Myopathy Due To Calsequestrin And SERCA1 Protein Overload — Comprehensive Disease Report

Disease: Myopathy due to calsequestrin and SERCA1 protein overload MONDO ID: MONDO:0014546 | OMIM: 616231 ("Myopathy, vacuolar, with CASQ1 aggregates; VMCQA") Causal gene: CASQ1 (calsequestrin-1), chromosome 1q21 Category: Mendelian (autosomal dominant) Date: 2026-10-15

Summary

Myopathy due to calsequestrin and SERCA1 protein overload is an ultra-rare, autosomal dominant, adult-onset, benign and slowly progressive skeletal-muscle disease caused by heterozygous missense mutations in CASQ1, the gene encoding the fast-twitch skeletal-muscle isoform of calsequestrin. The disorder was first defined morphologically in 2006 as a "surplus protein myopathy" in which muscle fibers contained non-staining vacuolar inclusions immunoreactive for the sarco/endoplasmic reticulum Ca²⁺-ATPase SERCA1 (ATP2A1) and/or calsequestrin (PMID: 16714317). Eight years later the causal lesion was identified as the heterozygous missense mutation CASQ1 c.731A>G, p.Asp244Gly (D244G), segregating as a founder mutation in Italian families (PMID: 25116801, PMID: 26136523).

Mechanistically, the Asp244 residue sits within a high-affinity Ca²⁺-binding site in Domain II of calsequestrin. The mutation causes the protein to lose Ca²⁺ binding and aggregate abnormally into electron-dense sarcoplasmic reticulum (SR) vacuoles that co-sequester SERCA1 and the ryanodine receptor RyR1, predominantly within type II (fast) fibers. Aggregated calsequestrin dissociates from the junctional SR, reducing SR Ca²⁺ storage and impairing Ca²⁺ release — a defect that has been termed a "CASQ1-couplonopathy" (PMID: 27196359). The downstream clinical picture is exercise intolerance, myalgia, mild-to-moderate slowly progressive proximal weakness, and mild-to-moderate elevation of serum creatine kinase (hyperCKemia), often presenting in the sixth decade of life (PMID: 30258016).

The disease is benign in prognosis and does not shorten life expectancy. There is no approved disease-specific therapy; management is supportive and includes physiotherapy, cardiac surveillance (rare subclinical cardiac findings), and genetic counseling for the dominant trait. A theoretical malignant-hyperthermia/heat-sensitivity concern arises from the related Casq1-null mouse model, in which antioxidants and estrogens are protective; these pharmacologic strategies remain unproven in humans. The disease is modeled by D244G knock-in and Casq1-knockout mice.

1. Disease Information

Overview. This is a hereditary vacuolar myopathy of skeletal muscle characterized by intracellular accumulation ("overload") of two terminal-cisternae SR proteins — calsequestrin-1 (CASQ1) and SERCA1 (ATP2A1) — forming inclusions within muscle fibers. It was originally delineated purely by muscle biopsy morphology and immunohistochemistry as a "SERCA1 and calsequestrin storage myopathy" / "surplus protein myopathy" (PMID: 16714317), and later unified genetically under mutations in CASQ1.

Key identifiers.

Synonyms / alternative names: - Myopathy due to calsequestrin and SERCA1 protein overload - Vacuolar myopathy with CASQ1 aggregates (VMCQA) - CASQ1-related myopathy - SERCA1 and calsequestrin storage myopathy - Protein aggregate myopathy with CASQ1 aggregates - CASQ1-couplonopathy (mechanistic designation)

Information source. Knowledge is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO) and from individual patient reports/case series in the primary literature (Italian and Chinese families), not from large EHR datasets. The total reported experience worldwide is on the order of 30–40 patients.

2. Etiology

Disease causal factors. The disease is purely genetic (Mendelian, monogenic). It is caused by heterozygous gain-of-function/dominant missense mutations in CASQ1. There is no infectious or primary environmental cause.

Genetic risk factors. The principal causal variant is CASQ1 p.Asp244Gly (c.731A>G), a founder mutation in Italian families sharing a common haplotype (PMID: 26136523). Additional pathogenic alleles at the same or nearby residues broaden the allelic spectrum: - p.Asp244His (c.730G>C) — reported in two unrelated Chinese families (PMID: 41699400), establishing residue 244 as a mutational hotspot. - p.Gly103Asp — reported in one Italian family, with a distinctive tubular-aggregate histology (PMID: 30258016). - p.Met87Thr — a separate variant weakly associated with malignant hyperthermia susceptibility rather than the overload myopathy (PMID: 26416891).

Environmental risk factors. None established as causal. Theoretical triggers relevant to muscle Ca²⁺ handling — strenuous exercise, heat exposure, and volatile anesthetics — are implicated only from the Casq1-null mouse (see Section 15), not confirmed in the human overload myopathy.

Protective factors. No human genetic or environmental protective factors are established. In the Casq1-null mouse model, estrogens reduce oxidative stress and protect against lethal hyperthermic episodes (PMID: 29062464), and antioxidants (N-acetylcysteine, Trolox) are protective (PMID: 26132720) — but these pertain to the knockout MH phenotype, not the overload myopathy in humans.

Gene–environment interactions. Not formally characterized for the human disease. The mechanistic hypothesis — that a Ca²⁺-handling defect might be unmasked by heat/anesthetic/exercise stress — derives from the knockout model and remains inferred, not demonstrated, for patients.

3. Phenotypes

The clinical spectrum is best defined by the largest cohort to date: 22 CASQ1-mutated patients from 12 families (21 with p.Asp244Gly, 1 with p.Gly103Asp) (PMID: 30258016).

Key quotes. "Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging" (PMID: 30258016). "Three patients presented subclinical cardiac abnormalities" (ibid.).

Quality-of-life impact. Because the disease is mild and slowly progressive, functional impact is limited; most patients remain ambulant. HyperCKemia may be the only manifestation, and many carriers are likely under-ascertained ("it is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed" — PMID: 30258016). No disease-specific QoL instrument (EQ-5D/SF-36/PROMIS) data are available.

4. Genetic/Molecular Information

Causal gene — CASQ1 (calsequestrin-1):

Pathogenic variants.

Variant classification notes. The Domain-II residue Asp244 is highly conserved ("a highly conserved residue" — PMID: 41699400); recurrence across independent populations (Italy, China) supports pathogenicity under ACMG criteria (PS1/PM1/PM5 — same residue, different substitutions).

Allele frequency. These are private/ultra-rare variants, essentially absent from population databases (gnomAD); the Italian cases share a single founder haplotype.

Somatic vs germline. All reported variants are germline, segregating in an autosomal dominant fashion.

Functional consequences. The mutation is best characterized as a dominant, toxic gain-of-function / dominant-negative aggregation defect combined with loss of normal Ca²⁺-buffering at the junctional SR: mutant CASQ1 loses high-affinity Ca²⁺ binding and aggregates abnormally, sequestering wild-type CASQ1 and partner proteins (SERCA1, RyR1).

Modifier genes. None established.

Epigenetic information / chromosomal abnormalities. Not applicable/not reported; this is a point-mutation monogenic disorder with no described epigenetic or structural chromosomal component.

5. Environmental Information

Environmental factors. None causally established. The disorder is monogenic. As a theoretical consideration (extrapolated from the knockout model, not the human overload myopathy), heat stress and volatile halogenated anesthetics could stress skeletal-muscle Ca²⁺ homeostasis.

Lifestyle factors. Strenuous exercise is a presenting trigger of symptoms (exercise intolerance, myalgia) but is not a disease cause.

Infectious agents. Not applicable — no infectious etiology.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. A heterozygous CASQ1 missense mutation at/near a Domain-II high-affinity Ca²⁺-binding site (p.Asp244Gly, p.Asp244His, or p.Gly103Asp) arises in the germline → leads to a structurally altered calsequestrin monomer.
2. Loss of two coordinating Ca²⁺ ions in the mutant structure weakens the hydrophobic core of Domain II (demonstrated crystallographically for D244G) → results in loss of high-affinity Ca²⁺ binding at elevated Ca²⁺ (PMID: 26416891).
3. Impaired Ca²⁺ binding reduces the ability of CASQ1 to form normal elongated polymers and instead causes abrupt, abnormal aggregation (PMID: 26416891).
4. Aggregated mutant (and co-recruited wild-type) CASQ1 leads to the formation of electron-dense SR vacuoles that co-sequester SERCA1 (ATP2A1) and RyR1, preferentially in type II fibers (PMID: 25116801).
5. In parallel (branch), the mutation causes CASQ1 to partially dissociate from the junctional SR and accumulate in the ER (shown in the D244G knock-in mouse) → reduces junctional CASQ1 content and SR Ca²⁺ stores (PMID: 33786938).
6. Reduced junctional calsequestrin and disrupted couplon architecture result in less Ca²⁺ release from the SR of mutant fibers compared with controls (patient-derived myotubes) → defining a "CASQ1-couplonopathy" (PMID: 27196359).
7. Chronically altered Ca²⁺ handling and protein overload lead to the clinical phenotype: exercise intolerance, myalgia, mild proximal weakness, and hyperCKemia (PMID: 30258016).

CASQ1 D244G/D244H/G103D (germline, heterozygous)
        │  (Domain II high-affinity Ca2+ site)
        ▼
Loss of 2 Ca2+ ions → weakened Domain II hydrophobic core   [crystallography, in vitro]
        │
        ├──────────────► Abnormal/abrupt aggregation; loss of normal polymerization
        │                        │
        │                        ▼
        │                Electron-dense SR vacuoles sequestering CASQ1 + SERCA1 + RyR1
        │                (type II fibers)  → "surplus protein / overload"
        │
        └──────────────► Partial dissociation of CASQ1 from junctional SR → ER accumulation [KI mouse]
                                 │
                                 ▼
                    ↓ Junctional CASQ1, ↓ SR Ca2+ store → ↓ SR Ca2+ release ("couplonopathy")
                                 │
                                 ▼
          Adult-onset, slowly progressive, mild proximal myopathy + hyperCKemia

Detail by category

• Molecular pathways. Excitation–contraction (EC) coupling: SR Ca²⁺ storage/release through the RyR1–DHPR couplon; Ca²⁺ reuptake via SERCA1. Calsequestrin is the principal luminal Ca²⁺ buffer that modulates RyR1 gating.
• Cellular processes. Protein aggregation / proteostasis failure in the SR; vacuole formation; altered intracellular Ca²⁺ signaling. GO suggestions: GO:0006874 (cellular calcium ion homeostasis), GO:0051209 (release of sequestered calcium ion into cytosol), GO:0005513 (detection of calcium ion), GO:0006457 (protein folding).
• Protein dysfunction. Loss of high-affinity Ca²⁺ binding, impaired polymerization, and toxic aggregation — a mixed loss-of-buffer + gain-of-aggregation mechanism. Normal CASQ1 binds ~80 Ca²⁺ ions and polymerizes to form the SR terminal-cisternae matrix.
• Metabolic changes. Secondary; chronically impaired Ca²⁺ cycling can affect fatigue resistance/energy metabolism in fast fibers (exercise intolerance), though not directly profiled in patients.
• Immune system involvement. None; this is a non-inflammatory, non-autoimmune protein-aggregate myopathy.
• Tissue damage mechanisms. Chronic vacuolar accumulation and Ca²⁺ dysregulation in type II fibers; mild myofiber stress releasing CK. In the knockout MH model, oxidative stress is central — but that is the loss-of-function phenotype.
• Biochemical abnormalities. Defective luminal SR Ca²⁺ buffering (ion-handling defect) rather than an enzyme deficiency.
• Subcellular localization. SR terminal cisternae / junctional SR lumen (GO:0033018 sarcoplasmic reticulum lumen region, GO:0014701 junctional sarcoplasmic reticulum membrane); pathologic mislocalization to the ER (GO:0005783 endoplasmic reticulum).

Cell types involved. Skeletal muscle fibers, specifically fast-twitch type II fibers — CL:0000190 (fast muscle cell) / CL:0008002 (skeletal muscle fiber).

7. Anatomical Structures Affected

• Organ/system level. Primary: skeletal muscle (musculoskeletal system). Distribution is proximal and bilateral/symmetric — quadriceps (anterior thigh), scapular/periscapular muscles (scapular winging). Secondary: heart — subclinical cardiac abnormalities in ~14% (3/22) (PMID: 30258016).
• Tissue/cell level. Striated muscle tissue; predominantly type II (fast-twitch) fibers contain the vacuolar aggregates.
• Subcellular level. Sarcoplasmic reticulum terminal cisternae / junctional SR; abnormal accumulation in the endoplasmic reticulum.
• UBERON/CL suggestions. UBERON:0001134 (skeletal muscle tissue), UBERON:0011907 (quadriceps femoris), UBERON:0000948 (heart, secondary), UBERON:0002349 (myocardium); CL:0000190 (fast muscle cell). GO cellular component: GO:0016529 (sarcoplasmic reticulum), GO:0033018, GO:0005783.
• Lateralization. Bilateral, symmetric proximal involvement.

8. Temporal Development

• Onset. Adult, typically the sixth decade; onset is insidious/chronic. HyperCKemia may precede or exist without overt weakness.
• Progression. Slowly progressive; weakness remains mild-to-moderate; patients generally remain ambulant. Muscle MRI shows a recurrent fibrofatty substitution pattern (reported in 11 patients) (PMID: 30258016).
• Disease course. Chronic, lifelong, but benign; no reported end-stage/wheelchair-dependent phase as a rule.
• Patterns. No spontaneous remission; no relapsing-remitting pattern. Symptoms (myalgia, exercise intolerance) may fluctuate with activity. Critical periods for intervention are not defined because no disease-modifying therapy exists.

9. Inheritance and Population

• Epidemiology. Ultra-rare. The world literature totals roughly 30–40 reported patients, concentrated in Italy (founder p.Asp244Gly) plus isolated Chinese families. Orphanet prevalence: unknown, <1/1,000,000. Likely under-ascertained because mild cases escape biopsy (PMID: 30258016).
• Inheritance pattern. Autosomal dominant (heterozygous missense variants).
• Penetrance / expressivity. Appears high but with variable expressivity (ranging from isolated hyperCKemia to symptomatic proximal weakness); formal penetrance estimates are not established.
• Genetic anticipation / mosaicism. Not applicable (not a repeat-expansion disorder); germline mosaicism not reported.
• Founder effects. Yes — a shared Italian founder haplotype for p.Asp244Gly (PMID: 26136523).
• Consanguinity / carrier frequency. Not relevant to a dominant disorder; carrier frequency not meaningfully defined.
• Population demographics. Italian (founder) and Chinese families reported; both sexes affected; adult age distribution (sixth decade typical).

10. Diagnostics

• Laboratory. Serum creatine kinase mildly-to-moderately elevated (hyperCKemia), sometimes the sole abnormality (HP:0003236).
• Muscle biopsy (diagnostic cornerstone). Vacuoles in type II fibers appearing "empty" on H&E, Gomori trichrome, and NADH-tetrazolium reductase stains, but strongly positive for SR proteins (SERCA1/ATP2A1 and calsequestrin) by immunohistochemistry; immunoblot shows increased SERCA1 and calsequestrin (PMID: 16714317; PMID: 30258016). The p.Gly103Asp variant additionally shows NADH-positive tubular aggregates. Electron microscopy: electron-dense SR vacuoles.
• Imaging. Muscle MRI shows a recurrent fibrofatty substitution pattern.
• Electrophysiology. EMG may show myopathic features; patient-derived myotubes show reduced SR Ca²⁺ release on Ca²⁺ imaging/electrophysiology (research setting) (PMID: 27196359).
• Genetic testing. Confirmatory. Recommended approach: single-gene testing of CASQ1 (targeting the Asp244 hotspot) or a myopathy/limb-girdle gene panel; WES/WGS are useful for undiagnosed cases, especially given the characteristic biopsy. Chromosomal microarray, karyotyping, FISH, mtDNA testing, and repeat-expansion testing are not applicable.
• Clinical criteria / differential diagnosis. No formal consensus criteria; diagnosis rests on the triad of (1) adult-onset mild proximal myopathy/hyperCKemia, (2) SR-protein-positive type II fiber vacuoles, and (3) a pathogenic CASQ1 variant. Differential diagnoses: tubular aggregate myopathies (STIM1/ORAI1), other protein-aggregate/vacuolar myopathies, limb-girdle muscular dystrophies, and idiopathic hyperCKemia.
• Screening. Cascade genetic testing of at-risk relatives in known families. No population newborn/carrier screening (ultra-rare, dominant, benign).

11. Outcome/Prognosis

• Survival/mortality. Benign; life expectancy is not reported to be reduced; no disease-specific mortality established.
• Morbidity/function. Mild-to-moderate proximal weakness with slow progression; most patients remain ambulant and functionally independent. Rare subclinical cardiac abnormalities (~14%) warrant surveillance but have not been linked to adverse outcomes.
• Disease course/complications. Chronic but stable-to-slowly-progressive. Theoretical anesthetic/heat risk is extrapolated from the knockout model and remains unproven in patients.
• Prognostic factors. None validated. Genotype may influence histology (tubular aggregates with p.Gly103Asp) but not clearly prognosis.
• Supporting quote. Patients "later developed mild to moderate, slowly progressive proximal weakness" (PMID: 30258016).

12. Treatment

• Pharmacotherapy. No approved disease-specific or targeted drug. Management is supportive.
• Advanced therapeutics (gene/cell/RNA). None in clinical use; the dominant aggregation mechanism could in principle be amenable to allele-specific knockdown (ASO/siRNA) in the future, but no such program is reported.
• Supportive/rehabilitative. Physiotherapy, graded exercise modification for exercise intolerance/myalgia, periodic cardiac surveillance given rare subclinical cardiac findings.
• Experimental / mechanistic leads. From the Casq1-null mouse (loss-of-function MH model, distinct from the overload disease): antioxidants (N-acetylcysteine, Trolox) protected against lethal halothane/heat-triggered hypermetabolic episodes, reducing mortality from ~79–86% to ~20–33% (PMID: 26132720), and estrogens reduced oxidative stress and mortality (PMID: 29062464). These suggest antioxidant strategies and anesthetic/heat precautions as rational but unproven approaches in humans.
• Treatment outcomes / adverse events. Not applicable (no disease-specific therapy).
• NCIT suggestions. NCIT:C15336 (Supportive Care), NCIT:C15682 (Physical Therapy), NCIT:C98225 (Genetic Counseling), NCIT:C265 (Antioxidant) — all general/supportive.

13. Prevention

• Primary prevention. None for a Mendelian disorder.
• Secondary prevention. Early detection via cascade genetic testing in known families; recognition of isolated hyperCKemia prompting biopsy/genetics.
• Tertiary prevention. Cardiac surveillance; prudent anesthetic and heat precautions (theoretical, extrapolated from the knockout model).
• Immunization / public health / environmental interventions. Not applicable.
• Counseling. Genetic counseling for autosomal dominant inheritance (50% transmission risk); theoretical prenatal/preimplantation genetic testing is possible but rarely indicated given the benign course.

14. Other Species / Natural Disease

• Taxonomy / orthologs. Mouse ortholog Casq1: MGI:1309468, NCBI Gene 12372, Ensembl ENSMUSG00000007122. CASQ1 is highly conserved across mammals.
• Natural disease in other species. No naturally occurring animal homolog of this specific overload myopathy is reported (OMIA). Disease knowledge in animals comes from engineered models (Section 15).
• Comparative biology. Calsequestrin's role in SR Ca²⁺ storage and EC coupling is evolutionarily conserved, underpinning the translational relevance of mouse models.
• Transmission. Not applicable (non-communicable genetic disease; no zoonotic potential).

15. Model Organisms

Two complementary mouse models anchor the mechanistic understanding, and cellular systems recapitulate the aggregation phenotype.

Rescue evidence. Re-introduction of wild-type CASQ1 by cDNA electrotransfer in Casq1-null muscle restores junctional SR targeting, terminal-cisternae ultrastructure, and Ca²⁺ transient amplitude (PMID: 22049211) — confirming CASQ1's causal role in both Ca²⁺ homeostasis and terminal-cisternae structure.

Model limitations. The Casq1-null mouse models loss of function and its dominant feature is MH/heat susceptibility, which is not the primary human overload phenotype; the knock-in D244G mouse better reflects the human dominant aggregation/couplonopathy. Resources: MGI (Casq1, MGI:1309468).

Mechanistic Model / Interpretation

The convergent human (biopsy, patient-myotube electrophysiology, 22-patient cohort), in vitro (crystallography, cell aggregation), and mouse (D244G knock-in, Casq1 knockout) evidence defines a single coherent model:

A heterozygous CASQ1 missense mutation at/near a Domain II high-affinity Ca²⁺ site (D244G / D244H / G103D) → loss of Ca²⁺ binding + abnormal aggregation → electron-dense SR/ER vacuoles sequestering CASQ1, SERCA1, and RyR1 in type II fibers → dissociation of CASQ1 from the junctional SR → reduced SR Ca²⁺ storage and release (CASQ1-couplonopathy) → adult-onset, slowly progressive, mild proximal myopathy with hyperCKemia.

Upstream events are molecular/biophysical (the mutation, loss of Ca²⁺ coordination, aggregation); downstream events are physiological and clinical (impaired EC coupling, weakness, CK leak). The disease unifies two apparently opposite effects — a gain of toxic protein (the "overload"/surplus protein storage) and a loss of functional junctional buffering (the couplonopathy) — into one pathogenic cascade. Notably, calsequestrin dysfunction produces two divergent human phenotypes depending on the allele: the benign dominant overload myopathy (D244G/D244H/G103D) versus a weak malignant-hyperthermia association (M87T), with the knockout mouse illustrating the MH/heat-stress extreme of the loss-of-function axis.

Evidence Base

Notable verbatim support. - "The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+)-binding sites of CASQ1 and alters the kinetics of Ca(2+) release in muscle fibers." (PMID: 25116801) - "D244G aggregates abruptly and abnormally … D244G crystallized in low Ca(2+) concentrations lacks two Ca(2+) ions normally present in wild type that weakens the hydrophobic core of Domain II." (PMID: 26416891) - "Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls." (PMID: 27196359) - "The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)." (PMID: 33786938)

Limitations and Knowledge Gaps

1. Small evidence base. Only ~30–40 patients worldwide; cohort statistics (e.g., 22-patient series) dominate, so penetrance, true prevalence, and genotype–phenotype correlations are imprecise.
2. Ascertainment bias. Mild/isolated-hyperCKemia cases likely under-diagnosed without muscle biopsy, so the spectrum may be broader and milder than reported.
3. Mechanistic duality unresolved in humans. The human overload myopathy vs the knockout MH/heat-stress phenotype are modeled in different systems; whether human D244G patients carry a clinically meaningful anesthetic/heat risk is not demonstrated — the precaution is extrapolated.
4. No human therapeutic data. Antioxidant/estrogen protection is only shown in Casq1-null mice; no trials in patients.
5. Cardiac involvement. The significance of subclinical cardiac abnormalities (~14%) is unclear; CASQ1 is the skeletal isoform (cardiac CASQ2 is distinct), so the cardiac finding needs mechanistic clarification.
6. Omics gaps. No transcriptomic, proteomic, metabolomic, or single-cell profiling specific to this disease is available.

Proposed Follow-up Experiments / Actions

1. Natural-history registry across Italian and Chinese families (and new cases) to quantify penetrance, progression rate, and cardiac risk prospectively.
2. Anesthetic/heat-stress risk assessment in D244G knock-in mice and, cautiously, retrospective review of patient anesthetic exposures to test whether the MH/heat risk translates to the overload myopathy.
3. Test antioxidant (NAC) and estrogen pathways in the D244G knock-in (not only knockout) model to determine relevance to the overload phenotype.
4. Allele-specific knockdown (ASO/siRNA) proof-of-concept targeting mutant CASQ1 transcripts in patient myotubes to address the dominant aggregation mechanism.
5. Deep muscle proteomics/transcriptomics of patient biopsies to map the full "surplus protein" composition and secondary stress responses.
6. Structural studies of D244H and G103D (beyond D244G) to confirm shared loss-of-Ca²⁺-binding mechanism across the allelic spectrum.
7. Cardiac evaluation protocol to clarify whether skeletal CASQ1 variants have any genuine cardiac phenotype or whether findings are incidental.