Defective Skeletal Muscle Excitation-Contraction Coupling
  biological_scale: CELLULAR
  description: >-
    The functional core of the disease. Depolarization of the T-tubule membrane no
    longer efficiently triggers release of calcium from the sarcoplasmic reticulum,
    so the myofibre generates less force for a given electrical stimulus. The
    contractile machinery itself and gross triad architecture are comparatively
    preserved, which is why this is a coupling failure rather than a structural
    myopathy in the usual sense. In patient muscle, KCl-induced depolarization
    produced significantly reduced sarcoplasmic-reticulum calcium release.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DECREASED
  - preferred_term: skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: DECREASED
  downstream:
  - target: Congenital Muscle Weakness
    causal_link_type: DIRECT
    description: >-
      Less calcium released per depolarization means less force per stimulus, from
      fetal life onward.
  - target: Anesthetic-Triggered Malignant Hyperthermia Susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same triad lesion confers susceptibility to pharmacologically triggered
      uncontrolled calcium release, but the steps connecting STAC3 loss to the MH
      trigger cascade are not established.
  evidence:
  - reference: PMID:30168660
    reference_title: >-
      STAC3 variants cause a congenital myopathy with distinctive dysmorphic
      features and malignant hyperthermia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, KCl-induced membrane depolarization resulted in significantly
      reduced sarcoplasmic reticulum Ca2+ release.
    explanation: >-
      Demonstrates the coupling defect in muscle from patients rather than only in
      model systems.
  - reference: PMID:23736855
    reference_title: >-
      Stac3 is a component of the excitation-contraction coupling machinery and
      mutated in Native American myopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases
      excitation-contraction coupling.
    explanation: >-
      Shows the patient allele itself, not just a null, reduces EC coupling.
- name: Congenital Muscle Weakness
  biological_scale: ORGANISM
  description: >-
    Reduced force generation produces generalized hypotonia and weakness present at
    birth, with the characteristic myopathic facies and ptosis reflecting
    involvement of facial and levator musculature. Bulbar weakness gives feeding
    difficulty and aspiration risk; respiratory and paraspinal weakness gives
    restrictive lung disease and, over time, progressive kyphoscoliosis and short
    stature. Palatal anomalies including cleft palate are part of the same
    congenital pattern. Curated separately from the contracture node below because
    the two have different proximate causes — weakness is the direct consequence of
    reduced force, whereas contractures come from the reduced fetal movement that
    weakness produces.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Reduced Fetal Movement and Congenital Joint Contracture
    causal_link_type: DIRECT
    description: >-
      Weak fetal muscle moves the joints less, and joints that do not move in utero
      form fixed contractures.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have weakness with myopathic facies, scoliosis,
      kyphosis or kyphoscoliosis, and contractures.
    explanation: >-
      GeneReviews summary of the core musculoskeletal phenotype.
  - reference: PMID:36030003
    reference_title: >-
      STAC3 related congenital myopathy: A case series of seven Comorian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by congenital weakness and arthrogryposis, cleft palate,
      ptosis, short stature, kyphoscoliosis, talipes deformities, and
      susceptibility to malignant hyperthermia (MH) triggered by anesthesia
    explanation: >-
      Independent statement of the same clinical constellation in a non-Lumbee
      cohort.
- name: Reduced Fetal Movement and Congenital Joint Contracture
  biological_scale: ORGANISM
  description: >-
    The fetal-akinesia arm. Weak intrauterine movement leaves joints fixed in
    position, producing the contracture spectrum seen at birth — isolated talipes
    equinovarus at the mild end through arthrogryposis multiplex congenita at the
    severe end. Decreased fetal movement is directly documented in the majority of
    STAC3 patients in a cohort that recorded it, which is what makes this a separate
    mechanistic step rather than a restatement of weakness.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:39966651
    reference_title: >-
      Biallelic variants in RYR1 and STAC3 are predominant causes of
      King-Denborough Syndrome in an African cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, cleft palate (40%), talipes equinovarus (50%), and cryptorchidism
      (16%) were frequently observed, with a higher incidence than in some other
      cohorts, reinforcing the unique phenotypic characteristics of KDS-like
      presentations in African patients.
    explanation: >-
      Quantifies the contracture-spectrum burden in a cohort whose STAC3 arm is the
      larger of the two genotype groups.
  - reference: PMID:36030003
    reference_title: >-
      STAC3 related congenital myopathy: A case series of seven Comorian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by congenital weakness and arthrogryposis, cleft palate,
      ptosis, short stature, kyphoscoliosis, talipes deformities, and
      susceptibility to malignant hyperthermia (MH) triggered by anesthesia
    explanation: >-
      Places arthrogryposis and talipes among the defining congenital features.
- name: Anesthetic-Triggered Malignant Hyperthermia Susceptibility
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Exposure to halogenated volatile anaesthetics or succinylcholine can
    precipitate a hypermetabolic malignant hyperthermia crisis. This is a genuinely
    separate consequence of the triad lesion rather than a severity marker of the
    myopathy: it is incompletely penetrant, patients may have had several
    uneventful anaesthetics before a crisis, and in reported STAC3 patients it
    occurs without pathogenic RYR1 or CACNA1S variants. The mechanistic route from
    STAC3 loss to triggered uncontrolled calcium release is not established, and
    this entry does not assert one.
  genes:
  - preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:40262809
    reference_title: >-
      STAC3 gene congenital myopathy and malignant hyperthermia: a crossroads
      between neurology and anesthesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report three MH crises, in two boys and one girl, 2 to 15 years old. All
      of them received halogenated agents and one additionally received
      succinylcholine.
    explanation: >-
      Documents the triggering agents in confirmed STAC3 patients.
  - reference: PMID:40262809
    reference_title: >-
      STAC3 gene congenital myopathy and malignant hyperthermia: a crossroads
      between neurology and anesthesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients presented two to four previous uneventful general anesthesia.
    explanation: >-
      Supports the statement that an uneventful prior anaesthetic does not exclude
      risk.
  - reference: PMID:40262809
    reference_title: >-
      STAC3 gene congenital myopathy and malignant hyperthermia: a crossroads
      between neurology and anesthesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MH crises in this series of patients with STAC3 gene mutations
      demonstrated variable clinical characteristics (expressivity) and occurrence
      (penetrance).
    explanation: >-
      Supports incomplete penetrance and variable expressivity of the MH trait.
- name: Skeletal Muscle Lipid Accumulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    An emerging and deliberately hedged branch. Increased lipid content in skeletal
    muscle has been noted in patients, and a CRISPR stac3-knockout zebrafish
    reproduces it, with elevated neutral lipid levels appearing alongside
    cytoskeletal and myogenic-regulator changes. Whether the lipid accumulation is
    a driver of weakness or a downstream consequence of it is explicitly
    unresolved, and the supporting measurements are in zebrafish, not human muscle.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:39592070
    reference_title: >-
      Early life lipid overload in Native American Myopathy is phenocopied by stac3
      knockout in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These muscle alterations were associated with elevated neutral lipid levels
      starting at 5 dpf and persisting beyond 7 dpf.
    explanation: >-
      Reports the lipid finding in the zebrafish knockout that motivates this node.
  - reference: PMID:39592070
    reference_title: >-
      Early life lipid overload in Native American Myopathy is phenocopied by stac3
      knockout in zebrafish.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, NAM patients demonstrated increased lipids in skeletal muscle,
      but it is unclear if neutral lipids are associated with altered muscle
      function in NAM.
    explanation: >-
      States both the human observation and the explicit uncertainty about its
      functional significance, which is why this node is curated at low confidence.
phenotypes:
- category: Musculoskeletal
  name: Congenital Hypotonia
  frequency: VERY_FREQUENT
  description: >-
    Generalized hypotonia present at birth; often the presenting sign and the
    reason for referral.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAC3 disorder, or Native American myopathy, is characterised by congenital
      myopathy, hypotonia, musculoskeletal and palatal anomalies, and
      susceptibility to malignant hyperthermia.
    explanation: >-
      Names congenital hypotonia as a defining feature; the cohort was ascertained
      through hypotonia referrals.
- category: Craniofacial
  name: Myopathic Facies
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Characteristic myopathic facial appearance with facial hypomimia, progressive
    narrowing of the face, and inability to elevate the corners of the mouth.
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have weakness with myopathic facies, scoliosis,
      kyphosis or kyphoscoliosis, and contractures.
    explanation: >-
      GeneReviews lists myopathic facies among the near-universal features.
- category: Ophthalmologic
  name: Ptosis
  frequency: VERY_FREQUENT
  description: >-
    Bilateral ptosis from weakness of the levator palpebrae superioris; may require
    surgical correction to prevent deprivation amblyopia.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common findings are ptosis, abnormalities of the palate (including
      cleft palate), and short stature.
    explanation: >-
      GeneReviews lists ptosis as a common finding.
- category: Craniofacial
  name: Cleft Palate
  frequency: VERY_FREQUENT
  description: >-
    Palatal abnormality, most often cleft palate but including high-arched (ogival)
    palate. A palatal abnormality was present in 93% of the Southern African
    clinical cohort.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly,
      59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis
      multiplex congenita, and 22% had a history suggestive of malignant
      hyperthermia.
    explanation: >-
      Quantifies palatal involvement at 93%, supporting the VERY_FREQUENT band.
- category: Musculoskeletal
  name: Arthrogryposis Multiplex Congenita
  frequency: FREQUENT
  description: >-
    Multiple congenital joint contractures, spanning a spectrum from isolated
    talipes to full arthrogryposis multiplex congenita. Reported in 38% of the
    Southern African clinical cohort.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly,
      59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis
      multiplex congenita, and 22% had a history suggestive of malignant
      hyperthermia.
    explanation: >-
      Gives the 38% figure underlying the FREQUENT band.
- category: Musculoskeletal
  name: Talipes Equinovarus
  frequency: FREQUENT
  description: >-
    Congenital clubfoot, reported in 59% of the Southern African clinical cohort
    and in Brazilian cases.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly,
      59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis
      multiplex congenita, and 22% had a history suggestive of malignant
      hyperthermia.
    explanation: >-
      Gives the 59% figure underlying the FREQUENT band.
- category: Musculoskeletal
  name: Kyphoscoliosis
  frequency: FREQUENT
  description: >-
    Progressive spinal deformity — scoliosis, kyphosis, or kyphoscoliosis —
    requiring surveillance and often bracing or surgical correction. A spinal
    anomaly was present in 52% of the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly,
      59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis
      multiplex congenita, and 22% had a history suggestive of malignant
      hyperthermia.
    explanation: >-
      Gives the 52% spinal-anomaly figure underlying the FREQUENT band.
- category: Growth
  name: Short Stature
  frequency: FREQUENT
  description: Reduced linear growth, reported in roughly two-thirds of affected individuals.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common findings are ptosis, abnormalities of the palate (including
      cleft palate), and short stature.
    explanation: >-
      GeneReviews lists short stature among the common findings.
- category: Gastrointestinal
  name: Feeding Difficulties
  frequency: FREQUENT
  description: >-
    Poor feeding and dysphagia from bulbar and facial weakness, sometimes requiring
    nasogastric or gastrostomy feeding; a major contributor to aspiration risk.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAC3 disorder is characterized by congenital myopathy, musculoskeletal
      involvement of the trunk and extremities, feeding difficulties, and delayed
      motor milestones.
    explanation: >-
      GeneReviews names feeding difficulties as a defining feature.
- category: Neurologic
  name: Delayed Motor Milestones
  frequency: FREQUENT
  description: >-
    Delayed attainment of head control, sitting and independent walking, with
    considerable variation; some individuals achieve independent ambulation and
    others remain non-ambulant.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAC3 disorder is characterized by congenital myopathy, musculoskeletal
      involvement of the trunk and extremities, feeding difficulties, and delayed
      motor milestones.
    explanation: >-
      GeneReviews names delayed motor milestones as a defining feature.
- category: Respiratory
  name: Restrictive Respiratory Insufficiency
  frequency: FREQUENT
  description: >-
    Restrictive lung disease from respiratory and paraspinal muscle weakness
    compounded by kyphoscoliosis. With aspiration pneumonia, the principal
    determinant of mortality.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Risk for malignant hyperthermia susceptibility and restrictive lung disease
      are increased.
    explanation: >-
      GeneReviews explicitly flags increased risk of restrictive lung disease.
  - reference: PMID:37626540
    reference_title: >-
      Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy
      with Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary function tests (PFTs) revealed a moderate restrictive lung disease.
    explanation: >-
      Documents the restrictive pattern on formal pulmonary function testing.
- category: Anesthetic
  name: Malignant Hyperthermia Susceptibility
  frequency: OCCASIONAL
  diagnostic: true
  description: >-
    Susceptibility to a hypermetabolic malignant hyperthermia crisis triggered by
    halogenated volatile anaesthetics or succinylcholine. The frequency band here is
    set by the figures that are directly quotable from cited cohorts — a suggestive
    history in 22% of the Southern African clinical cohort, and an observed crisis in
    18% of a South African King-Denborough cohort — and should be read as a floor
    rather than an estimate of true susceptibility. Reported rates across series span
    roughly 13% to 56%, and the reason for that spread is structural, not statistical:
    the trait only declares itself on exposure to a triggering agent, so a cohort's
    rate partly measures how many of its patients happened to have surgery without
    precautions. Penetrance is incomplete even among the exposed.
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  evidence:
  - reference: PMID:39966651
    reference_title: >-
      Biallelic variants in RYR1 and STAC3 are predominant causes of
      King-Denborough Syndrome in an African cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighteen (41%) participants had undergone surgery. Among this subset, MH was
      observed in eight (18%) participants from the STAC3 group.
    explanation: >-
      Second cohort figure underlying the OCCASIONAL band.
  - reference: PMID:39966651
    reference_title: >-
      Biallelic variants in RYR1 and STAC3 are predominant causes of
      King-Denborough Syndrome in an African cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reliable data on MH are challenging to collect since this is only expected to
      develop upon administration of volatile anaesthetic gasses (isoflurane) or
      succinylcholine
    explanation: >-
      States the ascertainment problem that makes any cohort rate a floor, which is
      why the band is set conservatively rather than from the highest reported
      series.
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Risk for malignant hyperthermia susceptibility and restrictive lung disease
      are increased.
    explanation: >-
      GeneReviews states the increased malignant hyperthermia risk.
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly,
      59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis
      multiplex congenita, and 22% had a history suggestive of malignant
      hyperthermia.
    explanation: >-
      Gives the 22% cohort figure for a suggestive malignant hyperthermia history.
- category: Neurologic
  name: Normal Intellect
  description: >-
    Cognition is typically normal. Recorded explicitly because it is a useful
    discriminator from syndromic congenital myopathies and because preserved
    intellect shapes educational and rehabilitation planning.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Risk for malignant hyperthermia susceptibility and restrictive lung disease
      are increased. Intellect is typically normal.
    explanation: >-
      GeneReviews states that intellect is typically spared. The quote carries the
      preceding sentence so it states a finding rather than a bare clause.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Undescended testes in affected males, reported in the cumulative GeneReviews
    series and among the dysmorphic features of the King-Denborough-like African
    cohort. No frequency band is assigned because the available denominator mixes
    STAC3 and RYR1 patients.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:39966651
    reference_title: >-
      Biallelic variants in RYR1 and STAC3 are predominant causes of
      King-Denborough Syndrome in an African cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients exhibit a range of KDS characteristics, including myopathy,
      ptosis, malar hypoplasia, skeletal and other dysmorphic features,
      cryptorchidism, and, in some cases, documented episodes of MH following
      surgery.
    explanation: >-
      Lists cryptorchidism among the features of the cohort in which STAC3 was one
      of the two causal genes; PARTIAL because the description covers the mixed
      RYR1/STAC3 cohort rather than STAC3 patients alone.
- category: Auditory
  name: Sensorineural Hearing Impairment
  frequency: VERY_RARE
  description: >-
    Bilateral hearing loss reported in a single Brazilian patient. Curated as a
    single-report observation, not an established feature.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:37626540
    reference_title: >-
      Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy
      with Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he had bilateral hearing loss (threshold of 50 dB in the right
      ear and 70 dB in the left), and polysomnography revealed an obstructive sleep
      apnea syndrome.
    explanation: >-
      Single-patient report; supports the observation but not a frequency estimate.
genetic:
- name: STAC3
  association: Genetic Mutation
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Biallelic pathogenic STAC3 variants are the sole established cause. The
    recurrent c.851G>C (p.Trp284Ser) allele in the first SH3 domain accounts for
    the great majority of reported patients worldwide; nonsense, frameshift and
    splice-site alleles and an SH3-domain deletion have also been described.
  evidence:
  - reference: PMID:23736855
    reference_title: >-
      Stac3 is a component of the excitation-contraction coupling machinery and
      mutated in Native American myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reveal that a mutation in human STAC3 is the genetic basis of the
      debilitating Native American myopathy (NAM)
    explanation: >-
      Original identification of STAC3 as the causal gene.
  - reference: PMID:37626540
    reference_title: >-
      Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy
      with Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital
      myopathy and Native American myopathy (NAM), is a condition caused by
      biallelic missense pathogenic variants in STAC3, which encodes an important
      protein necessary for the excitation-relaxation coupling machinery in the
      muscle.
    explanation: >-
      Confirms the gene-disease relationship and the biallelic requirement under
      the CMYP13 designation.
- name: STAC3 c.851G>C recurrent allele
  association: Genetic Mutation
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  notes: >-
    Originally interpreted as a Lumbee founder allele, the recurrent c.851G>C
    variant is now recognised across African, Afro-Caribbean, Comorian, Middle
    Eastern, South American and other populations, with allele-frequency data
    pointing to an African origin. The reframing is clinically consequential: the
    "Native American myopathy" label suppressed diagnostic suspicion outside one
    ancestry group.
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The spread of this variant worldwide and the allele frequency higher in the
      African/African-American ancestry than the Admixed Americans, strongly
      indicates that the STAC3 c.851 G > C variant has an African origin which may
      be due to an ancient mutation with migration and population bottlenecks.
    explanation: >-
      States the revised origin hypothesis for the recurrent allele.
  - reference: PMID:36030003
    reference_title: >-
      STAC3 related congenital myopathy: A case series of seven Comorian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Local history and geography may explain the overrepresentation of NAM in the
      Comorian Archipelago with a founder effect.
    explanation: >-
      Documents a second, independent founder population for the same allele.
environmental:
- name: Exposure to halogenated volatile anaesthetics or succinylcholine
  description: >-
    The only established environmental determinant in this disorder. It does not
    cause or modify the underlying myopathy; it converts a latent triad
    susceptibility into an acute, potentially fatal hypermetabolic crisis.
  influences_mechanisms:
  - target: Anesthetic-Triggered Malignant Hyperthermia Susceptibility
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Halogenated agents and depolarizing neuromuscular blockers are the documented
      triggers of malignant hyperthermia crises in patients with biallelic STAC3
      variants.
    evidence:
    - reference: PMID:40262809
      reference_title: >-
        STAC3 gene congenital myopathy and malignant hyperthermia: a crossroads
        between neurology and anesthesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report three MH crises, in two boys and one girl, 2 to 15 years old.
        All of them received halogenated agents and one additionally received
        succinylcholine.
      explanation: >-
        Directly links the exposure to crises in STAC3 patients.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Anesthetic agents with a high risk of
      triggering malignant hyperthermia.
    explanation: >-
      GeneReviews records the exposure as the disorder's designated agent to avoid.
treatments:
- name: Avoidance of Malignant Hyperthermia Triggering Anaesthetics
  description: >-
    The single most consequential intervention in this disorder. Halogenated
    volatile anaesthetics and depolarizing neuromuscular blockers are avoided
    outright; total intravenous anaesthesia is used instead, with dantrolene
    immediately available. A previous uneventful general anaesthetic does not
    establish safety.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Anesthetic-Triggered Malignant Hyperthermia Susceptibility
    treatment_effect: INHIBITS
    description: >-
      Removing the pharmacologic trigger prevents the crisis; it does not modify
      the underlying triad lesion.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Anesthetic agents with a high risk of
      triggering malignant hyperthermia.
    explanation: >-
      GeneReviews management guidance naming trigger avoidance.
  - reference: PMID:40262809
    reference_title: >-
      STAC3 gene congenital myopathy and malignant hyperthermia: a crossroads
      between neurology and anesthesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuromuscular patients with findings suggestive of STAC3 myopathy should
      increase diagnostic suspicion regarding the risk of MH.
    explanation: >-
      Supports pre-emptive recognition as the basis for anaesthetic planning.
- name: Physical and Occupational Therapy
  description: >-
    Range-of-motion work, stretching, splinting and adaptive devices to maintain
    mobility and limit contracture progression.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Occupational and physical therapy needs regarding range of motion and
      mobility.
    explanation: >-
      GeneReviews management guidance for the musculoskeletal manifestations.
- name: Orthopaedic Management of Spinal and Limb Deformity
  description: >-
    Bracing and surgical correction for progressive scoliosis and for talipes
    deformity.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Routine monitoring of growth, musculoskeletal complications
      (e.g., scoliosis and/or joint contractures), speech development, swallowing
      function, respiratory function, and educational needs.
    explanation: >-
      Establishes scoliosis and contractures as monitored, managed complications.
- name: Cleft Palate Repair by a Multidisciplinary Craniofacial Team
  description: >-
    Timing and technique of palatal surgery are decided by a craniofacial team
    because the anaesthetic and respiratory comorbidities of this disorder change
    the risk calculus relative to isolated cleft palate.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to the medical comorbidities in STAC3 disorder, decisions regarding type
      and timing of cleft palate surgery should be determined by a multidisciplinary
      craniofacial team.
    explanation: >-
      GeneReviews guidance, including the reason the decision is team-based.
- name: Ptosis Repair
  description: >-
    Surgical correction of ptosis (levator resection or frontalis sling) to prevent
    deprivation amblyopia and improve the visual field. Whether it is delivered by an
    ophthalmologist within the craniofacial team or as a separate intervention
    depends on how that team is organised — and either way it inherits the
    anaesthetic constraint that governs every procedure in this disorder.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depending on the structure of the managing craniofacial team, interventions
      for ptosis may be undertaken by an ophthalmologist as part of team care, or as
      an insertion intervention.
    explanation: >-
      GeneReviews management guidance for ptosis, including who delivers it.
- name: Nutritional and Feeding Support
  description: >-
    Speech-language pathology and nutrition assessment, specialized feeding
    equipment, and nasogastric or gastrostomy feeding when oral intake is unsafe or
    inadequate.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Routine monitoring of growth, musculoskeletal complications
      (e.g., scoliosis and/or joint contractures), speech development, swallowing
      function, respiratory function, and educational needs.
    explanation: >-
      Establishes swallowing function and growth as monitored domains driving
      feeding intervention.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence risk of 25% per pregnancy for carrier couples;
    carrier and prenatal testing are available once the familial variants are
    known. Relevant well beyond the Lumbee population given the worldwide
    distribution of the recurrent allele.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At conception, each sib of an affected individual has a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of
      being unaffected and not a carrier.
    explanation: >-
      Provides the recurrence risk that genetic counselling communicates.
histopathology:
- name: Non-Specific Myopathic Muscle Biopsy
  frequency: FREQUENT
  description: >-
    Muscle biopsy is abnormal in most patients who undergo it, but the findings are
    non-specific: type 1 fibre predominance is the commonest single pattern,
    followed by generic myopathic features, mild atrophic fibres, and type 2 fibre
    predominance. There is no defining structural lesion of the kind that names
    other congenital myopathies (no cores, no rods, no central nuclei as a defining
    feature), which is precisely why biopsy cannot make this diagnosis and molecular
    testing must. Increased lipid droplets and subsarcolemmal mitochondrial
    accumulation have also been described on electron microscopy and are the human
    counterpart of the lipid finding modelled in zebrafish.
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal muscle biopsy histology results were reported in 11/16 patients
      (69%). and included documented type 1 muscle fibre predominance (5/11 (45%)),
      features of non-specific myopathy (3/11 (27%)), mild atrophic fibres (2/11
      (18%)), and type 2 muscle fibre predominance (1/11 (9%)).
    explanation: >-
      Quantifies both the yield and the pattern distribution of muscle biopsy in a
      genotype-confirmed cohort.
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy histology was abnormal in most patients who underwent the
      procedure (69%), with non-specific myopathy features being most common,
      consistent with previous reports
    explanation: >-
      States the non-specificity that limits the diagnostic value of biopsy here.
diagnosis:
- name: Molecular Genetic Testing of STAC3
  description: >-
    Diagnosis rests on biallelic pathogenic STAC3 variants in a proband with a
    compatible phenotype. Targeted testing for c.851G>C is a reasonable first step
    in populations where the allele is common; otherwise a congenital myopathy
    panel or exome sequencing is used. The key practice point is that ancestry must
    not gate the test.
  evidence:
  - reference: PMID:31219695
    reference_title: STAC3 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of STAC3 disorder is established in a proband with suggestive
      clinical findings and biallelic pathogenic variants in STAC3 identified by
      molecular genetic testing.
    explanation: >-
      States the diagnostic standard.
  - reference: PMID:30168660
    reference_title: >-
      STAC3 variants cause a congenital myopathy with distinctive dysmorphic
      features and malignant hyperthermia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study demonstrates that STAC3 gene analysis should be included in the
      diagnostic work up of patients of any ethnicity presenting with congenital
      myopathy, in particular if a history of MH-like episodes is reported.
    explanation: >-
      Explicit recommendation that testing not be restricted by ancestry.
- name: Genetics-Before-Biopsy Testing Strategy
  description: >-
    A sequencing decision that is specific to this disorder rather than generic
    good practice: because muscle biopsy requires anaesthesia and this disorder
    carries malignant hyperthermia risk, the biopsy is itself a hazard, and its
    yield is non-specific anyway. Genetic testing should therefore come first. The
    same logic applies to the diagnostic yield of targeted testing: 25 of 127 (20%)
    samples referred for congenital hypotonia in one Southern African laboratory
    cohort were homozygous for the founder allele, so in that setting a single
    targeted test resolves a fifth of the referral population without any procedure.
  evidence:
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a patient with suspected STAC3 disorder, genetic testing should be
      performed as the first line investigation, instead of a muscle biopsy which
      could pose a risk for MH.
    explanation: >-
      States the testing-order recommendation and the reason for it.
  - reference: PMID:38824262
    reference_title: >-
      STAC3 disorder: a common cause of congenital hypotonia in Southern African
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3
      c.851 G > C.
    explanation: >-
      Quantifies the diagnostic yield of targeted testing in a congenital-hypotonia
      referral population.
- name: Electromyography
  description: >-
    Shows a myopathic pattern. Supportive rather than diagnostic, and it does not
    distinguish this disorder from other congenital myopathies.
  evidence:
  - reference: PMID:37626540
    reference_title: >-
      Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy
      with Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electromyography (EMG) revealed a myopathic pattern-polyphasic,
      short-duration, low-amplitude motor unit action potentials, and early
      recruitment.
    explanation: >-
      Describes the electrophysiological findings.
- name: Serum Creatine Kinase
  description: >-
    Normal or only mildly elevated, so a normal CK does not argue against the
    diagnosis. Recorded because a normal CK is a common reason congenital myopathy
    is dismissed.
  evidence:
  - reference: PMID:37626540
    reference_title: >-
      Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy
      with Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Creatine phosphokinase (CK) levels were normal.
    explanation: >-
      Documents a normal CK in a genetically confirmed patient.
differential_diagnoses:
- name: King-Denborough syndrome
  description: >-
    Congenital myopathy with dysmorphic features and malignant hyperthermia
    susceptibility. The relationship is one of overlap rather than exclusion: in a
    South African cohort of 44 patients diagnosed clinically with King-Denborough
    syndrome, biallelic STAC3 and RYR1 variants were the two predominant causes, so
    a King-Denborough phenotype is a reason to test STAC3, not to stop.
  distinguishing_features:
  - Genotype rather than phenotype discriminates the two labels
  - RYR1 is the alternative causal gene in this presentation
  evidence:
  - reference: PMID:39966651
    reference_title: >-
      Biallelic variants in RYR1 and STAC3 are predominant causes of
      King-Denborough Syndrome in an African cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study identified RYR1 and STAC3 mutations as the predominant genetic
      causes of KDS in this cohort, with mutations in both genes exhibiting
      autosomal recessive inheritance.
    explanation: >-
      Establishes the genetic overlap between the two clinical labels.
- name: Central core myopathy
  description: >-
    RYR1-related congenital myopathy that also features contractures, respiratory
    insufficiency and malignant hyperthermia susceptibility.
  disease_term:
    preferred_term: central core myopathy
    term:
      id: MONDO:0007294
      label: central core myopathy
  distinguishing_features:
  - Characteristic central cores on muscle biopsy
  - RYR1 rather than STAC3 genotype
  - Frequently autosomal dominant rather than recessive
- name: Carey-Fineman-Ziter syndrome
  description: >-
    Congenital myopathy sharing the upturned nasal tip, micrognathia, generalized
    muscle hypoplasia and delayed motor milestones. Clinically the most useful
    differential in this entry, because the discriminating feature is exactly the one
    that changes management. Bound to the phenotypic-series parent rather than to
    Carey-Fineman-Ziter syndrome 1 (MONDO:0800437, the MYMK-related form), because
    the differential holds across the series and type 2 has a different causal gene.
  disease_term:
    preferred_term: Carey-Fineman-Ziter syndrome
    term:
      id: MONDO:0031415
      label: Carey-Fineman-Ziter syndrome
  distinguishing_features:
  - No malignant hyperthermia susceptibility, so anaesthetic precautions differ
  - A different causal gene — MYMK in Carey-Fineman-Ziter syndrome 1
- name: Moebius syndrome
  description: >-
    Overlaps through cleft palate, talipes, short stature, scoliosis and
    contractures, and is genetically heterogeneous.
  disease_term:
    preferred_term: Moebius syndrome
    term:
      id: MONDO:0008006
      label: Moebius syndrome
  distinguishing_features:
  - Obligatory impairment of ocular abduction and other cranial nerve findings
  - No malignant hyperthermia susceptibility
- name: X-linked myotubular myopathy
  description: >-
    A severe congenital myopathy that is mechanistically unrelated — X-linked,
    caused by loss of the MTM1 lipid phosphatase, without malignant hyperthermia
    susceptibility. Listed here specifically because it is the entity a name-based
    search for this disorder is most likely to be confused with.
  distinguishing_features:
  - X-linked rather than autosomal recessive inheritance
  - MTM1 genotype
  - No malignant hyperthermia susceptibility
animal_models:
- name: stac3 mi34 null zebrafish
  species: Zebrafish
  genotype: stac3 mi34 splice-donor mutation (functionally null)
  publication: PMID:23736855
  description: >-
    The founding model. An unbiased forward genetic screen for zebrafish locomotor
    mutants isolated mi34, mapped it to stac3, and thereby identified the human
    disease gene — the model preceded and produced the gene-disease association
    rather than following it.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Mutant muscle shows greatly reduced calcium transients with intact contractile
      machinery and grossly normal triad anatomy, isolating the defect to coupling
      itself.
    limitations: >-
      A functional null, so it models the severe end of the human allelic spectrum
      rather than the hypomorphic missense biology of most patients; larvae die and
      the model cannot address the progressive musculoskeletal deformity or the
      malignant hyperthermia trait.
    evidence:
    - reference: PMID:23736855
      reference_title: >-
        Stac3 is a component of the excitation-contraction coupling machinery and
        mutated in Native American myopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ca2+ transients were greatly reduced in both mutant slow and fast twitch
        fibers (Fig. 2b,c). Thus EC coupling in skeletal muscles was defective in
        the mi34 mutants.
      explanation: >-
        Reports the calcium-release measurement that grounds the coupling claim.
- name: stac3 NAM knock-in zebrafish
  species: Zebrafish
  genotype: stac3 encoding the W-to-S substitution equivalent to human p.Trp284Ser
  publication: PMID:28003463
  description: >-
    Knock-in of the patient allele rather than a null, making it the closer model of
    human founder-variant biology.
  modeled_mechanisms:
  - target: Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reduced DHPR/CaV1.1 levels, functionality and stability in the presence of the
      patient-equivalent substitution.
    limitations: >-
      The knock-in also shows increased caffeine-induced calcium release and
      increased internal store calcium, a gain-of-release phenotype whose relation to
      the human malignant hyperthermia trait has not been established; reading it as
      an MH mechanism would overstate the evidence.
    evidence:
    - reference: PMID:28003463
      reference_title: >-
        Congenital myopathy results from misregulation of a muscle Ca2+ channel by
        mutant Stac3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using electron microscopy, electrophysiology, and dynamic imaging of
        zebrafish muscle fibers, we find significantly reduced DHPR levels,
        functionality, and stability in stac3 mutants.
      explanation: >-
        The measurement behind the channel-assembly claim.
- name: stac3 CRISPR knockout zebrafish (lipid phenotype)
  species: Zebrafish
  genotype: stac3-/- CRISPR/Cas9 knockout
  publication: PMID:39592070
  description: >-
    A CRISPR knockout used to follow early skeletal muscle development, which
    surfaced neutral lipid accumulation alongside the expected weakness.
  modeled_mechanisms:
  - target: Skeletal Muscle Lipid Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces the increased muscle lipid noted clinically in patients, with a
      developmental time course.
    limitations: >-
      Whether lipid accumulation contributes to weakness or merely accompanies it is
      unresolved in both the model and patients; the knockout does not survive past
      11 days post-fertilization, so no chronic or adult phenotype can be assessed.
    evidence:
    - reference: PMID:39592070
      reference_title: >-
        Early life lipid overload in Native American Myopathy is phenocopied by
        stac3 knockout in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we determined that loss of stac3 leads to delayed larval hatching which
        corresponds with muscle weakness and decreased whole-body Ca2+ level during
        early skeletal development
      explanation: >-
        Reports the model's core muscle phenotype in which the lipid finding was
        observed.
discussions:
- discussion_id: stac3_cav11_interaction_paradox
  kind: OPEN_QUESTION
  prompt: >-
    If excitation-contraction coupling is clearly impaired in STAC3-patient muscle,
    but the STAC3-CaV1.1 interaction and CaV1.1 sarcolemmal localization are not
    measurably disrupted in that same tissue, what is the proximate lesion?
  attaches_to:
  - pathophysiology#Failure of STAC3-Dependent CaV1.1 Assembly at the Triad
  rationale: >-
    The intuitive model — patient variant disrupts STAC3 binding to CaV1.1,
    therefore coupling fails — is supported by biophysical work on the isolated
    W284S SH3 domain and by reduced DHPR levels in zebrafish, but the study that
    looked in human patient muscle found the interaction preserved. Compounding
    this, the SH3/II-III loop contact that W284S disrupts has since been shown to be
    facilitating rather than strictly required for coupling, while the essential
    contact is the one made by the N-terminal region. Curating a single clean chain
    here would paper over a genuine discrepancy between model systems and patient
    tissue.
  proposed_experiments:
  - experiment_id: stac3_patient_myotube_charge_movement
    name: Quantify CaV1.1 charge movement and STAC3 occupancy in patient-derived myotubes
    description: >-
      Measure gating charge, calcium release and STAC3-CaV1.1 stoichiometry side by
      side in myotubes carrying p.Trp284Ser, to determine whether the deficit lies in
      channel voltage sensing, in coupling efficiency, or in a step downstream of a
      normally assembled complex.
  evidence:
  - reference: PMID:30168660
    reference_title: >-
      STAC3 variants cause a congenital myopathy with distinctive dysmorphic
      features and malignant hyperthermia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle
      samples showed that the protein interaction between STAC3 and CaV 1.1 was not
      significantly affected by the STAC3 variants.
    explanation: >-
      The patient-tissue result that creates the discrepancy.
  - reference: PMID:30168660
    reference_title: >-
      STAC3 variants cause a congenital myopathy with distinctive dysmorphic
      features and malignant hyperthermia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the precise pathomechanism remains to be elucidated, our functional
      characterization of STAC3 variants revealed that defective ECC is not a result
      of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.
    explanation: >-
      The authors state the open pathomechanism explicitly.
- discussion_id: stac3_mh_trigger_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what mechanism does loss of STAC3 confer susceptibility to
    anaesthetic-triggered malignant hyperthermia, given that affected patients do
    not carry pathogenic RYR1 or CACNA1S variants?
  attaches_to:
  - pathophysiology#Anesthetic-Triggered Malignant Hyperthermia Susceptibility
  rationale: >-
    Malignant hyperthermia susceptibility is one of the clinically decisive features
    of this disorder, yet the causal chain from an adaptor-protein loss to triggered
    uncontrolled calcium release is not worked out. It is not simply a more severe
    version of the coupling defect: the coupling defect reduces calcium release,
    while the crisis is an excess of it. The zebrafish knock-in does show increased
    caffeine-induced release and elevated store calcium, which is suggestive, but
    that has not been connected to volatile-anaesthetic triggering in patients.
  proposed_experiments:
  - experiment_id: stac3_halothane_contracture_myotubes
    name: Halothane and caffeine response in STAC3-null and W284S myotubes
    description: >-
      Compare halothane- and caffeine-evoked contracture and calcium release in
      myotubes reconstituted with wild-type STAC3, W284S STAC3, and no STAC3, on an
      otherwise wild-type RYR1 background, to test whether STAC3 loss is sufficient
      to produce a trigger-sensitive phenotype.
  evidence:
  - reference: PMID:28003463
    reference_title: >-
      Congenital myopathy results from misregulation of a muscle Ca2+ channel by
      mutant Stac3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+
      release across a wide range of concentrations in the absence of altered
      caffeine sensitivity as well as increased Ca2+ in internal stores, which is
      consistent with increased SR luminal Ca2+
    explanation: >-
      The suggestive model-organism observation, recorded as partial support because
      it has not been tied to anaesthetic triggering in patients.
notes: >-
  Naming and identity. This entry is filed under the MONDO label "Bailey-Bloch
  congenital myopathy" but the same disorder appears in the literature as Native
  American myopathy (NAM), STAC3 disorder, and congenital myopathy 13 (CMYP13).
  Curators and search tools should treat all four as the same entity.

  Two disambiguation hazards are worth recording. First, X-linked myotubular
  myopathy (MTM1) is a superficially similar severe congenital myopathy and is a
  common wrong resolution for name-based searches; it is X-linked, has no malignant
  hyperthermia association, and is the subject of a gene-replacement programme that
  has nothing to do with this disorder. Second, the deep-research report used to
  seed this entry cited "PMID:30178658" for the Zaharieva et al. 2018 Human
  Mutation cohort. That identifier resolves to an unrelated solid-state solar-cell
  paper; the correct identifier is PMID:30168660, which is what this entry cites.
  The report's own reference-validation pass did not catch it, because the wrong
  PMID does resolve to a real article — a reminder that "reference resolved" is not
  "reference correct".

  The 1987 Bailey and Bloch case report (PMID:3631569) that gives the disorder its
  eponym has no abstract in the cached record, so it is listed under references for
  provenance only and carries no evidence snippet.

  Two things a reader may expect and will not find. There is no `progression:`
  section: the frequently quoted figure of 36% mortality by age 18 appears in the
  GeneReviews full text and in the discussion of the original zebrafish paper, but
  not in either cached abstract, so it is not snippet-quotable and is deliberately
  omitted rather than cited to a source that does not contain it. And no `datasets:`
  block is present, because dataset relevance triage is a manual step that was not
  performed for this entry.

  Scope. Malignant hyperthermia susceptibility is curated here as a feature of this
  disorder. Non-syndromic malignant hyperthermia susceptibility, where STAC3 appears
  as a qualified susceptibility gene alongside RYR1 and CACNA1S, is curated
  separately in Malignant_Hyperthermia_of_Anesthesia.
references:
- reference: PMID:31219695
  title: STAC3 Disorder.
  tags:
  - GeneReviews
- reference: PMID:3631569
  title: Malignant hyperthermia in a three-month-old American Indian infant.
📚

References & Deep Research

References

2
PMID:31219695
STAC3 Disorder.
No top-level findings curated for this source.
PMID:3631569
Malignant hyperthermia in a three-month-old American Indian infant.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-08-15T19:15:40.231316

1. Disease Information

Overview: Bailey-Bloch Congenital Myopathy (BBCM) is a rare autosomal recessive congenital myopathy caused by biallelic loss-of-function variants in STAC3, which encodes an adaptor protein essential for skeletal-muscle excitation-contraction (EC) coupling. It presents at birth with profound hypotonia, arthrogryposis/congenital contractures, a distinctive myopathic facial gestalt, cleft/high-arched palate, short stature, progressive spinal deformity, and — distinctively among congenital myopathies — a substantial risk of malignant hyperthermia susceptibility (MHS) upon exposure to volatile anesthetics or depolarizing muscle relaxants (GeneReviews, NBK542808; PMID:3631569).

Key identifiers: | Resource | ID | |---|---| | OMIM (phenotype) | #255995 (CMYO13) | | OMIM (gene) | *615521 (STAC3) | | MONDO | MONDO:0009722 | | Gene | STAC3, chromosome 12q13.3 | | GeneReviews | NBK542808 |

Synonyms: Native American Myopathy (NAM); Congenital Myopathy 13 (CMYO13); STAC3 disorder; STAC3-related congenital myopathy; STAC3 myopathy.

Evidence provenance: Information is derived from aggregated case-series/cohort resources — the GeneReviews synopsis (44 cumulative cases), a Southern African cohort of 31 homozygotes among 127 hypotonia referrals (PMID:38824262/39080471), a 19-patient international cohort (PMID:30178658), a Comorian case series (PMID:36030003), and individual case reports (Brazil, PMID:37626540) — rather than single-EHR extraction. The disorder was originally population-specific (Lumbee), and later series establish it as pan-ethnic.

2. Etiology

Disease causal factor: Purely genetic — biallelic (homozygous or compound heterozygous) pathogenic loss-of-function variants in STAC3. There is no known environmental, infectious, or purely mechanistic (non-genetic) trigger for the baseline myopathy; however, environmental/pharmacologic triggers (volatile anesthetics, succinylcholine) precipitate the acute malignant hyperthermia crisis in susceptible carriers of biallelic variants (GeneReviews NBK542808).

Genetic risk factors: - Founder variant: c.851G>C (p.Trp284Ser), a missense substitution in the STAC3 SH3 domain, is the near-exclusive variant in the Lumbee population and the most frequently reported variant worldwide, including in patients of African, Comorian, Southern African, and South American ancestry with no known Lumbee lineage (PMID:37626540; PMID:38824262; PMID:36030003). - Additional pathogenic variants reported: c.862A>T (p.Lys288Ter, nonsense); c.432+4A>T (splice donor); c.763_766delCTCT (p.Leu255Ilefs*58, frameshift); c.997-1G>T (splice acceptor) (GeneReviews NBK542808; PMID:30178658). - No large deletions/duplications have been identified to date. - Carrier frequency: the p.Trp284Ser allele is present in gnomAD at ~33/141,000 alleles in heterozygosity (PMID:37626540); among enrolled Lumbee tribal members (~60,000), disease prevalence is estimated at ~1 in 5,000 (GeneReviews NBK542808).

Environmental risk factors: None identified as causal for the underlying myopathy. The critical environmental/pharmacologic exposure is anesthetic triggering agents (halogenated volatile anesthetics, succinylcholine), which precipitate malignant hyperthermia crises in a substantial minority of biallelic STAC3 variant carriers (43% in the GeneReviews cohort; 22% in the Southern African cohort) (GeneReviews NBK542808; PMID:38824262).

Protective factors: None specifically documented. Avoidance of MH-triggering anesthetic agents functionally prevents the acute MH phenotype but does not modify the baseline myopathy.

Gene-environment interaction: The clearest documented interaction is genotype (biallelic STAC3 LOF) × pharmacologic exposure (volatile anesthetic/succinylcholine) → malignant hyperthermia crisis, mediated through STAC3's structural role at the triad junction alongside the canonical MH genes RYR1 and CACNA1S; notably, in the Brazilian case report, both patients tested negative for RYR1/CACNA1S variants, indicating STAC3 itself — independent of the classical MH genes — confers MHS (PMID:37626540).

3. Phenotypes

Frequencies below are drawn from the GeneReviews cumulative synopsis (n=44) unless otherwise noted; a large independent Southern African cohort (n=31 homozygotes for c.851G>C) is given in parallel where frequencies diverge (PMID:38824262).

Clinical signs / physical manifestations

Phenotype Frequency (GeneReviews, n≈40-44) Frequency (S. Africa, n=31) Suggested HPO term*
Hypotonia (congenital) 100% (41/41) — HP:0001252 Hypotonia
Myopathic facies (ptosis, inability to elevate mouth corners, progressive facial narrowing) 100% (44/44) — HP:0002058 Myopathic facies
Ptosis 85% (33/39) — HP:0000508 Ptosis
Poor feeding / feeding difficulty 73% (29/40) — HP:0011968 Feeding difficulties
Congenital contractures / arthrogryposis (talipes to AMC spectrum) 81% (35/43) AMC 38%; talipes equinovarus 59% HP:0002804 Arthrogryposis multiplex congenita; HP:0001762 Talipes equinovarus
Spinal deformity (scoliosis/kyphosis/kyphoscoliosis) 79% (31/39) 52% HP:0002650 Scoliosis / HP:0002751 Kyphoscoliosis
Short stature 66% (19/29) — HP:0004322 Short stature
Palatal anomaly 82% (36/44) 93% HP:0000175 Cleft palate (57% specifically)
Malignant hyperthermia susceptibility 43% (19/44) 22% (history suggestive) HP:0001954 Malignant hyperthermia
Respiratory impairment 55% (16/29) — HP:0002093 Respiratory insufficiency
Cryptorchidism (in males) 62% (13/21) — HP:0000028 Cryptorchidism
Bilateral hearing loss (case report) reported — HP:0000365 Hearing impairment

*HPO codes are suggested from standard, well-established terms; confirm with OAK lookup per dismech curation protocol before committing.

Onset: Congenital — hypotonia, contractures, facial features, and palatal anomalies are present at birth or noted prenatally (severe end of spectrum can present with prenatal onset) (PMID:30178658).

Severity/progression: Highly variable — the 2018 international cohort (PMID:30178658) explicitly describes a spectrum "ranging from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype." Scoliosis and contractures tend to be progressive; motor function can plateau or decline (some individuals lose ambulation and become wheelchair-dependent by adolescence), while others achieve independent walking and even running (GeneReviews NBK542808).

Behavioral/cognitive: Intellect is normal in the majority of affected individuals; mild intellectual disability is rare (GeneReviders NBK542808).

Laboratory abnormalities: Serum creatine kinase (CK) may be normal or mildly elevated (nonspecific, as in many congenital myopathies) — not a reliable diagnostic discriminator (GeneReviews NBK542808 background; UChicago Congenital Myopathy panel infosheet).

Quality of life impact: Feeding difficulties requiring enteral support, respiratory insufficiency requiring ventilatory assistance, and progressive scoliosis/contractures substantially affect mobility and daily functioning; no formal EQ-5D/SF-36 disease-specific QOL studies were identified in this search.

4. Genetic/Molecular Information

Causal gene: STAC3 (SH3 and Cysteine-Rich Domain 3), OMIM *615521, chromosome 12q13.3. Encodes a 364-amino-acid, ~41.4 kDa protein with an N-terminal cysteine-rich (C1) domain and two SH3 domains (GeneReviews NBK542808).

Pathogenic variants (5 documented; ClinVar entries exist, e.g. RCV001457863): 1. c.851G>C (p.Trp284Ser) — missense; founder variant in Lumbee population, now reported worldwide (most common by far) 2. c.862A>T (p.Lys288Ter) — nonsense 3. c.432+4A>T — splice donor site variant 4. c.763_766delCTCT (p.Leu255Ilefs*58) — frameshift deletion 5. c.997-1G>T — cryptic/canonical splice acceptor variant (PMID:30178658)

Variant classification: All reported variants are classified pathogenic/likely pathogenic under ACMG/AMP criteria in the disease context (biallelic state required for disease).

Allele frequency: The founder p.Trp284Ser variant is present in gnomAD heterozygosity at ~33/141,000 alleles (PMID:37626540); markedly enriched (estimated ~1 in 5,000 disease prevalence) among the ~60,000 enrolled Lumbee tribal members (GeneReviews NBK542808).

Origin: Germline only — no somatic BBCM has been described.

Functional consequence: All known pathogenic variants are loss-of-function. Structural/functional work shows the p.Trp284Ser substitution disrupts the SH3-domain interaction between STAC3's C-terminal region and the II-III cytoplasmic loop of CaV1.1 (the skeletal-muscle L-type calcium channel/dihydropyridine receptor, DHPR), which "decreases the quantity, organization, stability, and voltage sensitivity of Ca²⁺ channels" (GeneReviews NBK542808; PMID:28003463; PMC12333939).

Modifier genes: None established. No genotype-phenotype correlation between specific variants and disease severity has been demonstrated to date (GeneReviews NBK542808).

Chromosomal abnormalities: No large deletions/duplications or chromosomal rearrangements have been identified in confirmed cases — pathogenic variants are exclusively small sequence-level changes.

Epigenetic information: No disease-specific epigenetic (DNA methylation/histone) studies were identified in this search.

5. Environmental Information

Environmental/pharmacologic factors: The dominant environmental modifier is anesthetic exposure. Volatile halogenated anesthetics (halothane, isoflurane, sevoflurane) and depolarizing neuromuscular blockers (succinylcholine, decamethonium) are established triggers of malignant hyperthermia crises in biallelic STAC3 variant carriers and must be strictly avoided (GeneReviews NBK542808).

Lifestyle factors: Not applicable — this is a congenital, fully genetically determined disorder; no lifestyle modifiers of penetrance or expressivity were identified.

Infectious agents: Not causally implicated; however, aspiration-related pneumonia is a documented cause of morbidity/mortality secondary to bulbar/feeding dysfunction rather than a primary infectious etiology (GeneReviews NBK542808).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular trigger: Biallelic loss-of-function STAC3 variants (most commonly p.Trp284Ser) disrupt the STAC3 adaptor protein's SH3-domain-mediated binding to the II-III cytoplasmic loop of CaV1.1 (the skeletal-muscle dihydropyridine receptor / voltage sensor) (PMC12333939; PMID:28003463).
  2. Molecular consequence: Loss of proper STAC3-CaV1.1 interaction decreases the quantity, membrane organization, stability, and voltage sensitivity of the CaV1.1 (L-type Ca²⁺ channel) complex at the triad junction (GeneReviews NBK542808).
  3. Cellular consequence: Impaired excitation-contraction (EC) coupling — voltage sensing at the T-tubule fails to efficiently trigger ryanodine receptor 1 (RYR1)-mediated Ca²⁺ release from the sarcoplasmic reticulum. Zebrafish and murine functional studies show significantly reduced KCl-depolarization-induced and caffeine-induced SR Ca²⁺ release (PMID:23736855; PMID:28003463; PMID:30178658).
  4. Tissue consequence: Reduced/disorganized myofibrillar contraction, muscle hypotrophy, and — in null models — complete failure of fetal muscle contraction; histopathology shows small type I and/or II fibers, fiber-type disproportion, increased central nuclei, and increased lipid droplets/subsarcolemmal mitochondrial accumulation on electron microscopy (GeneReviews NBK542808).
  5. Organism consequence: Congenital hypotonia, weakness, contractures/arthrogryposis, myopathic facies, respiratory insufficiency, and impaired growth/short stature.
  6. Parallel branch — malignant hyperthermia susceptibility: The same triad-complex disruption independently confers susceptibility to pharmacologically triggered, dysregulated SR Ca²⁺ release (a hypermetabolic crisis) upon volatile-anesthetic/succinylcholine exposure — though the precise mechanistic link between STAC3 dysfunction and the MH trigger cascade "remains elusive" per current literature (EMHG summary; PMID:30178658).

Molecular pathway: Skeletal-muscle excitation-contraction coupling — the CaV1.1 (DHPR)–STAC3–RYR1 triad complex. This is a specialized calcium-signaling pathway, not a canonical annotated KEGG/Reactome pathway per se, but overlaps GO biological processes: "skeletal muscle contraction" (GO:0003009), "regulation of cytosolic calcium ion concentration" (GO:0051480), "voltage-gated calcium channel activity" (GO:0005245), "muscle filament sliding" (GO:0030049).

Cellular processes involved: Voltage sensing, calcium channel trafficking/stabilization, sarcoplasmic reticulum calcium release, myofibrillogenesis, muscle fiber-type specification (STAC3 has been separately shown to regulate hypertrophy and fiber-type composition; PMC4828897).

Protein dysfunction: Loss-of-function of a scaffolding/adaptor protein (not itself a channel), disrupting the structural stability and voltage-coupling of the CaV1.1-RYR1 triad supercomplex, rather than a classic enzymatic loss (PMC12333939).

Suggested GO terms: GO:0003009 (skeletal muscle contraction), GO:0051480 (regulation of cytosolic calcium ion concentration), GO:0005245 (voltage-gated calcium channel activity), GO:0014901 (myotube differentiation involved in skeletal muscle regeneration — for developmental aspects).

Suggested CL terms: CL:0000188 (skeletal muscle fiber / myocyte), CL:0000192 (smooth muscle myocyte — not applicable here; skeletal-muscle-specific), CL:0002372 (myotube).

Molecular profiling: No transcriptomic, proteomic, or metabolomic disease-specific datasets were identified in this search; the field has relied predominantly on targeted electrophysiology, calcium imaging, and ultrastructural (EM) studies in zebrafish/mouse models rather than omics profiling.

7. Anatomical Structures Affected

Organ level: - Primary: Skeletal muscle (generalized, all muscle groups affected to varying degree) — UBERON:0001134 (skeletal muscle tissue) - Secondary/complications: Respiratory system (diaphragmatic/intercostal weakness → respiratory insufficiency, pulmonary hypoplasia); craniofacial skeleton and palate (cleft/high-arched palate); axial skeleton (progressive scoliosis/kyphoscoliosis); ocular (ptosis — levator palpebrae superioris muscle); auditory system (hearing loss reported in case report); reproductive (cryptorchidism) - Body systems involved: Musculoskeletal (primary), respiratory, craniofacial/orofacial, ocular, and — via the MH mechanism — a systemic hypermetabolic crisis affecting multiple organ systems acutely.

Tissue/cell level: Skeletal muscle fibers (Type I and Type II, variably small/disproportionate); triad junction (T-tubule/SR junctional complex) is the specific subcellular structure of primary pathology.

Subcellular level (GO Cellular Component): - Sarcoplasmic reticulum (GO:0016529) - T-tubule / triad junction (GO:0014802, triad) - Plasma membrane / sarcolemma (voltage sensor localization) - Mitochondria (subsarcolemmal accumulation noted on EM)

Localization: Generalized/systemic muscle involvement rather than focal; facial muscles (myopathic facies, ptosis), palatal musculature, axial/paraspinal muscles, distal limb muscles (talipes), and respiratory muscles are all clinically prominent. No consistent lateralization pattern is reported (bilateral/symmetric involvement typical of congenital myopathies).

8. Temporal Development

Onset: Congenital — present at birth or detectable prenatally in severe cases (reduced fetal movement consistent with arthrogryposis is plausible antenatally, though not explicitly quantified in the sources reviewed). Onset pattern is essentially always congenital/neonatal rather than later-onset (GeneReviews NBK542808; PMID:30178658).

Progression: Disease course is variable and described along a spectrum: - Severe/prenatal-onset end: Profound weakness at birth, high early mortality risk - Milder end: Slowly progressive congenital myopathy with better long-term motor function (PMID:30178658)

Musculoskeletal features (scoliosis, contractures) are typically progressive over childhood; some patients require serial casting/bracing/surgery for progressive spinal and limb deformity. Motor function among evaluable individuals (n=15 in GeneReviews cohort) ranged from independent walking (11) to limited ambulation (2), running (1), and independent sitting only (1); a subset become wheelchair-dependent by adolescence (GeneReviews NBK542808).

Disease duration/course: Chronic, lifelong — non-remitting. Approximately 36% mortality by age 18 years, with pulmonary hypoplasia and aspiration-related pneumonia as documented causes of death (GeneReviews NBK542808).

Critical periods: The neonatal/early infancy period is the highest-risk window (respiratory failure, feeding failure); any anesthetic exposure at any age constitutes an acute high-risk period for malignant hyperthermia crisis.

9. Inheritance and Population

Epidemiology: - Originally described exclusively in the Lumbee Native American tribe of North Carolina; estimated prevalence ~1 in 5,000 among the ~60,000 enrolled Lumbee tribal members (GeneReviews NBK542808) - Now documented across multiple, geographically and ethnically diverse populations: Brazil (PMID:37626540), Comoros Islands (7 patients, PMID:36030003), Southern Africa (31 homozygotes identified among 127 congenital-hypotonia referrals — making it a common cause of congenital hypotonia in that regional cohort, PMID:38824262), and individuals of African ancestry more broadly - Exact global incidence/prevalence outside the Lumbee founder population is not yet formally quantified but is clearly under-ascertained historically due to the eponymic "Native American" framing biasing clinical suspicion away from other ancestries — explicitly flagged in the literature: "STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy" (PMID:30178658)

Inheritance pattern: Autosomal recessive (biallelic pathogenic variants required).

Penetrance: Appears fully penetrant for the myopathy phenotype in biallelic carriers (i.e., no unaffected homozygotes reported), though expressivity (severity) is highly variable. Malignant hyperthermia susceptibility penetrance is incomplete/variable (43% GeneReviews cohort; 22% Southern African cohort had a suggestive MH history) — not all biallelic carriers have documented MH events, and absence of a prior uneventful anesthetic does not exclude risk (GeneReviews NBK542808).

Expressivity: Markedly variable, from prenatal-onset severe disease to slowly progressive milder myopathy (PMID:30178658). No genotype-phenotype correlation for variant type/severity has been established.

Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).

Founder effects: Strong founder effect for c.851G>C (p.Trp284Ser) in the Lumbee population; the same variant recurring as the dominant allele in unrelated non-Lumbee populations worldwide suggests either an ancient founder event, mutational hotspot, or (most likely per literature) simply that this residue (Trp284) is a critical, highly conserved hotspot for loss-of-function substitution.

Consanguinity: Not specifically required — Brazilian and other non-Lumbee cases have been reported in patients from non-consanguineous parents (PMID:37626540), consistent with a carrier frequency high enough that unrelated at-risk matings occur, particularly given the apparent broader-than-expected allele distribution.

Carrier frequency: Estimated at ~33/141,000 alleles in heterozygosity in gnomAD population data for the founder variant (PMID:37626540); locally much higher within the Lumbee population (consistent with ~1/5,000 disease prevalence implying carrier frequency around 1 in ~35-40 if Hardy-Weinberg assumptions hold in that subpopulation).

Population demographics: - Sex ratio: Autosomal recessive — expected 1:1 male:female, though cryptorchidism as a reported feature is obviously male-specific - Geographic distribution: Originally North Carolina (Lumbee), now global — Brazil, Comoros, Southern Africa, and other regions with African-ancestry populations - Age distribution: Congenital onset in all reported cases; cohort ages at diagnosis/report span infancy through adolescence/adulthood among survivors

10. Diagnostics

Molecular genetic testing (primary diagnostic modality): - Targeted single-variant testing: For individuals of confirmed or suspected Lumbee ancestry, targeted analysis for c.851G>C (p.Trp284Ser) is recommended first-line - Single-gene STAC3 sequencing: Detects small indels, missense, nonsense, and splice-site variants; if only one or zero pathogenic variants found, follow with gene-targeted deletion/duplication analysis (though none has been identified to date) - Multigene congenital myopathy panel: Recommended when clinical suspicion is present but genetic cause not narrowed — note some panels historically omitted STAC3 due to rarity/eponymic obscurity - Exome sequencing (preferred) or genome sequencing: When the diagnosis is not initially considered / broader differential needed (GeneReviews NBK542808)

Clinical/histopathologic tests: - Muscle biopsy: variable findings — small Type I and/or Type II fibers, fiber-type disproportion, increased central nuclei, increased lipid droplets and/or subsarcolemmal mitochondrial accumulation on electron microscopy (GeneReviews NBK542808) - Serum creatine kinase: normal or mildly elevated (nonspecific) - Respiratory functional testing: polysomnography (sleep apnea/hypoxia screening), spirometry/pulmonary function testing - No STAC3-specific circulating biomarker has been established

Differential diagnosis (per GeneReviews): | Condition | Gene | Distinguishing features | |---|---|---| | Central core disease | RYR1 | Also has respiratory insufficiency, contractures, arthrogryposis, MH susceptibility; may show external ophthalmoplegia, CK elevation | | Carey-Fineman-Ziter syndrome | MYMK | Similar upturned nasal tip, micrognathia, generalized muscle hypoplasia, delayed motor milestones; no MH susceptibility — key discriminator | | Moebius syndrome | Multiple/heterogeneous | Overlapping cleft palate, talipes, short stature, scoliosis, contractures; distinguished by obligatory ocular abduction impairment/cranial nerve findings |

Genetic counseling / newborn or cascade screening: No population newborn-screening program specific to STAC3 was identified. Targeted carrier screening/cascade testing is clinically relevant in the Lumbee population and in families with a known proband.

Diagnostic criteria: No formal consensus diagnostic-criteria document (e.g., DSM/ICD-style) was identified beyond the GeneReviews clinical + molecular confirmation framework; diagnosis rests on clinical phenotype consistent with the disorder plus biallelic STAC3 pathogenic variants.

11. Outcome/Prognosis

Survival/mortality: Approximately 36% mortality by age 18 years in the cumulative GeneReviews cohort, with pulmonary hypoplasia and aspiration-related pneumonia as the documented causes of death (GeneReviews NBK542808). Severity spans a spectrum from prenatal-onset/early lethal disease to survivable, slowly progressive myopathy (PMID:30178658).

Morbidity/function: Motor outcomes among survivors are heterogeneous: independent ambulation achievable in a majority of evaluable cases in one cohort (11/15), but a subset lose ambulation and become wheelchair-dependent by adolescence. Respiratory insufficiency (55% in one cohort) and feeding/nutritional compromise are major sources of ongoing morbidity requiring long-term multidisciplinary management (GeneReviews NBK542808).

Complications: Aspiration pneumonia, progressive scoliosis/kyphoscoliosis potentially requiring surgical correction, ptosis-related visual impairment if uncorrected, malignant hyperthermia crisis (potentially fatal if not immediately recognized and treated) upon inadvertent anesthetic exposure.

Prognostic factors: No validated quantitative prognostic biomarkers or scoring system identified; disease severity appears to vary independent of specific variant identity (no established genotype-phenotype correlation) (GeneReviews NBK542808).

12. Treatment

Current status: No disease-modifying or curative therapy exists. GeneReviews states explicitly: "No treatment halts or reverses the manifestations of STAC3 disorder" (NBK542808). This stands in contrast to the unrelated disease X-linked myotubular myopathy (MTM1), which has an AAV8 gene-replacement candidate (resamirigene bilparvovec/AT132) in clinical development via the ASPIRO trial (NCT03199469) — that program is specific to MTM1/XLMTM and is not applicable to STAC3/Bailey-Bloch disease. Notably, an early-stage French research initiative (ANR-funded, "STAC3 disorder: gene therapy and malignant hyperthermia") is investigating gene-therapy approaches specifically for STAC3 disorder, but this appears to be at a preclinical/research-planning stage rather than a registered clinical trial — treat as an emerging research direction, not an established treatment, pending primary-literature confirmation.

Management is entirely supportive/multidisciplinary, per GeneReviews:

Musculoskeletal (NCIT:C15302 Physical Therapy; NCIT:C16186 Orthopedic Surgical Procedure): - Physical and occupational therapy for range of motion and mobility - Contracture management: stretching, night splints, serial casting - Orthopedic intervention for talipes deformity and progressive scoliosis (bracing progressing to surgical correction) - Adaptive devices for activities of daily living; avoidance of prolonged immobilization

Feeding/Nutrition (NCIT:C15447 Dietary Intervention): - Speech-language pathology and nutrition assessment - Specialized feeding equipment, nasogastric or enteral (gastrostomy) tube feeding as needed - Aspiration-risk evaluation

Respiratory: - Polysomnography, spirometry/pulmonary function monitoring - Noninvasive or invasive ventilatory support as needed - Mechanical cough-assist devices - Aggressive prevention/treatment of respiratory infections

Surgical/other: - Ptosis repair (levator resection or frontalis sling) to prevent amblyopia/visual impairment - Multidisciplinary craniofacial team management of cleft palate repair timing/technique - Speech therapy for dysarthria - Hearing assessment/audiology referral

Genetic counseling (NCIT:C15240): Recommended for families, given autosomal recessive inheritance and 25% recurrence risk for future pregnancies of carrier parents.

Anesthesia/perioperative management — the single most critical, disease-defining treatment consideration: Strict avoidance of volatile halogenated anesthetics (halothane, isoflurane, sevoflurane) and depolarizing neuromuscular blockers (succinylcholine, decamethonium) is mandatory due to malignant hyperthermia risk; total intravenous anesthesia (TIVA) protocols and dantrolene availability are standard-of-care precautions in this population (GeneReviews NBK542808).

Surveillance schedule (per GeneReviews): - Growth: every visit - Neuromuscular assessment: every 3-4 months (infants <12 months); every 6-12 months (older children/adults) - Respiratory: at least annually, more often if symptomatic - Feeding/nutrition: every visit

13. Prevention

Primary prevention: Not applicable in the traditional sense (fully genetic, congenital disorder) — the principal preventive intervention is genetic counseling and reproductive planning (carrier testing, prenatal diagnosis, preimplantation genetic diagnosis) for at-risk families, particularly within the Lumbee community and other populations where the founder variant has been documented.

Secondary prevention: Early recognition via clinical suspicion and STAC3 testing in any patient presenting with congenital hypotonia/myopathy — explicitly recommended by Zaharieva et al. (PMID:30178658) as a diagnostic-pathway improvement, since delayed/missed diagnosis (from assuming the "Native American" eponym excludes other ancestries) delays appropriate anesthesia precautioning.

Tertiary prevention (preventing complications in affected individuals): This is where the bulk of "prevention" activity concentrates for this disorder — anesthesia-protocol avoidance of MH triggers is the single highest-yield preventive intervention (preventing a potentially fatal acute crisis); proactive orthopedic bracing to slow scoliosis progression; proactive respiratory surveillance to catch early insufficiency; proactive feeding evaluation to reduce aspiration risk.

Genetic/carrier screening: Targeted variant screening (for c.851G>C) is feasible and low-cost in populations with known founder-variant enrichment; broader carrier screening is not yet a standard public-health program outside of at-risk-population contexts.

Public health/behavioral interventions: No population-level public health program specific to this disorder was identified.

14. Other Species / Natural Disease

Naturally occurring disease in other species: No naturally occurring STAC3-related myopathy in non-human species (companion animals, livestock, wildlife) was identified in this search — unlike some other congenital myopathy genes with OMIA entries, STAC3 disorder appears to be studied exclusively through engineered/induced animal models (see Section 15) rather than as a spontaneously occurring veterinary disease.

Orthologous gene: STAC3 is highly conserved across vertebrates — the critical Trp284 residue "is completely conserved between various mammals and zebrafish," underscoring its fundamental structural role in EC coupling machinery (search synthesis from PMID:23736855/PMID:28003463 literature).

Comparative biology: The excitation-contraction coupling machinery (CaV1.1-STAC3-RYR1 triad) is deeply conserved from zebrafish to mammals, which is precisely why zebrafish forward-genetic screens were able to identify stac3 as a novel EC-coupling component in the first place (PMID:23736855).

15. Model Organisms

Zebrafish (Danio rerio) — the founding/primary model system: - The gene was originally identified through an unbiased zebrafish locomotor forward-genetic screen, which isolated a paralytic mutant subsequently mapped to stac3 — this is how the human disease gene was discovered in the first place (Horstick et al., 2013, Nature Communications, PMID:23736855) - stac3-null zebrafish show paralysis, loss of voltage-dependent SR Ca²⁺ release, delayed larval hatching correlating with muscle weakness, and decreased whole-body Ca²⁺ levels during early skeletal muscle development - A zebrafish knock-in model of the human p.Trp284Ser (NAM) mutation (stac3^NAM) showed significantly reduced dihydropyridine receptor (DHPR/CaV1.1) levels, functionality, and stability, along with paradoxically increased caffeine-induced Ca²⁺ release — Linsley et al., 2017, PNAS, PMID:28003463 - A 2024 zebrafish study found that early-life lipid overload in Native American myopathy is phenocopied by stac3 knockout, implicating a metabolic/lipid-handling dimension to the disease not previously appreciated (PMID:39592070) - Defects in F-actin cytoskeleton organization and slow-muscle-fiber structure were observed at 5-7 days post-fertilization in stac3 mutant larvae

Mouse (Mus musculus): - Stac3 knockout mice die perinatally from suffocation (respiratory failure due to complete EC-coupling failure), phenocopying other EC-coupling-null models (e.g., RYR1-null, CaV1.1-null) - Newborn Stac3-knockout mouse muscle fibers show centralized nuclei and disorganized myofibrils — directly recapitulating human muscle-biopsy findings (centralized nuclei is a described human histopathologic feature) - Skeletal muscles from Stac3-deleted mouse fetuses fail to contract altogether, consistent with defective EC coupling as the proximate cellular mechanism - STAC3 additionally regulates postnatal muscle growth, fiber-type composition, and hypertrophy signaling, based on a postnatal Stac3 gene-dosage study (PMC4828897)

Model fidelity assessment: Both zebrafish and mouse null models robustly recapitulate the core EC-coupling defect and the severe end of the human phenotypic spectrum (paralysis/perinatal lethality, centralized nuclei, disorganized myofibrils), supporting high translational fidelity for the core mechanism. However, complete null models in mouse are uniformly perinatal-lethal, which does not capture the milder, slowly progressive end of the human phenotypic spectrum seen with hypomorphic human alleles — the stac3^NAM knock-in zebrafish model is a closer approximation of the specific human founder-variant biology and is the more clinically relevant model for the malignant-hyperthermia-susceptibility mechanism specifically.

Applications: These models have been used to dissect (1) the core structural/electrophysiological mechanism of EC-coupling failure, (2) the specific molecular consequence of the p.Trp284Ser substitution on CaV1.1 stability/organization, and (3) an emerging metabolic/lipid-handling dimension of pathophysiology; they underlie the rationale for the nascent STAC3 gene-therapy research effort noted in Section 12.

Summary of Key Ontology Term Suggestions for KB Curation

Category Suggested term(s) Note
Disease MONDO:0009722 Verify against local MONDO closure
Gene STAC3 (HGNC symbol; verify HGNC numeric ID via lookup — not independently confirmed in this search) 12q13.3
Phenotypes HP:0001252 Hypotonia; HP:0002058 Myopathic facies; HP:0000508 Ptosis; HP:0011968 Feeding difficulties; HP:0002804 Arthrogryposis multiplex congenita; HP:0001762 Talipes equinovarus; HP:0002751 Kyphoscoliosis; HP:0004322 Short stature; HP:0000175 Cleft palate; HP:0001954 Malignant hyperthermia; HP:0002093 Respiratory insufficiency; HP:0000028 Cryptorchidism Verify each with OAK per dismech-terms skill before committing
Biological process (GO) GO:0003009 skeletal muscle contraction; GO:0051480 regulation of cytosolic calcium ion concentration; GO:0005245 voltage-gated calcium channel activity
Cellular component (GO) GO:0016529 sarcoplasmic reticulum; GO:0014802 triad (T-tubule/SR junction)
Cell type (CL) CL:0000188 skeletal muscle fiber; CL:0002372 myotube
Anatomy (UBERON) UBERON:0001134 skeletal muscle tissue
Treatment (NCIT) NCIT:C15302 Physical Therapy; NCIT:C16186 Orthopedic Surgical Procedure; NCIT:C15447 Dietary Intervention; NCIT:C15240 Genetic Counseling

PMID Reference List

  • PMID:3631569 — Bailey & Bloch, 1987 (original description)
  • PMID:23736855 — Horstick et al., 2013, Nat Commun (zebrafish screen identifying Stac3)
  • PMID:28003463 — Linsley et al., 2017, PNAS (stac3^NAM zebrafish mechanism)
  • PMID:30178658 — Zaharieva et al., 2018, Hum Mutat (largest international cohort, dysmorphic features, MHS)
  • PMID:36030003 — Comorian case series (7 patients)
  • PMID:37626540 — Brazilian patients case report
  • PMID:38824262 / PMID:39080471 — Southern African cohort (31 homozygotes; common cause of congenital hypotonia)
  • PMID:39592070 — 2024 zebrafish lipid-overload/knockout phenocopy study
  • GeneReviews NBK542808 — STAC3 Disorder (comprehensive clinical synthesis, n=44 cases)
  • OMIM #255995 (CMYO13) and *615521 (STAC3)

Sources: - Entry - #255995 - CONGENITAL MYOPATHY 13; CMYO13 - Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy with Malignant Hyperthermia Susceptibility - Bailey-Bloch Congenital Myopathy in Brazilian Patients - PubMed - Bailey-Bloch congenital myopathy - NIH Genetic Testing Registry (GTR) - STAC3 Disorder - GeneReviews® - STAC3 disorder: a common cause of congenital hypotonia in Southern African patients | European Journal of Human Genetics - STAC3 disorder: a common cause of congenital hypotonia in Southern African patients (PMC) - STAC3 related congenital myopathy: A case series of seven Comorian patients - PubMed - Stac3 is a component of the excitation–contraction coupling machinery and mutated in Native American myopathy | Nature Communications - Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3 | PNAS - STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility - Human Mutation - 615521 - SH3 AND CYSTEINE-RICH DOMAINS 3; STAC3 - Congenital Myopathy 13 - MalaCards - STAC3 stably interacts through its C1 domain with CaV1.1 in skeletal muscle triads | Scientific Reports - Early life lipid overload in Native American Myopathy is phenocopied by stac3 knockout in zebrafish - PubMed - The SH3 and cysteine-rich domain 3 (Stac3) gene is important to growth, fiber composition, and calcium release from the sarcoplasmic reticulum in postnatal skeletal muscle - STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling - STAC3 — European Malignant Hyperthermia Group - STAC3 disorder: gene therapy and malignant hyperthermia | ANR - Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy - eBioMedicine - X-linked myotubular myopathy | MedLink Neurology

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:28003463: "decreases the quantity, organization, stability, and voltage sensitivity of Ca²⁺ channels"
  • closest text in source: "Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+ These findings define critical roles for Stac3 in EC coupling and human disease."
  • PMC:PMC12333939: "decreases the quantity, organization, stability, and voltage sensitivity of Ca²⁺ channels"
  • Text part not found as substring: 'decreases the quantity, organization, stability, and voltage sensitivity of Ca²⁺ channels' (note: only abstract available for PMID:40779452, full text may contain this excerpt)
  • PMID:30178658: "STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy"
  • Text part not found as substring: 'STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy' (note: only abstract available for PMID:30178658, full text may contain this excerpt)