Bailey-Bloch Congenital Myopathy

Mendelian MONDO:0009722 Pathograph 51 Show in embeddings browser Congenital myopathy

Bailey-Bloch congenital myopathy is an autosomal recessive disorder caused by biallelic pathogenic STAC3 variants. STAC3 is a skeletal-muscle adaptor that supports CaV1.1 expression and its conformational coupling to RyR1-mediated calcium release. The recurrent p.Trp284Ser allele impairs coupling while retaining some channel-complex association and function. Congenital hypotonia and weakness occur with myopathic facies, ptosis, contractures, talipes, palatal abnormalities, feeding and respiratory difficulties, and spinal deformity. Clinical severity and course vary; some patients improve, whereas others develop progressive complications. Intellect is often preserved, but developmental delay and mild intellectual disability have also been reported. Volatile anesthetics and succinylcholine can trigger malignant hyperthermia, including after previous uneventful anesthesia. Originally described in the Lumbee population, STAC3 disorder occurs worldwide and should be considered regardless of ancestry.

Ask OpenScientist

Ask a research question about Bailey-Bloch Congenital Myopathy. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
1
Histopath.
58
Phenotypes
2
Gaps
51
Pathograph
2
Genes
7
Variants
12
Medical Actions
5
Differentials
11
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 REVIEW SYNTHESIS 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.
?

Discussions and Knowledge Gaps

2
How do variant-specific changes in STAC3 contacts alter voltage sensing and calcium-release efficiency in patient-derived muscle cells?
OPEN QUESTION stac3_cav11_interaction_paradox
Attached to
pathophysiology#Impaired SH3-Dependent Enhancement of Calcium Release
Patient-biopsy co-immunoprecipitation recovers a stable STAC3-CaV1.1 complex, whereas isolated SH3-interface and engineered myotube assays show impaired coupling enhancement. These assays measure different aspects of the complex. The two-contact model provides a compatible explanation, but matched voltage-sensing and release measurements in patient cells are still needed to quantify each contribution.
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."
Biopsy co-immunoprecipitation shows retained recoverable association; it does not test all individual interfaces.
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 2018 interpretation must be read with its assay limits and the later two-contact model.
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
Clinical STAC3-related crises establish an anesthetic-triggered susceptibility. Zebrafish mutant models show increased caffeine-evoked release and store calcium, whereas the single patient myotube culture had preserved store size and no increased agonist sensitivity. Neither finding alone establishes the mechanism of anesthetic-triggered malignant hyperthermia 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+"
Supporting model-organism observation that has not yet been tied to anesthetic triggering in patients.
⚙

Pathophysiology

8
Biallelic STAC3 Loss of Function
Biallelic STAC3 variants impair the skeletal-muscle adaptor. The recurrent hypomorphic missense allele c.851G>C (p.Trp284Ser) affects the first SH3 domain; splice-altering, frameshift and truncating alleles also occur. Loss of the SH3 interaction with the CaV1.1 II-III loop severely reduces calcium release while allowing residual channel-complex association through the N-terminal region. Complete loss in experimental models can additionally reduce junctional channel abundance.
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
Reduced CaV1.1 Junctional Expression Complete Stac3 loss reduces CaV1.1 junctional abundance in experimental systems; this route is allele- and model-dependent rather than a necessary step in every patient.
Impaired SH3-Dependent Enhancement of Calcium Release The recurrent SH3-domain substitution or truncation compromises STAC3-dependent enhancement of calcium release.
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 REVIEW SYNTHESIS In Vitro
"the most common mutation associated with STAC3 disorder, W284S in the SH3-1 domain, impairs the binding ability of STAC3"
The 2025 introduction summarizes earlier isothermal-calorimetry experiments on the W284S substitution.
Reduced CaV1.1 Junctional Expression
Loss of Stac3 reduces CaV1.1/DHPR junctional abundance in zebrafish and cultured muscle models. In C2C12 Stac3-knockout myotubes, CaV1.1 cluster number and intensity decreased; the STAC3 N-terminal fragment partly restored cluster intensity. This null-model phenotype is not universal in patient muscle: three patient biopsies had preserved bulk CaV1.1, STAC3 and DHPR-beta1a levels, and p.Trp284Ser can retain substantial channel function despite strongly impaired excitation-contraction coupling.
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.
Experimental models
C2C12 Stac3-knockout myotubes CELL LINE Measures the contribution of Stac3 loss to endogenous junctional CaV1.1 expression.
Animal models
stac3 mutant zebrafish channel-function assays Zebrafish recapitulates Measures reduced DHPR abundance and function in stac3-mutant preparations; the abstract does not assign every measurement to the same genotype.
Downstream
Defective Skeletal Muscle Excitation-Contraction Coupling Reduced junctional voltage-sensor abundance is a possible contributor to impaired coupling in null models, but the clustering measurement does not isolate this causal contribution. Preserved abundance in patient biopsies shows that channel depletion is not required for the human coupling defect.
Show evidence (2 references)
PMID:40779452 SUPPORT In Vitro
"Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)"
Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT Human Clinical
"Western blot analysis demonstrated no significant change in the content of any of the tested proteins in patient muscle samples"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: Patient biopsies PN2D, PN5 and PN6A retained bulk STAC3, CaV1.1 and DHPR-beta1a; this limits extrapolation from null models.
Impaired SH3-Dependent Enhancement of Calcium Release
The STAC3 SH3 region normally enhances CaV1.1-to-RyR1 conformational coupling. W284S or loss of the SH3 domains markedly reduces depolarization-induced calcium release, although the N-terminal CaV1.1 contact can sustain residual coupling. Stable recovery of STAC3 with CaV1.1 in patient co-immunoprecipitation assays does not measure every binding interface or demonstrate intact coupling.
Experimental models
F8 CaV1.1/Stac3 double-knockout myotube reconstitution CELL LINE Dissects N-terminal and SH3-dependent contributions.
Downstream
Defective Skeletal Muscle Excitation-Contraction Coupling Loss of the coupling-enhancing contact lowers depolarization-induced calcium release despite residual voltage-sensor function.
Show evidence (2 references)
PMID:40779452 SUPPORT In Vitro
"STAC3-NT fragment, which lacks the SH3 domains, can support EC coupling at levels comparable to STAC3-W280S"
Reconstitution establishes residual coupling without the SH3 domains; loss of this contact is not an all-or-none loss of CaV1.1 function.
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT Human Clinical
"No difference in the apparent interaction between CaV1.1 and the p.(Trp284Ser) STAC3 was observed as the anti-CaV1.1 antibody pulled down STAC3 in both, patient and control muscle samples"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: Co-immunoprecipitation of three patient biopsies establishes preserved recoverable complex association, not preserved SH3-interface function.
Defective Skeletal Muscle Excitation-Contraction Coupling
Depolarization elicits insufficient sarcoplasmic-reticulum calcium release. In cultured myotubes from one compound-heterozygous patient (PN5), the peak KCl response was approximately 10% of control, despite similar resting calcium, intracellular-store size and agonist EC50 values. Zebrafish rescue and engineered myotube experiments independently support the coupling defect. Preserved early triad architecture in models does not exclude later myofibrillar pathology or nonspecific biopsy abnormalities in patients.
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 ↓ DECREASED 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. skeletal muscle contraction GO:0003009 ↓ DECREASED 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.
Experimental models
PN5 patient-derived STAC3 myotubes PRIMARY CELL CULTURE Directly measures the patient-cell coupling defect.
F8 CaV1.1/Stac3 double-knockout myotube reconstitution CELL LINE Channel-tethered SH3 domains rescue the mutant coupling defect.
Stac3-null mouse primary myotubes PRIMARY CELL CULTURE Direct RyR activation bypasses the upstream coupling defect.
Isolated FDB fibers after postnatal Stac3 deletion PRIMARY CELL CULTURE Tests electrical excitation-to-calcium coupling in isolated fibers.
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.
Heat-induced stac3 NAM transgene rescue in mi34 zebrafish Zebrafish partially recapitulates Tests allele-specific rescue of calcium release in the null background.
Constitutive Stac3-null mouse Mouse partially recapitulates The constitutive-null model establishes the requirement for Stac3 in muscle function.
Tamoxifen-induced postnatal Stac3 deletion mouse Mouse partially recapitulates Contrasts electrical and direct-RyR stimulation in muscles from the induced mice.
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 (3 references)
PMID:30168660 SUPPORT In Vitro
"In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release."
This functional result was measured in cultured myotubes from one patient, PN5, not across all patient biopsies.
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.
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT In Vitro
"the KCl induced Ca 2+ release which was reduced to approximately 10% of that observed in control myotubes"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The functional assay used patient PN5 myotubes; PN2D cells failed to differentiate.
Congenital Muscle Weakness
Congenital generalized muscle weakness is a principal manifestation of STAC3 disorder. Facial, bulbar, respiratory and axial involvement contributes to the clinical phenotype, but the frequencies and course of individual complications vary.
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 Reduced prenatal movement is compatible with fetal muscle weakness; patient cohorts document their association without directly testing this causal step.
Generalized muscle weakness Clinical manifestation of the corresponding mechanism node.
Congenital Hypotonia Impaired congenital muscle function is associated with reduced tone. Weakness and hypotonia are related clinical outputs; the cohort does not isolate every physiological step connecting them.
Weak cry Reduced respiratory and bulbar muscle force can contribute to a weak neonatal cry; the clinical cohort documents the finding without testing the intervening physiology.
Neonatal respiratory distress Respiratory muscle involvement can contribute to neonatal distress. Palatal, pulmonary and aspiration-related factors can also contribute, so this is an inferred, nonexclusive route.
Myopathic Facies Facial muscle weakness contributes to the characteristic myopathic facial appearance.
Proximal muscle weakness Proximal weakness is part of the clinical distribution of the generalized muscle disorder.
Feeding Difficulties Weak suck and bulbar dysfunction contribute to feeding difficulty alongside palatal and mandibular abnormalities; the route is multifactorial.
Dysphagia Bulbar muscle dysfunction can contribute to impaired swallowing; cohort data establish dysphagia, while its individual contribution relative to structural abnormalities remains uncertain.
Delayed Motor Milestones Reduced force and mobility can delay motor acquisition. Contractures and other complications also affect function; the clinical literature does not isolate their relative contributions.
Restrictive Respiratory Insufficiency Respiratory muscle weakness can contribute to a restrictive ventilatory defect, with spinal or chest-wall abnormalities and aspiration-related lung disease modifying severity.
Show evidence (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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
Reduced fetal movement is reported in STAC3 disorder. It was documented in the pregnancy of the child with homozygous STAC3 p.Asp229Ter and in STAC3-specific cohort data. Reduced prenatal movement is a plausible contributor to congenital contractures, but the clinical association alone does not establish the full causal sequence.
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
Decreased fetal movement Clinical manifestation of the corresponding mechanism node.
Arthrogryposis Multiplex Congenita Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
Talipes Equinovarus Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
Camptodactyly Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
Show evidence (1 reference)
PMID:40779452 SUPPORT Human Clinical
"During pregnancy, polyhydramnios and reduced fetal movements were noted."
Pregnancy history of the child with homozygous STAC3 p.Asp229Ter.
Anesthetic-Triggered Malignant Hyperthermia Susceptibility
Mechanism confidence: Provisional
Patients with biallelic pathogenic STAC3 variants are susceptible to malignant hyperthermia after volatile anesthetics or succinylcholine. Crises have occurred after previous uneventful anesthetics and show variable severity. The molecular steps linking altered STAC3-dependent coupling to the hypermetabolic crisis remain incompletely established; clinical attack frequencies do not measure latent susceptibility in unexposed patients.
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.
Downstream
Malignant Hyperthermia Susceptibility Clinical manifestation of the corresponding mechanism node.
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
Mechanism confidence: Hypothetical
Increased skeletal-muscle lipids have been reported in patients, but their causal role in weakness is unresolved. A CRISPR stac3-null zebrafish study reported elevated neutral lipids from 5 days post-fertilization alongside cytoskeletal and myogenic abnormalities. The available abstract does not establish that its bulk lipid measurements are muscle-specific or prove lipid accumulation mediates the coupling defect.
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 elevated neutral lipids alongside muscle abnormalities in larvae; muscle-specific lipid localization is not established by the available abstract.
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 REVIEW SYNTHESIS 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."
The abstract summarizes prior human observations; its new experimental evidence is from zebrafish.
✶

Histopathology

1
Non-Specific Myopathic Muscle Biopsy FREQUENT
Biopsy abnormalities are variable and nonspecific. The Southern African study reported abnormal histology in 11/16 biopsied patients, normal findings in three and unavailable results in two. Type 1 fiber predominance, nonspecific myopathy and atrophic fibers occurred. The international cohort also documented occasional internal nuclei, myofibrillar loss and minicore areas on electron microscopy, despite broadly preserved triads. These findings do not provide a pathognomonic biopsy diagnosis.
Show evidence (3 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.
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT Human Clinical
"Electron microscopy analysis showed myofibrillar loss, irregular and broken Z -lines with mini-core areas with disrupted sarcomeres"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The full text contradicts an absolute absence of cores.
⬡

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.
●

Phenotypes

58
Digestive 2
Feeding Difficulties 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 REVIEW SYNTHESIS 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.
Dysphagia FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Swallowing difficulties | 13/24 (54)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Ear 4
Hearing impairment 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 (2 references)
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.
PMID:38824262 SUPPORT Human Clinical
"One bilateral conductive hearing loss, one hearing loss of unspecified type."
The Table 1 footnote distinguishes the two hearing-loss observations in the Southern African cohort.
Low-set ears OCCASIONAL HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Low-set ears Posteriorly rotated ears | 8/30 (27) 6/30 (20)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Posteriorly rotated ears OCCASIONAL HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Low-set ears Posteriorly rotated ears | 8/30 (27) 6/30 (20)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Conductive hearing loss Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777491 SUPPORT Human Clinical
"Past medical history was notable for conductive hearing loss diagnosed at age 7 years; he wears hearing aids."
The Puerto Rican proband had documented conductive hearing loss.
Eye 2
Ptosis 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:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Ptosisa | 16/30 (53) | 8/10 (80) | 18/18 (100) | 4/7 (57)"
Table 1 separates the present cohort from three comparison cohorts; the first denominator determines this frequency band.
Ophthalmoplegia OCCASIONAL HP:0000602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ophthalmoplegia (HP:0000602). HP:0000602 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Ophthalmoplegia | 3/24 (13)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Genitourinary 1
Cryptorchidism FREQUENT 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:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Unilateral/bilateral cryptorchidism | 7/16 (44)"
Table 1 reports the male-specific denominator.
Head and Neck 17
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:38824262 SUPPORT Human Clinical
"Neurological features that were almost universal included myopathic facies (96%), reduced muscle bulk (86%) and hypotonia (100%)."
The discussion summarizes Table 1, in which myopathic facies occurred in 27/28 assessed patients.
Cleft Palate 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
"Palatal abnormalities were noted at a high frequency, in 26/28 (93%); 11/28 (39%) had a cleft palate and 16/28 (57%) had a high-arched palate."
The cohort distinguishes cleft palate from high-arched palate; one individual had both.
High-arched palate FREQUENT High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... High-arched palate | 16/28 (57)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Tongue fasciculations OCCASIONAL HP:0001308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tongue fasciculations (HP:0001308). HP:0001308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Tongue fasciculations | 3/28 (11)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Plagiocephaly OCCASIONAL HP:0001357 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Plagiocephaly (HP:0001357). HP:0001357 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Plagiocephaly | 5/30 (17)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Epicanthus OCCASIONAL HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Epicanthic folds | 7/30 (23)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Downturned corners of mouth OCCASIONAL HP:0002714 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downturned corners of mouth (HP:0002714). HP:0002714 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Downturned corners of the mouth | 6/30 (20)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Open mouth OCCASIONAL HP:0000194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Open mouth (HP:0000194). HP:0000194 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Mouth held open | 6/30 (20)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Tented upper lip FREQUENT Tented upper lip vermilion HP:0010804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tented upper lip vermilion (HP:0010804). HP:0010804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Tented upper lip | 14/30 (47)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"the remaining 5/24 (21%), had head circumference measurements less than the 3rd centile and below −2 SD, which was of postnatal onset in two patients, and of unknown onset in three patients."
The full-text cohort report supplies this finding and its denominator.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Myopathic facies, micrognathia, and palatal anomalies can be seen in a number of neuromuscular disorders of varying etiologies"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews lists micrognathia among the suggestive clinical findings.
Scaphocephaly OCCASIONAL HP:0030799 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scaphocephaly (HP:0030799). HP:0030799 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39966651 SUPPORT Human Clinical
"Total (n = 44) | RYR1 (n = 14) | RYR1 (n = 17) | RYR1 (n = 3) | RYR1 (n = 3) | STAC3 (n = 30) ... Scaphocephaly | 6 (14%) | 2 (14%) | - | - | - | 4 (13%)"
The table header identifies the STAC3-specific column, preventing use of the mixed-cohort frequency.
Telecanthus HP:0000506 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telecanthus (HP:0000506). HP:0000506 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"short and/or downslanting palpebral fissures, and telecanthus"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.
Short palpebral fissures HP:0012745 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short palpebral fissure (HP:0012745). HP:0012745 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"short and/or downslanting palpebral fissures, and telecanthus"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"short and/or downslanting palpebral fissures, and telecanthus"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.
Long face HP:0000276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long face (HP:0000276). HP:0000276 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Over time, the face often becomes long and narrow."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.
Retrognathia HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Retrognathia | 2/30 (7) ... Microretrognathia | 6/30 (20)"
Table 1 records isolated retrognathia and microretrognathia separately.
Integument 1
Decreased palmar creases HP:0006184 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased palmar creases (HP:0006184). HP:0006184 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777491 SUPPORT Human Clinical
"There were decreased skin creases over distal interphalangeal joints (DIPs), wrists, palms, and plantar surface of feet"
The Qatari proband had explicitly documented palmar involvement.
Limbs 3
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.
Overlapping toes OCCASIONAL HP:0001845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping toe (HP:0001845). HP:0001845 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Overlapping toes | 4/29 (14)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Genu recurvatum HP:0002816 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu recurvatum (HP:0002816). HP:0002816 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Genu recurvatumh | 2/29 (7) | | 7/15 (47)"
Table 1 separates the current cohort from the earlier Zaharieva cohort.
Metabolism 1
Malignant Hyperthermia Susceptibility 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 (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS Human Clinical
"Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased."
GeneReviews states the increased malignant hyperthermia risk.
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... History suggestive of MH | 4/18 (22)"
The count is observed history among individuals with available anesthesia information, not a penetrance estimate. No frequency band is assigned to latent susceptibility.
Musculoskeletal 10
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
"A weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients."
The perinatal count supports congenital hypotonia and its frequency in this cohort.
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.
Kyphoscoliosis OCCASIONAL 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
"Clinical feature ... Number (n/N)(%) ... Kyphoscoliosis | 3/27 (11)"
Table 1 gives the specific kyphoscoliosis denominator, separately from all spine abnormalities.
Generalized muscle weakness VERY_FREQUENT HP:0003324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized muscle weakness (HP:0003324). HP:0003324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Reduced power (global) | 22/27 (81)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Proximal muscle weakness OCCASIONAL HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Reduced power (proximal>distal) | 3/27 (11)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Decreased muscle mass VERY_FREQUENT HP:0003199 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased muscle mass (HP:0003199). HP:0003199 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Reduced muscle bulk | 25/29 (86)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Camptodactyly FREQUENT HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Camptodactyly | 12/30 (40)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Scoliosis OCCASIONAL HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Scoliosisg | 8/27 (30)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Joint hypermobility OCCASIONAL HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Joint hyperlaxityi | 4/29 (14)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Pectus carinatum OCCASIONAL HP:0000768 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus carinatum (HP:0000768). HP:0000768 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Pectus carinatum | 7/28 (25)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Nervous System 7
Delayed Motor Milestones 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 REVIEW SYNTHESIS 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.
Hyporeflexia FREQUENT HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Hyporeflexia (global) | 18/29 (62)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Areflexia OCCASIONAL HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Areflexia (global) | 6/29 (21)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Global developmental delay | 23/27 (85)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Speech impairment FREQUENT Poor speech HP:0002465 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor speech (HP:0002465). HP:0002465 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Speech impairmentk | 13/17 (76)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
Mild intellectual disability HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38824262 SUPPORT Human Clinical
"Clinical feature ... Number (n/N)(%) ... Intellectual disabilitym | 2/6 (33)"
The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
PMID:38824262 SUPPORT Human Clinical
"Assessed in children age six years or more; all assessed as mild intellectual disability."
The Table 1 footnote specifies age and severity.
Obstructive sleep apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"polysomnography revealed an obstructive sleep apnea syndrome."
The report gives a measured sleep-related respiratory phenotype.
Prenatal and Birth 1
Decreased fetal movement HP:0001558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased fetal movement (HP:0001558). HP:0001558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40779452 SUPPORT Human Clinical
"During pregnancy, polyhydramnios and reduced fetal movements were noted."
Pregnancy history of the child with homozygous truncating STAC3 variant.
Respiratory 3
Restrictive Respiratory Insufficiency 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 REVIEW SYNTHESIS 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.
Neonatal respiratory distress FREQUENT HP:0002643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal respiratory distress (HP:0002643). HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"A high frequency of patients (18/26 (69%)) experienced respiratory distress at birth"
The full-text cohort report supplies this finding and its denominator.
Respiratory distress beyond the neonatal period HP:0002098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory distress (HP:0002098). HP:0002098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Respiratory difficulties that extended beyond, or occurred after the neonatal period, were noted in almost half of the patients (7/16 (44%))."
The cohort describes persistent or later respiratory distress without assigning a uniform physiological subtype.
Voice 1
Weak cry VERY_FREQUENT HP:0001612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weak cry (HP:0001612). HP:0001612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"A weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients."
The full-text cohort report supplies this finding and its denominator.
Growth 4
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:38824262 SUPPORT Human Clinical
"close to half of the patients (10/22 (45%)) were noted to be of short stature both below the 3rd centile and below −2 SD."
Longitudinal growth observations distinguish birth length from later short stature.
Small for gestational age FREQUENT HP:0001518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small for gestational age (HP:0001518). HP:0001518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Almost half of the patients were born small for gestational age (SGA) (11/25 (44%))."
The full-text cohort report supplies this finding and its denominator.
Failure to thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Failure to thrive (FTT) was noted in 17/26 (65%) patients."
The full-text cohort report supplies this finding and its denominator.
Decreased body weight FREQUENT HP:0004325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased body weight (HP:0004325). HP:0004325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"the majority (16/23 (70%)) of patients were underweight-for-age (weight below −2 SD), and 10/23 (43%) were severely underweight for age (weight below −3 SD)."
The full-text cohort report supplies this finding and its denominator.
Other 1
Normal Intellect
Show evidence (1 reference)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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 gene page 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.
Variants (7)
NM_145064.3:c.851G>C (p.Trp284Ser) Pathogenic
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Recurrent first-SH3-domain missense allele. Its functional effect is hypomorphic: calcium-release coupling is more impaired than residual channel-complex association.
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"Whole exome sequencing revealed a homozygous pathogenic variant c.851G>C (p.Trp284Ser) in the STAC3 gene (NM_145064.3)"
The clinical report identifies transcript, zygosity and pathogenic classification.
NM_145064.2:c.763_766delCTCT (p.Leu255IlefsTer58) Pathogenic
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Frameshift allele reported in trans with p.Trp284Ser in two Puerto Rican siblings; parental Sanger sequencing confirmed opposite parental origins.
Show evidence (2 references)
PMID:28777491 SUPPORT Human Clinical
"The mother was heterozygous for the STAC3 c.851G>C; p.Trp284Ser variant, and the father was heterozygous for the STAC3 c.763_766delCTCT;p.Leu255IlefsX58 variant"
Parental segregation establishes the compound-heterozygous genotype.
PMID:28777491 SUPPORT Human Clinical
"Here we present two non-Native American families, who were found to have STAC3 pathogenic variants."
The authors classify the reported familial variants as pathogenic.
NM_145064.2:c.997-1G>T
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Acceptor-splice allele in trans with c.851G>C. cDNA confirmed activation of an exon-12 cryptic acceptor and a 12-nucleotide in-frame deletion, removing four residues from the second SH3 domain.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"For the c.997-1G>T variant, cDNA studies confirmed activation of a cryptic acceptor site within exon 12 leading to deletion of 12 nucleotides from mature STAC3 RNA"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews summarizes the experimentally demonstrated transcript consequence.
NM_145064.2:c.862A>T (p.Lys288Ter) Pathogenic
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Nonsense allele reported with c.432+4A>T in a Turkish patient; the pair extends the allelic spectrum beyond the recurrent missense variant.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"identified compound heterozygous pathogenic STAC3 variants in one individual of Turkish ancestry that included a nonsense change (c.862A>T) and a splice donor site variant c.432+4A>T."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews identifies both variants and their reported pathogenic classification.
NM_145064.2:c.432+4A>T
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Splice-region allele reported with p.Lys288Ter. Lymphocyte cDNA showed exon-4 skipping and activation of a new intron-4 splice site; this is experimentally assessed splicing, not solely a prediction.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"cDNA studies confirmed two aberrant transcription products for the c.432+4A>T splicing variant in lymphocytes, including skipping of exon 4 and activation of a new splice site in intron 4"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews reports the observed transcript abnormalities.
NM_145064.3:c.685_686del (reported p.Asp229Ter)
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous two-nucleotide deletion reported to terminate STAC3 after residue 228, removing the SH3 domains. Both asymptomatic parents were heterozygous. Engineered expression of residues 1-228 retained limited coupling; this does not establish endogenous truncated-protein abundance in the patient.
Show evidence (2 references)
PMID:40779452 SUPPORT Human Clinical
"Sanger sequencing confirmed the homozygous Stac3 variant segregating from her asymptomatic heterozygous parents"
The single-patient report establishes recessive segregation.
PMID:40779452 SUPPORT In Vitro
"CaV1.1/Stac3-KO myotubes reconstituted with STAC3-1-228 exhibited calcium transients of only 20% the magnitude of those in myotubes reconstituted with WT STAC3"
The engineered construct establishes residual coupling in vitro.
NM_145064.3:c.834_836del (p.Asp279del) Uncertain Significance
Gene: STAC3 hgnc:28423 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in STAC3 (hgnc:28423). hgnc:28423 is a gene from the HUGO Gene Nomenclature Committee.
In-frame deletion reported in trans with c.851G>C in the African KDS-like cohort. Table 1 classifies it as VUS using PM2 and PM4; the authors propose functional relevance but do not demonstrate it. Narrative and table disagree on the number of carriers, so no resolved count is assigned.
Show evidence (1 reference)
PMID:39966651 SUPPORT Human Clinical
"STAC3(NM_145064.3):c.834_836del; p.Asp279deld | VUS | PM2 PM4 | Absent"
Table 1 explicitly classifies this deletion as a variant of uncertain significance.
STAC3 c.851G>C recurrent allele (Genetic Mutation)
Gene: STAC3 hgnc:28423 gene page 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."
The Comorian authors propose a founder effect; this passage does not establish an independent mutational origin.
💊

Medical Actions

12
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
Avoid volatile anesthetics and depolarizing muscle relaxants that trigger malignant hyperthermia. Anesthetic planning includes preparation of the anesthesia machine, availability of dantrolene and appropriate postoperative care. Previous uneventful anesthesia does not exclude risk.
Show evidence (3 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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.
PMID:40262809 SUPPORT REVIEW SYNTHESIS Human Clinical
"Anesthesia without triggering agents (halogenated agents and succinylcholine) should be performed, in addition to cleaning the anesthetic machine for halogenated agents. Dantrolene and an intensive care unit must be available."
The STAC3 case-series discussion specifies preparation and rescue capability.
Physical 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
Platform: Behavioral / lifestyle
Physical therapy addresses range of motion and mobility. Contracture management may include stretching, night splints or serial casts, with avoidance of prolonged immobilization.
Show evidence (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS Human Clinical
"Occupational and physical therapy needs regarding range of motion and mobility."
GeneReviews management guidance for the musculoskeletal manifestations.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"PT to improve range of motion; ... Stretching, night splints, or serial casts."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 gives specific contracture interventions.
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
Platform: Surgery
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 (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Often initial bracing is followed by progressive scoliosis requiring surgery."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 supports bracing and surgical management of progressive scoliosis.
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
Platform: Surgery
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 REVIEW SYNTHESIS 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
Platform: Surgery
Surgical options include levator resection or frontalis sling procedures, selected by the ophthalmology or craniofacial team to address visual obstruction. Every procedure requires STAC3-specific anesthetic precautions.
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 (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Surgical repair, such as levator resection or frontalis sling surgeries"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 identifies the surgical options.
Nutritional and Feeding Support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
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 (2 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 states the indications for enteral feeding.
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 REVIEW SYNTHESIS 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.
Occupational Therapy
Action: Occupational TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Occupational Therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. NCIT:C121351
Platform: Behavioral / lifestyle
Occupational therapy and adaptive equipment support mobility and activities of daily living.
Show evidence (1 reference)
PMID:31219695 SUPPORT REVIEW SYNTHESIS Human Clinical
"Occupational and physical therapy needs regarding range of motion and mobility. Use of adaptive devices for mobility and activities of daily living."
GeneReviews describes the supportive functional-care goals.
Speech and Swallowing Therapy
Action: Speech Language TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. NCIT:C159273
Platform: Behavioral / lifestyle
Speech-language assessment addresses dysarthria, palatal dysfunction, communication and swallowing. Interventions are individualized and may include speech therapy, feeding therapy or augmentative communication.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Interventions depend on etiology of speech issues & may include speech therapy, surgery, &/or use of assistive communication devices."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 describes individualized communication interventions.
PMID:37626540 SUPPORT Human Clinical
"The patient was treated with physical therapy, speech therapy for dysphagia, and pulmonary rehabilitation."
The Brazilian case report documents swallowing-focused speech therapy without estimating efficacy.
Ventilatory Support
Action: Mechanical VentilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Mechanical Ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. NCIT:C70909
Noninvasive or invasive ventilation is used according to respiratory impairment. Reported STAC3 cases range from nocturnal positive airway pressure to tracheostomy with continuous ventilation; support is individualized.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 lists respiratory-support options.
PMID:38088138 SUPPORT Human Clinical
"At 6 mo required tracheostomy with ventilatory support continuously"
The pulmonary case-series table documents continuous ventilatory support in one severely affected infant.
Assisted Airway Clearance
Action: Respiratory TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Respiratory Therapy (NCIT:C15322). NCIT:C15322 is a clinical intervention from the NCI Thesaurus. NCIT:C15322
Cough-assist devices may be needed when respiratory muscle weakness compromises airway clearance. The pulmonary case series documents prescription following declining cough peak flow and secretion-clearance difficulty.
Show evidence (1 reference)
PMID:38088138 SUPPORT Human Clinical
"assisted cough using positive and negative pressurewas prescribed due to a persistent decline in CPF and reported difficulty with airway clearance."
Table 1 documents the indication for cough assistance in case 3.
Dantrolene for Acute Malignant Hyperthermia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dantrolene CHEBI:4317 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dantrolene (CHEBI:4317). CHEBI:4317 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Acute malignant-hyperthermia management includes stopping the triggering anesthetic and administering dantrolene when indicated. In the Brazilian three-case series all survived; two received dantrolene and one improved after withdrawal of the inhaled trigger. This is crisis treatment, not disease-modifying therapy for the congenital myopathy.
Show evidence (1 reference)
PMID:40262809 SUPPORT Human Clinical
"All patients had good clinical outcomes and survived the MH crisis. One of them improved with the halogenated drug suspension, while the other two also received the specific MH antidote dantrolene."
Reports treatment and outcomes in the three STAC3-related crises.
🌍

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 REVIEW SYNTHESIS 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

6
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 (3 references)
PMID:31219695 SUPPORT REVIEW SYNTHESIS 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.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Identification of biallelic STAC3 variants of uncertain significance (or of one known STAC3 pathogenic variant and one STAC3 variant of uncertain significance) does not establish or rule out the diagnosis."
GeneReviews, STAC3 Disorder (NBK542808): A VUS must not be silently promoted to a diagnostic allele.
Genetics-Before-Biopsy Testing Strategy
In suspected STAC3 disorder, molecular testing can precede an anesthetized biopsy, whose findings are often nonspecific. Targeted c.851G>C testing identified 25/127 (20%) homozygotes in a selected Southern African laboratory series of hypotonia referrals already negative for SMN1 exon-7 deletion testing (114) or Prader-Willi testing (13). This is not an unselected population screening yield.
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
EMG may be normal or show nonspecific myopathic findings. It supports evaluation of muscle disease but does not establish or exclude STAC3 disorder.
Show evidence (2 references)
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.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Electromyogram revealed normal results in some individuals and evidence of myopathy in others"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes the variability in electrophysiology.
Serum Creatine Kinase
CK is often normal and a normal result does not exclude STAC3 disorder. In the Southern African cohort, 16/21 had normal levels and four had raised values; the manuscript does not account explicitly for the remaining measurement. Three elevations were two to three times the upper limit and one was four to five times; three were measured neonatally, when elevations can be nonspecific.
Show evidence (2 references)
PMID:37626540 SUPPORT Human Clinical
"Creatine phosphokinase (CK) levels were normal."
Documents a normal CK in a genetically confirmed patient.
PMID:38824262 SUPPORT Human Clinical
"Of the four raised CK levels, three were increased two to three times the upper limit of normal for age, and one was increased four to five times the upper limit of normal for age."
The full text does not support restricting all elevations to a mild category.
Respiratory and Sleep Assessment
Pulmonary assessment includes respiratory function, cough strength, secretion handling and sleep symptoms, with spirometry and polysomnography as appropriate. Normal early spirometry does not exclude later restrictive disease. A five-patient pulmonary series recommends six-monthly function testing; GeneReviews recommends at least annual pulmonary assessment, more often in infancy or with respiratory symptoms.
Show evidence (3 references)
PMID:38088138 SUPPORT PRIMARY RESULT Human Clinical
"respiratory function testing should be measured on a regular basis, i.e every six months despite initial normal findings."
The pulmonary series proposes regular assessment despite initially normal function.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 4 specifies sleep evaluation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Clinical eval at least annually but likely more often during infancy or when any signs of respiratory insufficiency, aspiration, &/or sleep apnea develop"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 6 provides the qualified surveillance interval.
Multidisciplinary Neuromuscular Surveillance
GeneReviews recommends review of respiratory status, speech, swallowing and musculoskeletal complications every three to four months in infancy and every six to twelve months in older children and adults, with growth and feeding safety assessed at visits.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Infants age <12 mos: every 3-4 mos ... Older children & adults: every 6-12 mos"
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 6 gives the neuromuscular follow-up intervals.
📈

Progression

2
Variable childhood course
In the Southern African clinical cohort, 6/27 were static at last assessment, 6/27 worsened and 15/27 improved; course was unknown for four additional patients. These retrospective trajectories do not establish uniformly nonprogressive disease. Respiratory and orthopedic complications can progress even when motor function improves.
Show evidence (1 reference)
PMID:38824262 SUPPORT Human Clinical
"Static at time of last clinical visit | 6/27 (22) ... Progressive worsening | 6/27 (22) ... Condition improving | 15/27 (56)"
Table 1 reports heterogeneous clinical courses using available-case denominators.
Historical childhood mortality
GeneReviews reports historical mortality of 36% by age 18, based on earlier reports, and three first-year deaths in a 14-person series. This is not a contemporary survival estimate across all ancestries or a malignant-hyperthermia-specific fatality rate. Reported causes included severe pulmonary hypoplasia and pneumonia-associated apnea.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Thirty-six percent of individuals affected with STAC3 disorder died by age 18 years ... In a study of 14 affected individuals, three died during the first year of life, one from severe pulmonary hypoplasia and one from apnea secondary to enterococcal pneumonia"
GeneReviews, STAC3 Disorder (NBK542808): The GeneReviews life-expectancy section summarizes historical cohorts; ascertainment and treatment era limit generalization.
📊

Prevalence

2
Lumbee Native American tribe, North Carolina
Birth Prevalence 20.0 per 100,000 1–9 per 10,000 (births)
A published comparison gives an estimated birth prevalence of 1 in 5,000 in the Lumbee population (20 per 100,000 births). This is a secondary estimate, not a new population survey in the Southern African study. GeneReviews describes the same numerical estimate as one in 5,000 Lumbee individuals, without specifying births; the measure designation here follows the cited Southern African paper and the source definitions are not interchangeable.
Show evidence (2 references)
PMID:38824262 SUPPORT REVIEW SYNTHESIS Human Clinical
"By comparison it is estimated that the birth prevalence in Lumbee Native Americans is 1 in 5000 within a total population of 60,000."
The source explicitly calls this an estimated birth prevalence.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"It is estimated that one in 5,000 Lumbee Native Americans has STAC3 disorder."
GeneReviews, STAC3 Disorder (NBK542808): GeneReviews supports the numerical estimate but does not identify it as a birth-prevalence measurement.
Southern African population (derived from healthy-cohort carrier rate)
Birth Prevalence 8.0 per 100,000 1–9 per 100,000 (births)
Predicted birth prevalence of approximately 1 in 12,500 from a carrier estimate of 5/278 healthy individuals of similar Southern African ancestry. The published range was 1:2,300–1:65,000. This prediction is not an observed national birth-registry rate.
Show evidence (2 references)
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.
PMID:38824262 SUPPORT Human Clinical
"We estimated the carrier frequency of this allele to be 1 in 56 (95% confidence interval 1:24–1:129), which predicts a birth prevalence of approximately 1 in 12,500 (range 1:2,300–1:65,000)"
The confidence range reflects uncertainty in a prediction based on the small carrier cohort.
🔀

Differential Diagnoses

5

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

King-Denborough syndrome Not Yet Curated MONDO:0020485
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 with facial weakness, palatal abnormalities and skeletal findings overlaps clinically with STAC3 disorder. Molecular testing distinguishes MYMK-related Carey-Fineman-Ziter syndrome 1 and other genetically defined forms from STAC3 disease.
Distinguishing Features
  • A different causal gene — MYMK in Carey-Fineman-Ziter syndrome 1
Moebius syndrome Not Yet Curated MONDO:0008006
Overlapping Features Congenital facial weakness and impaired ocular abduction can resemble STAC3 disorder. A Brazilian child initially suspected to have Moebius syndrome was diagnosed with biallelic STAC3 variants. Reported overlap and rare anesthesia complications make an absolute absence of malignant hyperthermia an unreliable discriminator.
Distinguishing Features
  • Obligatory impairment of ocular abduction and other cranial nerve findings
Show evidence (1 reference)
PMID:37626540 SUPPORT Human Clinical
"patient 2 was initially suspected to have MBS, which was rectified only after the genetic analysis was carried out, confirming the biallelic pathogenic variant p.Trp284Ser in STAC3"
Documents clinical misclassification resolved by molecular testing.
X-linked myotubular myopathy Not Yet Curated MONDO:0010683
Overlapping Features MTM1-related congenital myopathy can also present with severe neonatal hypotonia and respiratory insufficiency. Its X-linked inheritance and molecular cause distinguish it from autosomal recessive STAC3 disorder.
Distinguishing Features
  • X-linked rather than autosomal recessive inheritance
  • MTM1 genotype
🧫

Experimental Models

5
PN5 patient-derived STAC3 myotubes PRIMARY_CELL_CULTURE
Myotubes carrying p.Trp284Ser and c.997-1G>T showed reduced KCl- and 4-CMC-evoked peak calcium release. Resting cytosolic calcium, store size and agonist EC50 values did not differ significantly from controls. The second available patient culture, PN2D, failed to differentiate, so the functional evidence comes from one patient.
Cell source
Muscle-biopsy-derived primary myoblasts from compound-heterozygous patient PN5
Publication
PMID:30168660
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates Directly measures the patient-cell coupling defect.
Limitations: One compound-heterozygous patient; culture assays do not establish malignant-hyperthermia susceptibility mechanisms in vivo.
Show evidence (1 reference)
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT In Vitro
"the KCl induced Ca 2+ release which was reduced to approximately 10% of that observed in control myotubes"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The functional assay used patient PN5 myotubes; PN2D cells failed to differentiate.
Show evidence (1 reference)
url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf SUPPORT In Vitro
"the KCl induced Ca 2+ release which was reduced to approximately 10% of that observed in control myotubes"
Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The functional assay used patient PN5 myotubes; PN2D cells failed to differentiate.
F8 CaV1.1/Stac3 double-knockout myotube reconstitution CELL_LINE
Reconstitution with CaV1.1 and STAC3 fragments separates voltage-sensor function from calcium-release enhancement. N-terminal STAC3 supported residual coupling without SH3 domains. Targeting intact SH3 domains through a beta1a fusion rescued calcium release in W280S-expressing cells; untethered SH3 domains did not provide equivalent rescue.
Cell source
Immortalized F8 double-knockout myotubes
Publication
PMID:40779452
Pathograph links
Impaired SH3-Dependent Enhancement of Calcium Release partially recapitulates Dissects N-terminal and SH3-dependent contributions.
Show evidence (1 reference)
PMID:40779452 SUPPORT In Vitro
"we reconstituted different STAC3 fragments and mutants in double CaV1.1/Stac3-KO myotubes to examine the contribution of each of the 2 STAC3/CaV1.1 interactions"
Defines the engineered immortalized myotube system and its domain-reconstitution design.
Defective Skeletal Muscle Excitation-Contraction Coupling rescues Channel-tethered SH3 domains rescue the mutant coupling defect.
Limitations: Engineered overexpression in immortalized myotubes; delivery, safety and clinical efficacy remain untested.
Show evidence (1 reference)
PMID:40779452 SUPPORT In Vitro
"STAC3-CT-β1a expression remarkably increased the EC coupling calcium release observed in myotubes reconstituted with STAC3-W280S by 5-fold."
Targeted SH3-domain delivery rescued calcium release in cultured myotubes; this is not an animal or clinical treatment result.
Show evidence (2 references)
PMID:40779452 SUPPORT In Vitro
"we reconstituted different STAC3 fragments and mutants in double CaV1.1/Stac3-KO myotubes to examine the contribution of each of the 2 STAC3/CaV1.1 interactions"
Defines the engineered immortalized myotube system and its domain-reconstitution design.
PMID:40779452 SUPPORT In Vitro
"STAC3-CT-β1a expression remarkably increased the EC coupling calcium release observed in myotubes reconstituted with STAC3-W280S by 5-fold."
Targeted SH3-domain delivery rescued calcium release in cultured myotubes; this is not an animal or clinical treatment result.
C2C12 Stac3-knockout myotubes CELL_LINE
Endogenous channel-cluster imaging avoids exogenous CaV1.1 expression. Stac3 loss reduced cluster number and intensity; the N-terminal fragment partly restored intensity, while neither isolated fragment restored cluster number.
Cell source
CRISPR-edited immortalized C2C12 cells with endogenous CaV1.1
Publication
PMID:40779452
Pathograph links
Reduced CaV1.1 Junctional Expression partially recapitulates Measures the contribution of Stac3 loss to endogenous junctional CaV1.1 expression.
Limitations: Complete knockout in an immortalized muscle line differs from the recurrent hypomorphic patient allele.
Show evidence (1 reference)
PMID:40779452 SUPPORT In Vitro
"Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)"
Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
Show evidence (1 reference)
PMID:40779452 SUPPORT In Vitro
"Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)"
Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
Stac3-null mouse primary myotubes PRIMARY_CELL_CULTURE
Direct RyR activation by 4-chloro-m-cresol restored calcium release and contractility in cultured Stac3-null myotubes. This pharmacological bypass is a mechanistic experiment, not evidence for clinical agonist treatment.
Cell source
Cultured myotubes from Stac3-mutant mice
Publication
PMID:23818578
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates Direct RyR activation bypasses the upstream coupling defect.
Show evidence (1 reference)
PMID:23818578 SUPPORT In Vitro
"Muscle contractility and Ca(2+) release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol"
Direct RyR activation bypasses the upstream coupling defect.
Isolated FDB fibers after postnatal Stac3 deletion PRIMARY_CELL_CULTURE
Fura-4F imaging of isolated fibers showed reduced electrically evoked calcium transients. Resting calcium was modestly elevated; caffeine responses depended on whether fibers were resting or electrically stimulated. These isolated-fiber measurements are distinct from in-vivo grip testing.
Cell source
Flexor digitorum brevis fibers isolated from eight-week-old induced mice
Publication
PMID:27073615
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates Tests electrical excitation-to-calcium coupling in isolated fibers.
Show evidence (1 reference)
PMID:27073615 SUPPORT In Vitro
"Frequent electrostimulation increased the concentration of intracellular calcium in both Stac3fl/fl and Stac3fl/flTgCre myofibers ... but the increase was smaller in Stac3fl/flTgCre than in Stac3fl/fl myofibers at each of the frequencies tested"
Tests electrical excitation-to-calcium coupling in isolated fibers.
🐁

Animal Models

6
stac3 mi34 null zebrafish
The forward-genetic stac3 mi34 splice-donor mutant has severely reduced muscle calcium transients and locomotion. Early triads and contractile responses to caffeine were preserved, but myofibers broke down during larval development. Maternal stac3 transcript can contribute residual early function; a translation-blocking morpholino intensified immotility.
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 mutant zebrafish channel-function assays
Electron microscopy, electrophysiology and dynamic imaging showed reduced DHPR levels, functionality and stability in stac3-mutant muscle. NAM preparations also showed increased caffeine-evoked release and internal-store calcium without altered caffeine sensitivity. The retrieved abstract does not establish a genomic knock-in design.
Species
Zebrafish
Genotype
stac3 mutant and stac3 NAM preparations as reported in the 2017 study
Publication
PMID:28003463
Pathograph links
Reduced CaV1.1 Junctional Expression recapitulates fidelity: moderate Measures reduced DHPR abundance and function in stac3-mutant preparations; the abstract does not assign every measurement to the same genotype.
Limitations: The detailed construct design could not be verified from the retrieved abstract. Increased caffeine-evoked release does not by itself establish a mechanism of anesthetic-triggered malignant hyperthermia.
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.
Show evidence (1 reference)
PMID:28003463 SUPPORT Model Organism
"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"
Separates increased release magnitude from increased agonist sensitivity.
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 elevated neutral lipids alongside muscle abnormalities in larvae; muscle-specific lipid localization is not established by the available abstract.
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.
Heat-induced stac3 NAM transgene rescue in mi34 zebrafish
Mosaic heat-induced expression of the zebrafish substitution analogous to human W284S failed to restore swimming. Calcium transients remained reduced in fast-twitch but not slow-twitch fibers relative to wild-type Stac3 rescue. Wild-type human STAC3 rescued the motor phenotype.
Species
Zebrafish
Genotype
stac3 mi34 null larvae expressing hsp70-driven stac3 NAM mutant transgene
Publication
PMID:23736855
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates Tests allele-specific rescue of calcium release in the null background.
Limitations: Mosaic overexpression and residual maternal transcript differ from an endogenous homozygous human genotype; fast- and slow-fiber responses differed.
Show evidence (1 reference)
PMID:23736855 SUPPORT Model Organism
"The analogous W>S substitution was encoded in zebrafish stac3 (hsp70:stac3NAM-egfp) and expressed in stac3mi34 null mutant muscles to assay for phenotypic rescue."
This is expression of a mutant transgene in null larvae, not genomic knock-in.
Show evidence (1 reference)
PMID:23736855 SUPPORT Model Organism
"The analogous W>S substitution was encoded in zebrafish stac3 (hsp70:stac3NAM-egfp) and expressed in stac3mi34 null mutant muscles to assay for phenotypic rescue."
This is expression of a mutant transgene in null larvae, not genomic knock-in.
Constitutive Stac3-null mouse
Constitutive loss caused complete paralysis and perinatal lethality with musculoskeletal defects. Cultured myotubes retained responses to direct RyR agonism, supporting a defect upstream of calcium release rather than loss of the contractile apparatus.
Species
Mouse
Genotype
Homozygous Stac3 deletion
Publication
PMID:23818578
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates The constitutive-null model establishes the requirement for Stac3 in muscle function.
Limitations: A perinatal lethal null does not reproduce the typical surviving hypomorphic human genotype.
Show evidence (1 reference)
PMID:23818578 SUPPORT Model Organism
"homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling."
The constitutive-null model establishes the requirement for Stac3 in muscle function.
Tamoxifen-induced postnatal Stac3 deletion mouse
Male mice underwent inducible deletion of Stac3 exons 2-5 at four weeks and were assessed four weeks later. Limb muscle retained roughly 30% or less STAC3 protein despite near-absent transcript. Body and muscle growth, fiber cross-sectional area and grip strength declined; central nuclei increased without a change in total fiber number. The CAG driver is not muscle-specific.
Species
Mouse
Genotype
Stac3 fl/fl with CAG-Cre/Esr1 transgene; tamoxifen induction at four weeks
Publication
PMID:27073615
Pathograph links
Defective Skeletal Muscle Excitation-Contraction Coupling partially recapitulates Contrasts electrical and direct-RyR stimulation in muscles from the induced mice.
Limitations: Postnatal induction, residual protein and male-only experiments differ from congenital human disease; cellular calcium measurements were made in isolated fibers.
Show evidence (1 reference)
PMID:27073615 SUPPORT Model Organism
"postnatal Stac3 deletion reduced electrostimulation-induced but not the ryanodine receptor agonist caffeine-induced maximal force output in the limb muscles."
Contrasts electrical and direct-RyR stimulation in muscles from the induced mice.
{ }

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 disorder caused by biallelic pathogenic STAC3 variants. STAC3 is a skeletal-muscle adaptor that supports CaV1.1 expression and its conformational coupling to RyR1-mediated calcium release. The recurrent p.Trp284Ser allele impairs coupling while retaining some channel-complex association and function. Congenital hypotonia and weakness occur with myopathic facies, ptosis, contractures, talipes, palatal abnormalities, feeding and respiratory difficulties, and spinal deformity. Clinical severity and course vary; some patients improve, whereas others develop progressive complications. Intellect is often preserved, but developmental delay and mild intellectual disability have also been reported. Volatile anesthetics and succinylcholine can trigger malignant hyperthermia, including after previous uneventful anesthesia. Originally described in the Lumbee population, STAC3 disorder occurs worldwide and should be considered regardless of ancestry.
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.
    quote_role: REVIEW_SYNTHESIS
  - 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: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 20.0
  notes: >-
    A published comparison gives an estimated birth prevalence of 1 in 5,000 in the Lumbee population (20 per 100,000 births). This is a secondary estimate, not a new population survey in the Southern African study. GeneReviews describes the same numerical estimate as one in 5,000 Lumbee individuals, without specifying births; the measure designation here follows the cited Southern African paper and the source definitions are not interchangeable.
  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: By comparison it is estimated that the birth prevalence in Lumbee Native Americans is 1 in 5000 within a total population of 60,000.
    explanation: The source explicitly calls this an estimated birth prevalence.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: It is estimated that one in 5,000 Lumbee Native Americans has STAC3 disorder.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews supports the numerical estimate but does not identify it as a birth-prevalence measurement.'
- 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 prevalence of approximately 1 in 12,500 from a carrier estimate of 5/278 healthy individuals of similar Southern African ancestry. The published range was 1:2,300–1:65,000. This prediction is not an observed national birth-registry rate.
  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.
  - reference: PMID:38824262
    reference_title: 'STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We estimated the carrier frequency of this allele to be 1 in 56 (95% confidence interval 1:24–1:129), which predicts a birth prevalence of approximately 1 in 12,500 (range 1:2,300–1:65,000)
    explanation: The confidence range reflects uncertainty in a prediction based on the small carrier cohort.
pathophysiology:
- name: Biallelic STAC3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic STAC3 variants impair the skeletal-muscle adaptor. The recurrent hypomorphic missense allele c.851G>C (p.Trp284Ser) affects the first SH3 domain; splice-altering, frameshift and truncating alleles also occur. Loss of the SH3 interaction with the CaV1.1 II-III loop severely reduces calcium release while allowing residual channel-complex association through the N-terminal region. Complete loss in experimental models can additionally reduce junctional channel abundance.
  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: Reduced CaV1.1 Junctional Expression
    causal_link_type: DIRECT
    description: >-
      Complete Stac3 loss reduces CaV1.1 junctional abundance in experimental systems; this route is allele- and model-dependent rather than a necessary step in every patient.
    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: Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)
      explanation: Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
  - target: Impaired SH3-Dependent Enhancement of Calcium Release
    causal_link_type: DIRECT
    description: The recurrent SH3-domain substitution or truncation compromises STAC3-dependent enhancement of 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: STAC3-NT fragment, which lacks the SH3 domains, can support EC coupling at levels comparable to STAC3-W280S
      explanation: Reconstitution establishes residual coupling without the SH3 domains; loss of this contact is not an all-or-none loss of CaV1.1 function.
  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: >-
      The 2025 introduction summarizes earlier isothermal-calorimetry experiments on the W284S substitution.
    quote_role: REVIEW_SYNTHESIS
- name: Reduced CaV1.1 Junctional Expression
  biological_scale: MOLECULAR
  description: >-
    Loss of Stac3 reduces CaV1.1/DHPR junctional abundance in zebrafish and cultured muscle models. In C2C12 Stac3-knockout myotubes, CaV1.1 cluster number and intensity decreased; the STAC3 N-terminal fragment partly restored cluster intensity. This null-model phenotype is not universal in patient muscle: three patient biopsies had preserved bulk CaV1.1, STAC3 and DHPR-beta1a levels, and p.Trp284Ser can retain substantial channel function despite strongly impaired excitation-contraction coupling.
  genes:
  - preferred_term: CACNA1S
    term:
      id: hgnc:1397
      label: CACNA1S
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  downstream:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    causal_link_type: UNKNOWN
    description: >-
      Reduced junctional voltage-sensor abundance is a possible contributor to impaired coupling in null models, but the clustering measurement does not isolate this causal contribution. Preserved abundance in patient biopsies shows that channel depletion is not required for the human coupling defect.
    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: Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)
      explanation: The cluster measurement supports reduced junctional abundance; its contribution to reduced calcium release is an inference, not a separately isolated causal effect.
  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: Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)
    explanation: Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
  - reference: url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    reference_title: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Western blot analysis demonstrated no significant change in the content of any of the tested proteins in patient muscle samples
    explanation: 'Zaharieva et al. (2018; PMID:30168660), accepted manuscript: Patient biopsies PN2D, PN5 and PN6A retained bulk STAC3, CaV1.1 and DHPR-beta1a; this limits extrapolation from null models.'
- name: Impaired SH3-Dependent Enhancement of Calcium Release
  biological_scale: MOLECULAR
  description: The STAC3 SH3 region normally enhances CaV1.1-to-RyR1 conformational coupling. W284S or loss of the SH3 domains markedly reduces depolarization-induced calcium release, although the N-terminal CaV1.1 contact can sustain residual coupling. Stable recovery of STAC3 with CaV1.1 in patient co-immunoprecipitation assays does not measure every binding interface or demonstrate intact coupling.
  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: STAC3-NT fragment, which lacks the SH3 domains, can support EC coupling at levels comparable to STAC3-W280S
    explanation: Reconstitution establishes residual coupling without the SH3 domains; loss of this contact is not an all-or-none loss of CaV1.1 function.
  - reference: url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    reference_title: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No difference in the apparent interaction between CaV1.1 and the p.(Trp284Ser) STAC3 was observed as the anti-CaV1.1 antibody pulled down STAC3 in both, patient and control muscle samples
    explanation: 'Zaharieva et al. (2018; PMID:30168660), accepted manuscript: Co-immunoprecipitation of three patient biopsies establishes preserved recoverable complex association, not preserved SH3-interface function.'
  downstream:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    causal_link_type: DIRECT
    description: Loss of the coupling-enhancing contact lowers depolarization-induced calcium release despite residual voltage-sensor function.
    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: STAC3-NT fragment, which lacks the SH3 domains, can support EC coupling at levels comparable to STAC3-W280S
      explanation: Reconstitution establishes residual coupling without the SH3 domains; loss of this contact is not an all-or-none loss of CaV1.1 function.
- name: Defective Skeletal Muscle Excitation-Contraction Coupling
  biological_scale: CELLULAR
  description: >-
    Depolarization elicits insufficient sarcoplasmic-reticulum calcium release. In cultured myotubes from one compound-heterozygous patient (PN5), the peak KCl response was approximately 10% of control, despite similar resting calcium, intracellular-store size and agonist EC50 values. Zebrafish rescue and engineered myotube experiments independently support the coupling defect. Preserved early triad architecture in models does not exclude later myofibrillar pathology or nonspecific biopsy abnormalities in patients.
  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: IN_VITRO
    snippet: >-
      In particular, KCl-induced membrane depolarization resulted in significantly
      reduced sarcoplasmic reticulum Ca2+ release.
    explanation: >-
      This functional result was measured in cultured myotubes from one patient, PN5, not across all patient biopsies.
  - 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.
  - &id001
    reference: url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    reference_title: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the KCl induced Ca 2+ release which was reduced to approximately 10% of that observed in control myotubes
    explanation: 'Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The functional assay used patient PN5 myotubes; PN2D cells failed to differentiate.'
- name: Congenital Muscle Weakness
  biological_scale: ORGANISM
  description: >-
    Congenital generalized muscle weakness is a principal manifestation of STAC3 disorder. Facial, bulbar, respiratory and axial involvement contributes to the clinical phenotype, but the frequencies and course of individual complications vary.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Reduced Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced prenatal movement is compatible with fetal muscle weakness; patient cohorts document their association without directly testing this causal step.
    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: HUMAN_CLINICAL
      snippet: During pregnancy, polyhydramnios and reduced fetal movements were noted.
      explanation: Pregnancy history of the child with homozygous STAC3 p.Asp229Ter.
  - target: Generalized muscle weakness
    causal_link_type: DIRECT
    description: Clinical manifestation of the corresponding mechanism node.
    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: Clinical feature ... Number (n/N)(%) ... Reduced power (global) | 22/27 (81)
      explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  - target: Congenital Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired congenital muscle function is associated with reduced tone. Weakness and hypotonia are related clinical outputs; the cohort does not isolate every physiological step connecting them.
    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 weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients.
      explanation: The perinatal count supports congenital hypotonia and its frequency in this cohort. The source establishes the clinical manifestation; the causal contribution of muscle weakness is a qualified inference.
  - target: Weak cry
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced respiratory and bulbar muscle force can contribute to a weak neonatal cry; the clinical cohort documents the finding without testing the intervening physiology.
    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 weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients.
      explanation: The full-text cohort report supplies this finding and its denominator. The source establishes the clinical manifestation; the causal contribution of muscle weakness is a qualified inference.
  - target: Neonatal respiratory distress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Respiratory muscle involvement can contribute to neonatal distress. Palatal, pulmonary and aspiration-related factors can also contribute, so this is an inferred, nonexclusive route.
    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 high frequency of patients (18/26 (69%)) experienced respiratory distress at birth
      explanation: The full-text cohort report supplies this finding and its denominator. The source establishes the clinical manifestation; the causal contribution of muscle weakness is a qualified inference.
  - target: Myopathic Facies
    causal_link_type: DIRECT
    description: Facial muscle weakness contributes to the characteristic myopathic facial appearance.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The congenital myopathy is slowly progressive with myopathic facies. ... Strength is often decreased in facial, axial, and proximal limb muscles
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The chapter describes myopathic facies together with the distribution of muscle weakness.'
      quote_role: REVIEW_SYNTHESIS
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: Proximal weakness is part of the clinical distribution of the generalized muscle disorder.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Strength is often decreased in facial, axial, and proximal limb muscles
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The chapter explicitly identifies proximal muscle weakness.'
      quote_role: REVIEW_SYNTHESIS
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Weak suck and bulbar dysfunction contribute to feeding difficulty alongside palatal and mandibular abnormalities; the route is multifactorial.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Poor feeding may be due to a combination of structural differences ... and functional differences (e.g., weak suck, impaired coordination of feeding, abnormal tongue movements, respiratory insufficiency).
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The chapter identifies functional as well as structural contributors to feeding problems; weakness is not the sole cause.'
      quote_role: REVIEW_SYNTHESIS
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bulbar muscle dysfunction can contribute to impaired swallowing; cohort data establish dysphagia, while its individual contribution relative to structural abnormalities remains uncertain.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Poor feeding may be due to a combination of structural differences ... and functional differences (e.g., weak suck, impaired coordination of feeding, abnormal tongue movements, respiratory insufficiency).
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The chapter identifies functional as well as structural contributors to feeding problems; weakness is not the sole cause.'
      quote_role: REVIEW_SYNTHESIS
    - reference: PMID:38824262
      reference_title: 'STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical feature ... Number (n/N)(%) ... Swallowing difficulties | 13/24 (54)
      explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary. The contribution of bulbar weakness is inferred from the functional feeding abnormalities described in GeneReviews.
  - target: Delayed Motor Milestones
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced force and mobility can delay motor acquisition. Contractures and other complications also affect function; the clinical literature does not isolate their relative contributions.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Motor delays are most often present by infancy or very early childhood.
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The chapter places early motor delay within the congenital myopathy phenotype; the mechanistic contribution of weakness is inferred.'
      quote_role: REVIEW_SYNTHESIS
  - target: Restrictive Respiratory Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Respiratory muscle weakness can contribute to a restrictive ventilatory defect, with spinal or chest-wall abnormalities and aspiration-related lung disease modifying severity.
    evidence:
    - reference: PMID:38088138
      reference_title: "Pulmonary manifestations of STAC3 disorder: A case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These pre-clinical findings could explain the progressive respiratory muscle weakness and restrictive lung disease seen in our patients.
      explanation: The pulmonary case series explicitly proposes this link; it does not prove muscle weakness is the only cause of restriction.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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
  biological_scale: ORGANISM
  description: >-
    Reduced fetal movement is reported in STAC3 disorder. It was documented in the pregnancy of the child with homozygous STAC3 p.Asp229Ter and in STAC3-specific cohort data. Reduced prenatal movement is a plausible contributor to congenital contractures, but the clinical association alone does not establish the full causal sequence.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  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: HUMAN_CLINICAL
    snippet: During pregnancy, polyhydramnios and reduced fetal movements were noted.
    explanation: Pregnancy history of the child with homozygous STAC3 p.Asp229Ter.
  downstream:
  - target: Decreased fetal movement
    causal_link_type: DIRECT
    description: Clinical manifestation of the corresponding mechanism node.
    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: HUMAN_CLINICAL
      snippet: During pregnancy, polyhydramnios and reduced fetal movements were noted.
      explanation: Pregnancy history of the child with homozygous truncating STAC3 variant.
  - target: Arthrogryposis Multiplex Congenita
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
    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. The cohort establishes the congenital contracture phenotype; reduced fetal movement as a contributor is inferred, not experimentally demonstrated.
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
    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. The cohort establishes the congenital contracture phenotype; reduced fetal movement as a contributor is inferred, not experimentally demonstrated.
  - target: Camptodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced prenatal movement is a plausible contributor to congenital contracture formation. This sequence is inferred from the congenital myopathy and fetal-movement findings; the source does not establish it experimentally.
    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: Clinical feature ... Number (n/N)(%) ... Camptodactyly | 12/30 (40)
      explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary. The cohort establishes the congenital contracture phenotype; reduced fetal movement as a contributor is inferred, not experimentally demonstrated.
- name: Anesthetic-Triggered Malignant Hyperthermia Susceptibility
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Patients with biallelic pathogenic STAC3 variants are susceptible to malignant hyperthermia after volatile anesthetics or succinylcholine. Crises have occurred after previous uneventful anesthetics and show variable severity. The molecular steps linking altered STAC3-dependent coupling to the hypermetabolic crisis remain incompletely established; clinical attack frequencies do not measure latent susceptibility in unexposed patients.
  genes:
  - preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  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.
  downstream:
  - target: Malignant Hyperthermia Susceptibility
    causal_link_type: DIRECT
    description: Clinical manifestation of the corresponding mechanism node.
    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 states the increased malignant hyperthermia risk.
      quote_role: REVIEW_SYNTHESIS
- name: Skeletal Muscle Lipid Accumulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Increased skeletal-muscle lipids have been reported in patients, but their causal role in weakness is unresolved. A CRISPR stac3-null zebrafish study reported elevated neutral lipids from 5 days post-fertilization alongside cytoskeletal and myogenic abnormalities. The available abstract does not establish that its bulk lipid measurements are muscle-specific or prove lipid accumulation mediates the coupling defect.
  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: >-
      The abstract summarizes prior human observations; its new experimental evidence is from zebrafish.
    quote_role: REVIEW_SYNTHESIS
phenotypes:
- category: Musculoskeletal
  name: Congenital Hypotonia
  frequency: VERY_FREQUENT
  description: >-
    Neonatal hypotonia was documented in 27/28 (96%) of the Southern African clinical cohort with perinatal data. The larger lifetime hypotonia count was 31/31; these retrospective cohort observations do not establish population penetrance.
  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: A weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients.
    explanation: The perinatal count supports congenital hypotonia and its frequency in this cohort.
- category: Craniofacial
  name: Myopathic Facies
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    An expressionless myopathic face is common. Myopathic facies was reported in 27/28 (96%) of the Southern African cohort with data.
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  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: Neurological features that were almost universal included myopathic facies (96%), reduced muscle bulk (86%) and hypotonia (100%).
    explanation: The discussion summarizes Table 1, in which myopathic facies occurred in 27/28 assessed patients.
- category: Ophthalmologic
  name: Ptosis
  frequency: FREQUENT
  description: >-
    Ptosis was recorded in 16/30 (53%) of the Southern African cohort, with unilateral and bilateral involvement. Rates vary across cohorts.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  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: Clinical feature ... Number (n/N)(%) ... Ptosisa | 16/30 (53) | 8/10 (80) | 18/18 (100) | 4/7 (57)
    explanation: Table 1 separates the present cohort from three comparison cohorts; the first denominator determines this frequency band.
- category: Craniofacial
  name: Cleft Palate
  frequency: FREQUENT
  description: >-
    Cleft palate was documented in 11/28 (39%) of the Southern African clinical cohort. High-arched palate is a separate phenotype; the 26/28 rate for any palatal abnormality must not be assigned to cleft palate alone.
  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: Palatal abnormalities were noted at a high frequency, in 26/28 (93%); 11/28 (39%) had a cleft palate and 16/28 (57%) had a high-arched palate.
    explanation: The cohort distinguishes cleft palate from high-arched palate; one individual had both.
- 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: OCCASIONAL
  description: >-
    Kyphoscoliosis was reported in 3/27 (11%) of the Southern African cohort. Scoliosis alone, kyphosis alone and an unspecified spinal anomaly accounted for the other spine findings; the aggregate 52% is not the frequency of kyphoscoliosis. Spinal deformity can progress.
  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: Clinical feature ... Number (n/N)(%) ... Kyphoscoliosis | 3/27 (11)
    explanation: Table 1 gives the specific kyphoscoliosis denominator, separately from all spine abnormalities.
- category: Growth
  name: Short Stature
  frequency: FREQUENT
  description: Short stature was present in 10/22 (45%) at the last clinical assessment in the Southern African cohort. The age and availability of growth data varied; many had normal length at birth.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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: close to half of the patients (10/22 (45%)) were noted to be of short stature both below the 3rd centile and below −2 SD.
    explanation: Longitudinal growth observations distinguish birth length from later short stature.
- category: Gastrointestinal
  name: Feeding Difficulties
  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.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Delayed Motor Milestones
  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.
    quote_role: REVIEW_SYNTHESIS
- category: Respiratory
  name: Restrictive Respiratory Insufficiency
  description: >-
    Restrictive lung disease has been documented by pulmonary function testing. Broader respiratory difficulty is common, but its frequency cannot be assigned to a confirmed restrictive ventilatory defect. Respiratory weakness, spinal deformity and feeding-related complications can contribute to morbidity.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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
  diagnostic: true
  description: >-
    STAC3 disorder confers susceptibility to anesthetic-triggered malignant hyperthermia. Observed or suspected crises are not equivalent to the prevalence of susceptibility: 4/18 with recorded anesthetic histories in one STAC3 cohort had a suggestive event, while exposure/history was unknown for 13/31. Uneventful prior anesthesia does not exclude later risk. The mixed STAC3/RYR1 cohort must not supply a pooled susceptibility frequency.
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  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 states the increased malignant hyperthermia risk.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38824262
    reference_title: 'STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical feature ... Number (n/N)(%) ... History suggestive of MH | 4/18 (22)
    explanation: The count is observed history among individuals with available anesthesia information, not a penetrance estimate. No frequency band is assigned to latent susceptibility.
- category: Neurologic
  name: Normal Intellect
  description: >-
    Intellect is typically normal according to GeneReviews, but intellectual disability has been reported and should not be excluded by this usual pattern. Cognitive assessment must distinguish motor and speech limitations from intellectual function.
  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.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Unilateral or bilateral cryptorchidism was recorded in 7/16 (44%) of males with genital data in the genotype-confirmed Southern African cohort.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  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: Clinical feature ... Number (n/N)(%) ... Unilateral/bilateral cryptorchidism | 7/16 (44)
    explanation: Table 1 reports the male-specific denominator.
  frequency: FREQUENT
- category: Auditory
  name: Hearing impairment
  description: >-
    Bilateral hearing loss was reported in a Brazilian patient without a specified physiological subtype. Hearing loss also occurred in the Southern African cohort, including a conductive case. These observations do not justify classifying all hearing loss as sensorineural or assigning a VERY_RARE population frequency.
  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.
  - reference: PMID:38824262
    reference_title: 'STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One bilateral conductive hearing loss, one hearing loss of unspecified type.
    explanation: The Table 1 footnote distinguishes the two hearing-loss observations in the Southern African cohort.
- name: Generalized muscle weakness
  category: Musculoskeletal
  description: Reported in 22/27 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  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: Clinical feature ... Number (n/N)(%) ... Reduced power (global) | 22/27 (81)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: VERY_FREQUENT
- name: Proximal muscle weakness
  category: Musculoskeletal
  description: Reported in 3/27 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  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: Clinical feature ... Number (n/N)(%) ... Reduced power (proximal>distal) | 3/27 (11)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Decreased muscle mass
  category: Musculoskeletal
  description: Reported in 25/29 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Decreased muscle mass
    term:
      id: HP:0003199
      label: Decreased muscle mass
  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: Clinical feature ... Number (n/N)(%) ... Reduced muscle bulk | 25/29 (86)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: VERY_FREQUENT
- name: High-arched palate
  category: Craniofacial
  description: Reported in 16/28 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High 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: Clinical feature ... Number (n/N)(%) ... High-arched palate | 16/28 (57)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Camptodactyly
  category: Musculoskeletal
  description: Reported in 12/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  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: Clinical feature ... Number (n/N)(%) ... Camptodactyly | 12/30 (40)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Scoliosis
  category: Musculoskeletal
  description: Reported in 8/27 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  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: Clinical feature ... Number (n/N)(%) ... Scoliosisg | 8/27 (30)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Joint hypermobility
  category: Musculoskeletal
  description: Reported in 4/29 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  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: Clinical feature ... Number (n/N)(%) ... Joint hyperlaxityi | 4/29 (14)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Overlapping toes
  category: Musculoskeletal
  description: Reported in 4/29 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Overlapping toe
    term:
      id: HP:0001845
      label: Overlapping toe
  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: Clinical feature ... Number (n/N)(%) ... Overlapping toes | 4/29 (14)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Pectus carinatum
  category: Musculoskeletal
  description: Reported in 7/28 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  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: Clinical feature ... Number (n/N)(%) ... Pectus carinatum | 7/28 (25)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Dysphagia
  category: Gastrointestinal
  description: Reported in 13/24 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  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: Clinical feature ... Number (n/N)(%) ... Swallowing difficulties | 13/24 (54)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Hyporeflexia
  category: Neurologic
  description: Reported in 18/29 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  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: Clinical feature ... Number (n/N)(%) ... Hyporeflexia (global) | 18/29 (62)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Areflexia
  category: Neurologic
  description: Reported in 6/29 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  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: Clinical feature ... Number (n/N)(%) ... Areflexia (global) | 6/29 (21)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Ophthalmoplegia
  category: Ophthalmologic
  description: Reported in 3/24 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  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: Clinical feature ... Number (n/N)(%) ... Ophthalmoplegia | 3/24 (13)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Tongue fasciculations
  category: Neurologic
  description: Reported in 3/28 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Tongue fasciculations
    term:
      id: HP:0001308
      label: Tongue fasciculations
  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: Clinical feature ... Number (n/N)(%) ... Tongue fasciculations | 3/28 (11)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Global developmental delay
  category: Neurodevelopmental
  description: Reported in 23/27 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  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: Clinical feature ... Number (n/N)(%) ... Global developmental delay | 23/27 (85)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: VERY_FREQUENT
- name: Speech impairment
  category: Neurodevelopmental
  description: Reported in 13/17 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Poor speech
    term:
      id: HP:0002465
      label: Poor speech
  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: Clinical feature ... Number (n/N)(%) ... Speech impairmentk | 13/17 (76)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Plagiocephaly
  category: Craniofacial
  description: Reported in 5/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Plagiocephaly
    term:
      id: HP:0001357
      label: Plagiocephaly
  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: Clinical feature ... Number (n/N)(%) ... Plagiocephaly | 5/30 (17)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Low-set ears
  category: Craniofacial
  description: Reported in 8/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  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: Clinical feature ... Number (n/N)(%) ... Low-set ears Posteriorly rotated ears | 8/30 (27) 6/30 (20)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Posteriorly rotated ears
  category: Craniofacial
  description: Reported in 6/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  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: Clinical feature ... Number (n/N)(%) ... Low-set ears Posteriorly rotated ears | 8/30 (27) 6/30 (20)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Epicanthus
  category: Craniofacial
  description: Reported in 7/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  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: Clinical feature ... Number (n/N)(%) ... Epicanthic folds | 7/30 (23)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Downturned corners of mouth
  category: Craniofacial
  description: Reported in 6/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Downturned corners of mouth
    term:
      id: HP:0002714
      label: Downturned corners of mouth
  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: Clinical feature ... Number (n/N)(%) ... Downturned corners of the mouth | 6/30 (20)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Open mouth
  category: Craniofacial
  description: Reported in 6/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Open mouth
    term:
      id: HP:0000194
      label: Open mouth
  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: Clinical feature ... Number (n/N)(%) ... Mouth held open | 6/30 (20)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: OCCASIONAL
- name: Tented upper lip
  category: Craniofacial
  description: Reported in 14/30 assessed patients in the Southern African clinical cohort.
  phenotype_term:
    preferred_term: Tented upper lip vermilion
    term:
      id: HP:0010804
      label: Tented upper lip vermilion
  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: Clinical feature ... Number (n/N)(%) ... Tented upper lip | 14/30 (47)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  frequency: FREQUENT
- name: Mild intellectual disability
  category: Neurodevelopmental
  description: Mild intellectual disability was reported in 2/6 children assessed at age six years or older. This small age-restricted denominator should not be treated as a population prevalence; many other patients have preserved intellect.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  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: Clinical feature ... Number (n/N)(%) ... Intellectual disabilitym | 2/6 (33)
    explanation: The first data column of Table 1 gives the present Southern African clinical cohort; available-case denominators vary.
  - reference: PMID:38824262
    reference_title: 'STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Assessed in children age six years or more; all assessed as mild intellectual disability.
    explanation: The Table 1 footnote specifies age and severity.
- name: Neonatal respiratory distress
  category: Respiratory
  description: Respiratory distress at birth occurred in 18/26 (69%) patients with data; recorded severity varied.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  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 high frequency of patients (18/26 (69%)) experienced respiratory distress at birth
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: FREQUENT
- name: Weak cry
  category: Neurologic
  description: A weak cry at birth was recorded in 16/17 (94%) patients with data.
  phenotype_term:
    preferred_term: Weak cry
    term:
      id: HP:0001612
      label: Weak cry
  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 weak cry at birth (16/17 (94%)) and neonatal hypotonia (27/28 (96%)) were almost universally present in the patients.
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: VERY_FREQUENT
- name: Small for gestational age
  category: Growth
  description: Birth size was small for gestational age in 11/25 (44%) patients.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  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: Almost half of the patients were born small for gestational age (SGA) (11/25 (44%)).
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: FREQUENT
- name: Failure to thrive
  category: Growth
  description: Failure to thrive was reported in 17/26 (65%) patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  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: Failure to thrive (FTT) was noted in 17/26 (65%) patients.
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: FREQUENT
- name: Decreased body weight
  category: Growth
  description: Weight at last assessment was below -2 SD for age in 16/23 (70%) patients, including 10 below -3 SD.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  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 majority (16/23 (70%)) of patients were underweight-for-age (weight below −2 SD), and 10/23 (43%) were severely underweight for age (weight below −3 SD).
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: FREQUENT
- name: Microcephaly
  category: Craniofacial
  description: Head circumference at last visit was below the third centile and -2 SD in 5/24 (21%) patients. Onset was postnatal in two and unknown in three.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  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 remaining 5/24 (21%), had head circumference measurements less than the 3rd centile and below −2 SD, which was of postnatal onset in two patients, and of unknown onset in three patients.
    explanation: The full-text cohort report supplies this finding and its denominator.
  frequency: OCCASIONAL
- name: Conductive hearing loss
  category: Auditory
  description: Conductive hearing loss is reported across cohorts and may require hearing aids. It is distinct from the unspecified hearing loss in some reports.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:28777491
    reference_title: Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Past medical history was notable for conductive hearing loss diagnosed at age 7 years; he wears hearing aids.
    explanation: The Puerto Rican proband had documented conductive hearing loss.
- name: Obstructive sleep apnea
  category: Respiratory
  description: Polysomnography documented obstructive sleep apnea in a Brazilian patient; no population frequency is assigned.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  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: polysomnography revealed an obstructive sleep apnea syndrome.
    explanation: The report gives a measured sleep-related respiratory phenotype.
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia is part of the variable craniofacial phenotype. It may contribute to feeding and airway problems together with palatal anomalies.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Myopathic facies, micrognathia, and palatal anomalies can be seen in a number of neuromuscular disorders of varying etiologies
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews lists micrognathia among the suggestive clinical findings.'
    quote_role: REVIEW_SYNTHESIS
- name: Decreased palmar creases
  category: Dermatologic
  description: Reduced palmar and other flexion creases have been described in affected individuals; the combined finger/palmar frequency in cohort tables is not a palmar-only prevalence.
  phenotype_term:
    preferred_term: Decreased palmar creases
    term:
      id: HP:0006184
      label: Decreased palmar creases
  evidence:
  - reference: PMID:28777491
    reference_title: Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were decreased skin creases over distal interphalangeal joints (DIPs), wrists, palms, and plantar surface of feet
    explanation: The Qatari proband had explicitly documented palmar involvement.
- name: Decreased fetal movement
  category: Prenatal
  description: Reduced fetal movement may precede congenital hypotonia and contractures.
  phenotype_term:
    preferred_term: Decreased fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
  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: HUMAN_CLINICAL
    snippet: During pregnancy, polyhydramnios and reduced fetal movements were noted.
    explanation: Pregnancy history of the child with homozygous truncating STAC3 variant.
- name: Scaphocephaly
  category: Craniofacial
  frequency: OCCASIONAL
  description: Table 3 reports scaphocephaly in 4/30 (13%) of the STAC3 subgroup of the African KDS-like cohort, distinct from the RYR1 group.
  phenotype_term:
    preferred_term: Scaphocephaly
    term:
      id: HP:0030799
      label: Scaphocephaly
  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: Total (n = 44) | RYR1 (n = 14) | RYR1 (n = 17) | RYR1 (n = 3) | RYR1 (n = 3) | STAC3 (n = 30) ... Scaphocephaly | 6 (14%) | 2 (14%) | - | - | - | 4 (13%)
    explanation: The table header identifies the STAC3-specific column, preventing use of the mixed-cohort frequency.
- name: Telecanthus
  category: Craniofacial
  description: A variable craniofacial finding described in the GeneReviews clinical assessment; no universal frequency is assigned.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: short and/or downslanting palpebral fissures, and telecanthus
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.'
- name: Short palpebral fissures
  category: Craniofacial
  description: A variable craniofacial finding described in the GeneReviews clinical assessment; no universal frequency is assigned.
  phenotype_term:
    preferred_term: Short palpebral fissure
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: short and/or downslanting palpebral fissures, and telecanthus
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.'
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: A variable craniofacial finding described in the GeneReviews clinical assessment; no universal frequency is assigned.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: short and/or downslanting palpebral fissures, and telecanthus
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.'
- name: Long face
  category: Craniofacial
  description: A variable craniofacial finding described in the GeneReviews clinical assessment; no universal frequency is assigned.
  phenotype_term:
    preferred_term: Long face
    term:
      id: HP:0000276
      label: Long face
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Over time, the face often becomes long and narrow.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes this feature among the suggestive clinical findings.'
- name: Genu recurvatum
  category: Musculoskeletal
  description: Genu recurvatum was recorded in 2/29 (7%) of the Southern African cohort. The same comparative table reports 7/15 (47%) in the earlier international cohort; these different cohorts should not be pooled.
  phenotype_term:
    preferred_term: Genu recurvatum
    term:
      id: HP:0002816
      label: Genu recurvatum
  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: Genu recurvatumh | 2/29 (7) | | 7/15 (47)
    explanation: Table 1 separates the current cohort from the earlier Zaharieva cohort.
- name: Retrognathia
  category: Craniofacial
  description: Retrognathia and microretrognathia are reported; the combined small-and-receding-jaw category is distinct from isolated micrognathia.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  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: Retrognathia | 2/30 (7) ... Microretrognathia | 6/30 (20)
    explanation: Table 1 records isolated retrognathia and microretrognathia separately.
- name: Respiratory distress beyond the neonatal period
  category: Respiratory
  description: Respiratory distress beyond or after the neonatal period was recorded in 7/16 (44%) with available data in the Southern African cohort. This clinical finding is broader than a spirometry-confirmed restrictive defect.
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  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: Respiratory difficulties that extended beyond, or occurred after the neonatal period, were noted in almost half of the patients (7/16 (44%)).
    explanation: The cohort describes persistent or later respiratory distress without assigning a uniform physiological subtype.
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.
  variants:
  - name: NM_145064.3:c.851G>C (p.Trp284Ser)
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: 'Recurrent first-SH3-domain missense allele. Its functional effect is hypomorphic: calcium-release coupling is more impaired than residual channel-complex association.'
    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: Whole exome sequencing revealed a homozygous pathogenic variant c.851G>C (p.Trp284Ser) in the STAC3 gene (NM_145064.3)
      explanation: The clinical report identifies transcript, zygosity and pathogenic classification.
    clinical_significance: PATHOGENIC
  - name: NM_145064.2:c.763_766delCTCT (p.Leu255IlefsTer58)
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: Frameshift allele reported in trans with p.Trp284Ser in two Puerto Rican siblings; parental Sanger sequencing confirmed opposite parental origins.
    evidence:
    - reference: PMID:28777491
      reference_title: Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The mother was heterozygous for the STAC3 c.851G>C; p.Trp284Ser variant, and the father was heterozygous for the STAC3 c.763_766delCTCT;p.Leu255IlefsX58 variant
      explanation: Parental segregation establishes the compound-heterozygous genotype.
    - reference: PMID:28777491
      reference_title: Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here we present two non-Native American families, who were found to have STAC3 pathogenic variants.
      explanation: The authors classify the reported familial variants as pathogenic.
    clinical_significance: PATHOGENIC
  - name: NM_145064.2:c.997-1G>T
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: Acceptor-splice allele in trans with c.851G>C. cDNA confirmed activation of an exon-12 cryptic acceptor and a 12-nucleotide in-frame deletion, removing four residues from the second SH3 domain.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: For the c.997-1G>T variant, cDNA studies confirmed activation of a cryptic acceptor site within exon 12 leading to deletion of 12 nucleotides from mature STAC3 RNA
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews summarizes the experimentally demonstrated transcript consequence.'
      quote_role: REVIEW_SYNTHESIS
  - name: NM_145064.2:c.862A>T (p.Lys288Ter)
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: Nonsense allele reported with c.432+4A>T in a Turkish patient; the pair extends the allelic spectrum beyond the recurrent missense variant.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: identified compound heterozygous pathogenic STAC3 variants in one individual of Turkish ancestry that included a nonsense change (c.862A>T) and a splice donor site variant c.432+4A>T.
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews identifies both variants and their reported pathogenic classification.'
      quote_role: REVIEW_SYNTHESIS
    clinical_significance: PATHOGENIC
  - name: NM_145064.2:c.432+4A>T
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: Splice-region allele reported with p.Lys288Ter. Lymphocyte cDNA showed exon-4 skipping and activation of a new intron-4 splice site; this is experimentally assessed splicing, not solely a prediction.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: cDNA studies confirmed two aberrant transcription products for the c.432+4A>T splicing variant in lymphocytes, including skipping of exon 4 and activation of a new splice site in intron 4
      explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews reports the observed transcript abnormalities.'
      quote_role: REVIEW_SYNTHESIS
  - name: NM_145064.3:c.685_686del (reported p.Asp229Ter)
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    description: Homozygous two-nucleotide deletion reported to terminate STAC3 after residue 228, removing the SH3 domains. Both asymptomatic parents were heterozygous. Engineered expression of residues 1-228 retained limited coupling; this does not establish endogenous truncated-protein abundance in the patient.
    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: HUMAN_CLINICAL
      snippet: Sanger sequencing confirmed the homozygous Stac3 variant segregating from her asymptomatic heterozygous parents
      explanation: The single-patient report establishes recessive segregation.
    - 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: CaV1.1/Stac3-KO myotubes reconstituted with STAC3-1-228 exhibited calcium transients of only 20% the magnitude of those in myotubes reconstituted with WT STAC3
      explanation: The engineered construct establishes residual coupling in vitro.
  - name: NM_145064.3:c.834_836del (p.Asp279del)
    gene:
      preferred_term: STAC3
      term:
        id: hgnc:28423
        label: STAC3
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    description: In-frame deletion reported in trans with c.851G>C in the African KDS-like cohort. Table 1 classifies it as VUS using PM2 and PM4; the authors propose functional relevance but do not demonstrate it. Narrative and table disagree on the number of carriers, so no resolved count is assigned.
    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: STAC3(NM_145064.3):c.834_836del; p.Asp279deld | VUS | PM2 PM4 | Absent
      explanation: Table 1 explicitly classifies this deletion as a variant of uncertain significance.
- 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: >-
    The recurrent NM_145064.3:c.851G>C (p.Trp284Ser) allele occurs in multiple ancestry groups. Southern African shared-haplotype and allele-frequency findings support a founder hypothesis, but its geographic origin has not been conclusively established. Clinical recognition and testing should not be restricted to Lumbee ancestry.
  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: >-
      The Comorian authors propose a founder effect; this passage does not establish an independent mutational origin.
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.
    quote_role: REVIEW_SYNTHESIS
treatments:
- name: Avoidance of Malignant Hyperthermia Triggering Anaesthetics
  description: >-
    Avoid volatile anesthetics and depolarizing muscle relaxants that trigger malignant hyperthermia. Anesthetic planning includes preparation of the anesthesia machine, availability of dantrolene and appropriate postoperative care. Previous uneventful anesthesia does not exclude risk.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
  - 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: Anesthesia without triggering agents (halogenated agents and succinylcholine) should be performed, in addition to cleaning the anesthetic machine for halogenated agents. Dantrolene and an intensive care unit must be available.
    explanation: The STAC3 case-series discussion specifies preparation and rescue capability.
    quote_role: REVIEW_SYNTHESIS
- name: Physical Therapy
  description: >-
    Physical therapy addresses range of motion and mobility. Contracture management may include stretching, night splints or serial casts, with avoidance of prolonged immobilization.
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PT to improve range of motion; ... Stretching, night splints, or serial casts.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 gives specific contracture interventions.'
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Often initial bracing is followed by progressive scoliosis requiring surgery.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 supports bracing and surgical management of progressive scoliosis.'
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: REVIEW_SYNTHESIS
- name: Ptosis Repair
  description: >-
    Surgical options include levator resection or frontalis sling procedures, selected by the ophthalmology or craniofacial team to address visual obstruction. Every procedure requires STAC3-specific anesthetic precautions.
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Surgical repair, such as levator resection or frontalis sling surgeries
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 identifies the surgical options.'
    quote_role: REVIEW_SYNTHESIS
- 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: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 states the indications for enteral feeding.'
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: REVIEW_SYNTHESIS
- name: Occupational Therapy
  description: Occupational therapy and adaptive equipment support mobility and activities of daily living.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational 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. Use of adaptive devices for mobility and activities of daily living.
    explanation: GeneReviews describes the supportive functional-care goals.
    quote_role: REVIEW_SYNTHESIS
- name: Speech and Swallowing Therapy
  description: Speech-language assessment addresses dysarthria, palatal dysfunction, communication and swallowing. Interventions are individualized and may include speech therapy, feeding therapy or augmentative communication.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Interventions depend on etiology of speech issues & may include speech therapy, surgery, &/or use of assistive communication devices.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 describes individualized communication interventions.'
    quote_role: REVIEW_SYNTHESIS
  - 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: The patient was treated with physical therapy, speech therapy for dysphagia, and pulmonary rehabilitation.
    explanation: The Brazilian case report documents swallowing-focused speech therapy without estimating efficacy.
- name: Ventilatory Support
  description: Noninvasive or invasive ventilation is used according to respiratory impairment. Reported STAC3 cases range from nocturnal positive airway pressure to tracheostomy with continuous ventilation; support is individualized.
  treatment_term:
    preferred_term: Mechanical Ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 5 lists respiratory-support options.'
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38088138
    reference_title: "Pulmonary manifestations of STAC3 disorder: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 6 mo required tracheostomy with ventilatory support continuously
    explanation: The pulmonary case-series table documents continuous ventilatory support in one severely affected infant.
- name: Assisted Airway Clearance
  description: Cough-assist devices may be needed when respiratory muscle weakness compromises airway clearance. The pulmonary case series documents prescription following declining cough peak flow and secretion-clearance difficulty.
  treatment_term:
    preferred_term: Respiratory Therapy
    term:
      id: NCIT:C15322
      label: Respiratory Therapy
  evidence:
  - reference: PMID:38088138
    reference_title: "Pulmonary manifestations of STAC3 disorder: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: assisted cough using positive and negative pressurewas prescribed due to a persistent decline in CPF and reported difficulty with airway clearance.
    explanation: Table 1 documents the indication for cough assistance in case 3.
- name: Dantrolene for Acute Malignant Hyperthermia
  description: Acute malignant-hyperthermia management includes stopping the triggering anesthetic and administering dantrolene when indicated. In the Brazilian three-case series all survived; two received dantrolene and one improved after withdrawal of the inhaled trigger. This is crisis treatment, not disease-modifying therapy for the congenital myopathy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dantrolene
      term:
        id: CHEBI:4317
        label: dantrolene
  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: All patients had good clinical outcomes and survived the MH crisis. One of them improved with the halogenated drug suspension, while the other two also received the specific MH antidote dantrolene.
    explanation: Reports treatment and outcomes in the three STAC3-related crises.
histopathology:
- name: Non-Specific Myopathic Muscle Biopsy
  frequency: FREQUENT
  description: >-
    Biopsy abnormalities are variable and nonspecific. The Southern African study reported abnormal histology in 11/16 biopsied patients, normal findings in three and unavailable results in two. Type 1 fiber predominance, nonspecific myopathy and atrophic fibers occurred. The international cohort also documented occasional internal nuclei, myofibrillar loss and minicore areas on electron microscopy, despite broadly preserved triads. These findings do not provide a pathognomonic biopsy diagnosis.
  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.
  - reference: url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    reference_title: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electron microscopy analysis showed myofibrillar loss, irregular and broken Z -lines with mini-core areas with disrupted sarcomeres
    explanation: 'Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The full text contradicts an absolute absence of cores.'
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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Identification of biallelic STAC3 variants of uncertain significance (or of one known STAC3 pathogenic variant and one STAC3 variant of uncertain significance) does not establish or rule out the diagnosis.
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): A VUS must not be silently promoted to a diagnostic allele.'
    quote_role: REVIEW_SYNTHESIS
- name: Genetics-Before-Biopsy Testing Strategy
  description: >-
    In suspected STAC3 disorder, molecular testing can precede an anesthetized biopsy, whose findings are often nonspecific. Targeted c.851G>C testing identified 25/127 (20%) homozygotes in a selected Southern African laboratory series of hypotonia referrals already negative for SMN1 exon-7 deletion testing (114) or Prader-Willi testing (13). This is not an unselected population screening yield.
  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: >-
    EMG may be normal or show nonspecific myopathic findings. It supports evaluation of muscle disease but does not establish or exclude STAC3 disorder.
  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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electromyogram revealed normal results in some individuals and evidence of myopathy in others
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews describes the variability in electrophysiology.'
    quote_role: REVIEW_SYNTHESIS
- name: Serum Creatine Kinase
  description: >-
    CK is often normal and a normal result does not exclude STAC3 disorder. In the Southern African cohort, 16/21 had normal levels and four had raised values; the manuscript does not account explicitly for the remaining measurement. Three elevations were two to three times the upper limit and one was four to five times; three were measured neonatally, when elevations can be nonspecific.
  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.
  - 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 four raised CK levels, three were increased two to three times the upper limit of normal for age, and one was increased four to five times the upper limit of normal for age.
    explanation: The full text does not support restricting all elevations to a mild category.
- name: Respiratory and Sleep Assessment
  description: Pulmonary assessment includes respiratory function, cough strength, secretion handling and sleep symptoms, with spirometry and polysomnography as appropriate. Normal early spirometry does not exclude later restrictive disease. A five-patient pulmonary series recommends six-monthly function testing; GeneReviews recommends at least annual pulmonary assessment, more often in infancy or with respiratory symptoms.
  evidence:
  - reference: PMID:38088138
    reference_title: "Pulmonary manifestations of STAC3 disorder: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: respiratory function testing should be measured on a regular basis, i.e every six months despite initial normal findings.
    explanation: The pulmonary series proposes regular assessment despite initially normal function.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 4 specifies sleep evaluation.'
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical eval at least annually but likely more often during infancy or when any signs of respiratory insufficiency, aspiration, &/or sleep apnea develop
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 6 provides the qualified surveillance interval.'
    quote_role: REVIEW_SYNTHESIS
- name: Multidisciplinary Neuromuscular Surveillance
  description: GeneReviews recommends review of respiratory status, speech, swallowing and musculoskeletal complications every three to four months in infancy and every six to twelve months in older children and adults, with growth and feeding safety assessed at visits.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Infants age <12 mos: every 3-4 mos ... Older children & adults: every 6-12 mos'
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): GeneReviews Table 6 gives the neuromuscular follow-up intervals.'
    quote_role: REVIEW_SYNTHESIS
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.
  disease_term:
    preferred_term: King-Denborough syndrome
    term:
      id: MONDO:0020485
      label: King-Denborough syndrome
- 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 with facial weakness, palatal abnormalities and skeletal findings overlaps clinically with STAC3 disorder. Molecular testing distinguishes MYMK-related Carey-Fineman-Ziter syndrome 1 and other genetically defined forms from STAC3 disease.
  disease_term:
    preferred_term: Carey-Fineman-Ziter syndrome
    term:
      id: MONDO:0031415
      label: Carey-Fineman-Ziter syndrome
  distinguishing_features:
  - A different causal gene — MYMK in Carey-Fineman-Ziter syndrome 1
- name: Moebius syndrome
  description: >-
    Congenital facial weakness and impaired ocular abduction can resemble STAC3 disorder. A Brazilian child initially suspected to have Moebius syndrome was diagnosed with biallelic STAC3 variants. Reported overlap and rare anesthesia complications make an absolute absence of malignant hyperthermia an unreliable discriminator.
  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
  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: patient 2 was initially suspected to have MBS, which was rectified only after the genetic analysis was carried out, confirming the biallelic pathogenic variant p.Trp284Ser in STAC3
    explanation: Documents clinical misclassification resolved by molecular testing.
- name: X-linked myotubular myopathy
  description: >-
    MTM1-related congenital myopathy can also present with severe neonatal hypotonia and respiratory insufficiency. Its X-linked inheritance and molecular cause distinguish it from autosomal recessive STAC3 disorder.
  distinguishing_features:
  - X-linked rather than autosomal recessive inheritance
  - MTM1 genotype
  disease_term:
    preferred_term: X-linked myotubular myopathy
    term:
      id: MONDO:0010683
      label: X-linked myotubular myopathy
animal_models:
- name: stac3 mi34 null zebrafish
  species: Zebrafish
  genotype: stac3 mi34 splice-donor mutation (functionally null)
  publication: PMID:23736855
  description: >-
    The forward-genetic stac3 mi34 splice-donor mutant has severely reduced muscle calcium transients and locomotion. Early triads and contractile responses to caffeine were preserved, but myofibers broke down during larval development. Maternal stac3 transcript can contribute residual early function; a translation-blocking morpholino intensified immotility.
  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 mutant zebrafish channel-function assays
  species: Zebrafish
  genotype: stac3 mutant and stac3 NAM preparations as reported in the 2017 study
  publication: PMID:28003463
  description: >-
    Electron microscopy, electrophysiology and dynamic imaging showed reduced DHPR levels, functionality and stability in stac3-mutant muscle. NAM preparations also showed increased caffeine-evoked release and internal-store calcium without altered caffeine sensitivity. The retrieved abstract does not establish a genomic knock-in design.
  modeled_mechanisms:
  - target: Reduced CaV1.1 Junctional Expression
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Measures reduced DHPR abundance and function in stac3-mutant preparations; the abstract does not assign every measurement to the same genotype.
    limitations: >-
      The detailed construct design could not be verified from the retrieved abstract. Increased caffeine-evoked release does not by itself establish a mechanism of anesthetic-triggered malignant hyperthermia.
    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.
  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: 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
    explanation: Separates increased release magnitude from increased agonist sensitivity.
- 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 elevated neutral lipids alongside muscle abnormalities in larvae; muscle-specific lipid localization is not established by the available abstract.
    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.
- name: Heat-induced stac3 NAM transgene rescue in mi34 zebrafish
  species: Zebrafish
  genotype: stac3 mi34 null larvae expressing hsp70-driven stac3 NAM mutant transgene
  publication: PMID:23736855
  description: Mosaic heat-induced expression of the zebrafish substitution analogous to human W284S failed to restore swimming. Calcium transients remained reduced in fast-twitch but not slow-twitch fibers relative to wild-type Stac3 rescue. Wild-type human STAC3 rescued the motor phenotype.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: Tests allele-specific rescue of calcium release in the null background.
    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: The analogous W>S substitution was encoded in zebrafish stac3 (hsp70:stac3NAM-egfp) and expressed in stac3mi34 null mutant muscles to assay for phenotypic rescue.
      explanation: This is expression of a mutant transgene in null larvae, not genomic knock-in.
    limitations: Mosaic overexpression and residual maternal transcript differ from an endogenous homozygous human genotype; fast- and slow-fiber responses differed.
  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: The analogous W>S substitution was encoded in zebrafish stac3 (hsp70:stac3NAM-egfp) and expressed in stac3mi34 null mutant muscles to assay for phenotypic rescue.
    explanation: This is expression of a mutant transgene in null larvae, not genomic knock-in.
- name: Constitutive Stac3-null mouse
  species: Mouse
  genotype: Homozygous Stac3 deletion
  publication: PMID:23818578
  description: Constitutive loss caused complete paralysis and perinatal lethality with musculoskeletal defects. Cultured myotubes retained responses to direct RyR agonism, supporting a defect upstream of calcium release rather than loss of the contractile apparatus.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: The constitutive-null model establishes the requirement for Stac3 in muscle function.
    evidence:
    - reference: PMID:23818578
      reference_title: Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling.
      explanation: The constitutive-null model establishes the requirement for Stac3 in muscle function.
    limitations: A perinatal lethal null does not reproduce the typical surviving hypomorphic human genotype.
- name: Tamoxifen-induced postnatal Stac3 deletion mouse
  species: Mouse
  genotype: Stac3 fl/fl with CAG-Cre/Esr1 transgene; tamoxifen induction at four weeks
  publication: PMID:27073615
  description: Male mice underwent inducible deletion of Stac3 exons 2-5 at four weeks and were assessed four weeks later. Limb muscle retained roughly 30% or less STAC3 protein despite near-absent transcript. Body and muscle growth, fiber cross-sectional area and grip strength declined; central nuclei increased without a change in total fiber number. The CAG driver is not muscle-specific.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: Contrasts electrical and direct-RyR stimulation in muscles from the induced mice.
    evidence:
    - reference: PMID:27073615
      reference_title: "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."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: postnatal Stac3 deletion reduced electrostimulation-induced but not the ryanodine receptor agonist caffeine-induced maximal force output in the limb muscles.
      explanation: Contrasts electrical and direct-RyR stimulation in muscles from the induced mice.
    limitations: Postnatal induction, residual protein and male-only experiments differ from congenital human disease; cellular calcium measurements were made in isolated fibers.
discussions:
- discussion_id: stac3_cav11_interaction_paradox
  kind: OPEN_QUESTION
  prompt: >-
    How do variant-specific changes in STAC3 contacts alter voltage sensing and calcium-release efficiency in patient-derived muscle cells?
  attaches_to:
  - pathophysiology#Impaired SH3-Dependent Enhancement of Calcium Release
  rationale: >-
    Patient-biopsy co-immunoprecipitation recovers a stable STAC3-CaV1.1 complex, whereas isolated SH3-interface and engineered myotube assays show impaired coupling enhancement. These assays measure different aspects of the complex. The two-contact model provides a compatible explanation, but matched voltage-sensing and release measurements in patient cells are still needed to quantify each contribution.
  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: >-
      Biopsy co-immunoprecipitation shows retained recoverable association; it does not test all individual interfaces.
  - 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 2018 interpretation must be read with its assay limits and the later two-contact model.
- 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: >-
    Clinical STAC3-related crises establish an anesthetic-triggered susceptibility. Zebrafish mutant models show increased caffeine-evoked release and store calcium, whereas the single patient myotube culture had preserved store size and no increased agonist sensitivity. Neither finding alone establishes the mechanism of anesthetic-triggered malignant hyperthermia 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: >-
      Supporting model-organism observation that has not yet been tied to anesthetic triggering in patients.
notes: >-
  Bailey-Bloch congenital myopathy, Native American myopathy, STAC3 disorder and congenital myopathy 13 refer to the same disorder. Frequency estimates are cohort-specific and often use available-case denominators; reported cohorts may overlap and should not be summed without deduplication. Clinical course varies, and progressive respiratory or orthopedic complications can occur. Observed malignant-hyperthermia attacks do not estimate susceptibility in patients never exposed to triggering agents. The historical ancestry-based name should not restrict molecular testing. Nonsyndromic malignant hyperthermia susceptibility is covered 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.
experimental_models:
- name: PN5 patient-derived STAC3 myotubes
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Muscle-biopsy-derived primary myoblasts from compound-heterozygous patient PN5
  publication: PMID:30168660
  description: Myotubes carrying p.Trp284Ser and c.997-1G>T showed reduced KCl- and 4-CMC-evoked peak calcium release. Resting cytosolic calcium, store size and agonist EC50 values did not differ significantly from controls. The second available patient culture, PN2D, failed to differentiate, so the functional evidence comes from one patient.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: Directly measures the patient-cell coupling defect.
    evidence:
    - reference: url:https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
      reference_title: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the KCl induced Ca 2+ release which was reduced to approximately 10% of that observed in control myotubes
      explanation: 'Zaharieva et al. (2018; PMID:30168660), accepted manuscript: The functional assay used patient PN5 myotubes; PN2D cells failed to differentiate.'
    limitations: One compound-heterozygous patient; culture assays do not establish malignant-hyperthermia susceptibility mechanisms in vivo.
  evidence:
  - *id001
- name: F8 CaV1.1/Stac3 double-knockout myotube reconstitution
  experimental_model_type: CELL_LINE
  cell_source: Immortalized F8 double-knockout myotubes
  publication: PMID:40779452
  description: Reconstitution with CaV1.1 and STAC3 fragments separates voltage-sensor function from calcium-release enhancement. N-terminal STAC3 supported residual coupling without SH3 domains. Targeting intact SH3 domains through a beta1a fusion rescued calcium release in W280S-expressing cells; untethered SH3 domains did not provide equivalent rescue.
  modeled_mechanisms:
  - target: Impaired SH3-Dependent Enhancement of Calcium Release
    relationship: PARTIALLY_RECAPITULATES
    description: Dissects N-terminal and SH3-dependent contributions.
    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: we reconstituted different STAC3 fragments and mutants in double CaV1.1/Stac3-KO myotubes to examine the contribution of each of the 2 STAC3/CaV1.1 interactions
      explanation: Defines the engineered immortalized myotube system and its domain-reconstitution design.
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: RESCUES
    description: Channel-tethered SH3 domains rescue the mutant coupling defect.
    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: STAC3-CT-β1a expression remarkably increased the EC coupling calcium release observed in myotubes reconstituted with STAC3-W280S by 5-fold.
      explanation: Targeted SH3-domain delivery rescued calcium release in cultured myotubes; this is not an animal or clinical treatment result.
    limitations: Engineered overexpression in immortalized myotubes; delivery, safety and clinical efficacy remain untested.
  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: we reconstituted different STAC3 fragments and mutants in double CaV1.1/Stac3-KO myotubes to examine the contribution of each of the 2 STAC3/CaV1.1 interactions
    explanation: Defines the engineered immortalized myotube system and its domain-reconstitution design.
  - 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: STAC3-CT-β1a expression remarkably increased the EC coupling calcium release observed in myotubes reconstituted with STAC3-W280S by 5-fold.
    explanation: Targeted SH3-domain delivery rescued calcium release in cultured myotubes; this is not an animal or clinical treatment result.
- name: C2C12 Stac3-knockout myotubes
  experimental_model_type: CELL_LINE
  cell_source: CRISPR-edited immortalized C2C12 cells with endogenous CaV1.1
  publication: PMID:40779452
  description: Endogenous channel-cluster imaging avoids exogenous CaV1.1 expression. Stac3 loss reduced cluster number and intensity; the N-terminal fragment partly restored intensity, while neither isolated fragment restored cluster number.
  modeled_mechanisms:
  - target: Reduced CaV1.1 Junctional Expression
    relationship: PARTIALLY_RECAPITULATES
    description: Measures the contribution of Stac3 loss to endogenous junctional CaV1.1 expression.
    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: Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)
      explanation: Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
    limitations: Complete knockout in an immortalized muscle line differs from the recurrent hypomorphic patient allele.
  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: Lack of STAC3 caused a significant decrease in both the number of CaV1.1 clusters (–12%) and their fluorescence intensity (–30%)
    explanation: Quantifies the membrane-cluster phenotype in C2C12 Stac3-knockout myotubes.
- name: Stac3-null mouse primary myotubes
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Cultured myotubes from Stac3-mutant mice
  publication: PMID:23818578
  description: Direct RyR activation by 4-chloro-m-cresol restored calcium release and contractility in cultured Stac3-null myotubes. This pharmacological bypass is a mechanistic experiment, not evidence for clinical agonist treatment.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: Direct RyR activation bypasses the upstream coupling defect.
    evidence:
    - reference: PMID:23818578
      reference_title: Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Muscle contractility and Ca(2+) release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol
      explanation: Direct RyR activation bypasses the upstream coupling defect.
- name: Isolated FDB fibers after postnatal Stac3 deletion
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Flexor digitorum brevis fibers isolated from eight-week-old induced mice
  publication: PMID:27073615
  description: Fura-4F imaging of isolated fibers showed reduced electrically evoked calcium transients. Resting calcium was modestly elevated; caffeine responses depended on whether fibers were resting or electrically stimulated. These isolated-fiber measurements are distinct from in-vivo grip testing.
  modeled_mechanisms:
  - target: Defective Skeletal Muscle Excitation-Contraction Coupling
    relationship: PARTIALLY_RECAPITULATES
    description: Tests electrical excitation-to-calcium coupling in isolated fibers.
    evidence:
    - reference: PMID:27073615
      reference_title: "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."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Frequent electrostimulation increased the concentration of intracellular calcium in both Stac3fl/fl and Stac3fl/flTgCre myofibers ... but the increase was smaller in Stac3fl/flTgCre than in Stac3fl/fl myofibers at each of the frequencies tested
      explanation: Tests electrical excitation-to-calcium coupling in isolated fibers.
progression:
- phase: Variable childhood course
  notes: In the Southern African clinical cohort, 6/27 were static at last assessment, 6/27 worsened and 15/27 improved; course was unknown for four additional patients. These retrospective trajectories do not establish uniformly nonprogressive disease. Respiratory and orthopedic complications can progress even when motor function improves.
  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: Static at time of last clinical visit | 6/27 (22) ... Progressive worsening | 6/27 (22) ... Condition improving | 15/27 (56)
    explanation: Table 1 reports heterogeneous clinical courses using available-case denominators.
- phase: Historical childhood mortality
  notes: GeneReviews reports historical mortality of 36% by age 18, based on earlier reports, and three first-year deaths in a 14-person series. This is not a contemporary survival estimate across all ancestries or a malignant-hyperthermia-specific fatality rate. Reported causes included severe pulmonary hypoplasia and pneumonia-associated apnea.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Thirty-six percent of individuals affected with STAC3 disorder died by age 18 years ... In a study of 14 affected individuals, three died during the first year of life, one from severe pulmonary hypoplasia and one from apnea secondary to enterococcal pneumonia
    explanation: 'GeneReviews, STAC3 Disorder (NBK542808): The GeneReviews life-expectancy section summarizes historical cohorts; ascertainment and treatment era limit generalization.'
📚

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

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review STAC3 clinical spectrum, mechanisms, models and care using cached full texts · 2026-09-27T18:26:50Z · View source

Eligibility and scope: biallelic STAC3 congenital myopathy (MONDO:0009722; OMIM:255995), also called Native American myopathy/CMYP13. Both previous histories were CREATE/EDIT, with no REVIEW. This is a Mendelian disorder; anesthesia-triggered malignant hyperthermia is a complication, not an environmental disease. The branch was rebased onto origin/main before editing (116b24e6501970a6051d279bacdbf4d518380d5b). Named-entity and GeneReviews preflight passed. Research and its citation sidecar were read and compared against the entry; the research's erroneous PMID:30178658 was not propagated (the international STAC3 cohort is PMID:30168660). Content-completeness review: 1. Phenotypes — adequate after expansion from 15 to 58. Added weakness, muscle bulk, reflex, developmental, growth, respiratory, hearing, craniofacial and musculoskeletal findings using cohort tables and GeneReviews. Separated cleft from any palatal abnormality, kyphoscoliosis from any spinal abnormality, and restrictive physiology from nonspecific respiratory distress. Corrected ptosis, cryptorchidism and neonatal-hypotonia denominators. Added genu recurvatum, retrognathia and later respiratory distress in the final cross-check. Available-case counts are cohort-specific; cohorts may overlap. Rare isolated ASD/PDA and nonspecific skin/chest composites are nonblocking secondary findings, not assumed to define causal STAC3 manifestations. No common, specifically characterized research phenotype was intentionally left out. 2. Subtypes — N/A: no established mechanistically distinct STAC3 subtypes surfaced. King-Denborough is an overlapping clinical presentation, not a separate STAC3 molecular subtype. No artificial ancestry-based subtypes or severity subdivisions were created. 3. Mechanisms — adequate. Distinguished reduced junctional CaV1.1 abundance from loss of SH3-dependent coupling enhancement; patient-biopsy complex association does not establish every interface is intact. Qualified hypomorphic versus null effects and preserved early versus later abnormal muscle structure. Added clinically supported distal phenotype links without turning co-occurrence into established causality. The abundance-to-coupling edge is explicitly an inference with unknown directness. Lipid accumulation remains hypothetical and the anesthetic-trigger mechanism provisional. Trigger avoidance was removed as a claimed molecular inhibition of susceptibility. Models now include six animal and five cell/isolated-fiber systems, with genotype, assay and translational limits. 4. Treatments/trials — adequate. Added acute dantrolene, ventilation, cough assistance, occupational therapy, speech/swallowing management and specific surveillance schedules. Full GeneReviews supports contracture, orthopedic, feeding and ptosis care. No disease-specific Phase II-or-later treatment was identified in the bounded search. NCT02055248 is a broad completed observational facial-weakness study; a STAC3 paper is listed as background and does not prove cohort enrollment, so it was not added as a STAC3 trial. Other broad neuromuscular observational candidates do not establish STAC3-specific interventions. MTM1/ASPIRO NCT03199469 is out of scope. Engineered SH3-domain rescue remains an experimental model, not clinical therapy. 5. Genetics — adequate. Seven structured variants cover recurrent missense, splice-altering, nonsense, frameshift and in-frame deletion alleles. Reported cDNA effects are distinguished from predictions. Asp279del remains UNCERTAIN_SIGNIFICANCE as explicitly classified in Table 1, despite stronger causal language in the discussion. Pathogenic labels reflect cited author/review classifications, not a new independent ACMG assessment. Founder origin is a hypothesis; reported non-Lumbee families do not prove a universal shared haplotype. No validated modifier or genotype-severity correlation was identified. 6. Diagnostics/prognosis — adequate. Molecular confirmation, CK limitations, potentially normal EMG, nonspecific biopsy, pulmonary/sleep assessment and multidisciplinary follow-up are represented. Selected laboratory diagnostic yield is not population screening yield. Added heterogeneous clinical trajectories and historical mortality, explicitly not a contemporary all-population survival estimate or MH fatality rate. The Lumbee 1/5000 estimate is described as birth prevalence in the Southern African paper but as an individual-population estimate in GeneReviews; this source-definition difference is disclosed. Southern African birth prevalence is a carrier-frequency prediction with the published uncertainty range. 7. References — adequate. All added evidence items carry titles checked against generated cache metadata. URL/PDF cache titles are the extraction URLs; explanations identify the chapter/manuscript. PMID:3631569 remains bibliographic provenance only because no quotable abstract/full text was retrieved. Exact excerpts were checked with the repository validator. GeneReviews evidence spans clinical characteristics, diagnosis, management, inheritance/recurrence and avoidance; review-synthesis quotations are explicitly marked. 8. Overall consumption — adequate. Major research themes, full-text clinical detail, experimental models and important source limitations are incorporated. Speculative gene-therapy programs, bulk lipid measurements as proof of human muscle lipotoxicity, and unverified clinical-trial enrollment were not promoted to established disease claims. Sources consumed: full scientific text for PMIDs 38824262, 37626540, 39966651 (including regenerated tables and final discussion), 40262809, 40779452, 23736855, 27073615, 28777491 and 38088138; the full accepted manuscript for PMID:30168660 recovered from UCL; and the entire GeneReviews PDF recovered via NCBI /sites/books/NBK542808/pdf/Bookshelf_NBK542808.pdf. Abstracts for PMIDs 31219695, 28003463, 39592070, 23818578 and 36030003 were also consumed. Core sources were checked for public dataset accessions; no suitable disease-specific GEO/BioProject accession was identified in those sources. Targeted cDNA/qPCR and supplementary numerical measurements were not misrepresented as deposited transcriptomic datasets. Full-text recovery limits: the 2017 PNAS source (PMID:28003463) remained abstract-only after PMID/DOI retries and PMC/EuropePMC/publisher recovery attempts. The retrieved abstract does not verify a genomic knock-in. The lipid-study publisher route was inaccessible, so PMID:39592070 claims remain limited to its abstract; muscle localization and causal mediation are not inferred from bulk neutral lipid. PMID:23818578 remained abstract-only. Failed CAPTCHA cache attempts and an unused DOI/clinical-trial cache are excluded from the PR. All committed reference caches were generated using fetch-reference; none were hand-edited. Material source issues: the mixed RYR1/STAC3 cohort (PMID:39966651) has inconsistent genotype and phenotype counts across prose/tables; its pooled denominators were not assigned to STAC3 and its carrier-frequency/prevalence arithmetic was not adopted. The Southern African CK account names 16 normal and four raised values among 21 measurements, leaving one unexplained. Patient-cell calcium physiology in the 2018 paper comes from one compound-heterozygous culture, not all biopsied patients. The 2016 inducible mouse uses CAG-Cre/Esr1, not a muscle-specific driver, retains residual protein and does not show statistically significant CaV1.1 reduction. The 2013 zebrafish transgene rescue is mosaic expression in a null background, not genomic knock-in. The 2025 engineered SH3 rescue is in cultured myotubes, not treatment of patients or animals. Prior process notes removed from disease YAML are archived verbatim below. They describe the pre-review state; in particular, full GeneReviews recovery and dataset triage were subsequently completed as documented above. 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.

Create: Bailey-Bloch Congenital Myopathy (STAC3, MONDO:0009722) · 2026-08-15T19:32:15Z · View source

De novo curation of Bailey-Bloch congenital myopathy (STAC3 disorder / Native American myopathy / CMYP13). Deep research: claude_code provider via `just research-disorder claude_code Bailey-Bloch_Congenital_Myopathy`. The report was then reference-validated in place with `just validate-research-reference`: 15/15 references resolved, 0 unresolved; 3 quoted claims could not be matched to their cited sources, and none of those quotes were reused in this entry. NEC check: the report itself flagged X-linked myotubular myopathy as the likely wrong-entity resolution for this disorder name, and the entry records that hazard in notes and differential_diagnoses. One report citation was wrong on verification -- PMID:30178658 was cited for the Zaharieva 2018 Hum Mutat cohort but resolves to an unrelated solid-state solar-cell paper. The correct identifier PMID:30168660 was located via PubMed and is what the entry cites; the substitution is recorded in the entry notes. GeneReviews baseline: a chapter exists (PMID:31219695, STAC3 Disorder). It was fetched, used as the phenotype baseline, tagged GeneReviews in the top-level references block, and its Agents/Circumstances to Avoid content is reflected in the anaesthetic-avoidance treatment. Curated content: a six-node pathophysiology chain from biallelic STAC3 loss of function through failed CaV1.1 triad assembly to defective excitation-contraction coupling, with a parallel malignant-hyperthermia branch and a hedged skeletal-muscle lipid branch; 15 phenotypes with HPO bindings and cohort-derived frequency bands; genetic (including the reframing of c.851G>C from a Lumbee founder allele to one of probable African origin); an environmental anaesthetic-trigger entry linked into the pathograph via influences_mechanisms; six treatments; diagnosis; three differential diagnoses; three zebrafish models with modeled_mechanisms, fidelity and limitations; and two discussions recording the unresolved STAC3-CaV1.1 interaction paradox and the unknown MH trigger mechanism. Validation: `just validate` passed (schema, terms, references). `just count-verified-snippets` reported 60/60 verified against cached references. `just check-title-snippets` reported no new title-quoting snippets. Compliance 89.5% (weighted 89.9%). No datasets block was added: dataset relevance triage for an ultra-rare myopathy is a manual step that was not performed, and a bulk record was preferred absent over unverified.

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)