Musculoskeletal
for muscular dystrophies and congenital myopathies with exome sequencing
System Profile
Yield Comparison
Clinical Dimensions
- Progressive weakness
- CK elevation
- Gowers sign
- Exercise intolerance
- Delayed motor milestones from weakness
- Duchenne/Becker muscular dystrophy
- Limb-girdle muscular dystrophies
- Congenital myopathies
- Spinal muscular atrophy
- Metabolic myopathies
- Gowers' maneuver
- Proximal weakness
- Hypotonia
- Head lag
- Reduced muscle bulk
- Calf pseudohypertrophy
- Joint contractures
- Scapular winging
- Diminished reflexes
- Easy fatigue with minimal activity
- Difficulty climbing stairs
- Frequent falls
- Leg cramps
- Muscle pain
- Exercise intolerance
- Lifelong clumsiness
- Persistently elevated CK
- High aldolase and LDH
- Elevated transaminases from muscle breakdown
- Abnormal acylcarnitines
- Lactic acidosis post-exertion
- Myoglobinuria
- Muscle MRI with selective fatty infiltration patterns consistent with dystrophy or congenital myopathy
- Fibrofatty replacement
- EMG demonstrating myopathic or neuropathic changes
- Muscle biopsy with cores/rods/dystrophic changes
- Forearm exercise test abnormal
- Stress CK response abnormal
- History of rhabdomyolysis with anesthetics or statins
- Muscle breakdown with common meds
- Steroid-responsive myopathy
- Malignant hyperthermia reaction to anesthetics
- Muscle breakdown with minor exposure
- Myopathy-associated drug reactions
- Muscle biopsy
- Tendon lengthening
- Contracture release
- Spine surgery for neuromuscular scoliosis
- Achilles lengthening
- PT for proximal weakness
- Gait training
- Orthotic management
- Fatigue management
- Regular therapy to maintain function
- Orthotics
- Ankle-foot orthoses
- KAFOs
- Wheelchairs
- Standing frames
- Walkers for muscle weakness
- Neuromuscular specialist
- Repeated PT and orthopedics visits for weakness
- Neurology concerned for dystrophy or SMA
- Metabolic consults for myopathy
- Muscular dystrophy in maternal line
- Childhood-onset weakness in relatives
- Early wheelchair use
- Rhabdomyolysis history
- Unexplained exercise intolerance in family
- Active lifestyle but fatigue and weakness out of proportion
- No deconditioning or injury to explain weakness
- Patterns seen in family members
- Congenital hypotonia
- Arthrogryposis
- Weak cry
- Minimal spontaneous movement
- Prenatal decreased fetal movements
- Delayed early motor skills
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
Proximal weakness + elevated CK
Exercise intolerance + myoglobinuria
Hypotonia + respiratory insufficiency
Rhabdomyolysis + metabolic acidosis
Screening Decision Pathway
When to consider genetic testing for musculoskeletal presentations
graph TD
START["Patient Presents with\nMusculoskeletal Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["Delayed gross motor subscales on ASQ"]
SCREEN --> RF2["Screens showing persistent motor lag"]
SCREEN --> RF3["Abnormal hypotonia flags on early developmental ch..."]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> EVAL{"Multiple\nFlags Present?"}
EVAL -->|Yes| TEST["Order Genetic Testing\n(ES/GS)"]
EVAL -->|No| MONITOR["Continue Monitoring\nRe-evaluate if New Findings"]
TEST --> DX["Molecular Diagnosis\n50-89% yield"]
style TEST fill:#dcfce7,stroke:#16a34a,color:#14532d
style DX fill:#bbf7d0,stroke:#16a34a,color:#14532d
style MONITOR fill:#fef3c7,stroke:#d97706,color:#92400e
Screening Red Flags
Findings on routine screening that may indicate genetic etiology
- Delayed gross motor subscales on ASQ
- Screens showing persistent motor lag
- Abnormal hypotonia flags on early developmental checks
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Progressive muscle weakness with elevated CK
- Nondiagnostic muscle biopsy or panel
- Neuromuscular symptoms plus cardiac or respiratory involvement
- Multiple affected relatives
Key Evidence
Published studies supporting genetic testing for musculoskeletal conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Diagnostic Yield of Next-Generation Sequencing Applied to Ne... | 2018 | Cohort | None | 36.5% | RASopathies NGS panel with functional analysis improved diagnostic yield from 31... |
| Diagnostic Yield of Exome Sequencing in Myopathies: Experien... | 2021 | Cohort | None | 52% | 52% overall diagnostic yield (64% in pediatric, 35% in unspecified myopathies) a... |
| Whole Exome Sequencing for Ehlers-Danlos Syndrome Differenti... | 2022 | Cohort | None | None | WES enables molecular subtyping and differential diagnosis in clinically overlap... |
| Genetic basis of paediatric hyperCKaemia without muscle weak... | 2022 | Cohort | 34 | 74% | 74% genetic diagnostic yield in 34 pediatric patients with hyperCKaemia without ... |
| High diagnostic yield of targeted next-generation sequencing... | 2023 | Cohort | 146 | 46% | 46% diagnostic yield with targeted NGS panel in 146 patients with myopathy or mu... |
| Utilisation of exome sequencing for muscular disorders in Th... | 2023 | Cohort | 43 | 70% | 70% diagnostic yield with exome sequencing in 43 Thai pediatric muscular disorde... |
| Copy number variants from 4800 exomes contribute to ~7% of g... | 2023 | Cohort | 4800 | 7% | CNVs from exome data contribute ~7% of solved cases across movement disorders, m... |
| Mutational profile and genetic testing in a South African co... | 2023 | Cohort | 61 | 50% | ~50% solved rate in 61 South African patients with inherited neuropathies and he... |
Updated: 2026-02-24
Curated by: human
Status: human reviewed