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Duchenne/Becker Muscular Dystrophy Deletion/Duplication With Reflex to Sequencing

2011241

Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing 2011241

Method

Multiplex Ligation-Dependent Probe Amplification (MLPA)/Massively Parallel Sequencing

Most comprehensive DMD gene test for DMD or BMD
Deletion/duplication analysis is performed first
- If no large deletions or duplications are detected and/or results do not explain the clinical scenario, sequencing of the DMD gene is performed
Deletion/duplication and sequencing components are also orderable separately, see below

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate. Refer to the Laboratory Test Directory for additional test options.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked degenerative muscle disorders caused by pathogenic variants in the DMD gene. Testing for DMD variants can be used to confirm a diagnosis of DMD/BMD in symptomatic individuals or to determine carrier status for females with a family history of DMD/BMD or dilated cardiomyopathy (DCM). Prenatal testing for familial DMD variants is also available.

Disease Overview

Symptoms

DMD
- Delayed childhood milestones (eg, sitting, standing, walking, climbing) due to progressive symmetrical muscular weakness
- Cardiomyopathy onset: approximately 14 years
  - 95% have cardiovascular involvement
- Wheelchair dependence: typically by 12 years
- Laboratory findings
  - No observable dystrophin expression
  - Serum CK levels: significantly increased
BMD
- Later-onset muscle weakness
- Cardiomyopathy onset: approximately 15 years
- Wheelchair dependence: 20s-30s
- Laboratory findings
  - Dystrophin expression: 20-100%
  - Serum CK levels: increased
DMD-Associated Dilated Cardiomyopathy (DCM)
- Rapidly progressive disease course in the absence of skeletal myopathy
- Male age of onset: teens and 20s
- Female age of onset – 30s and 40s

Incidence

DMD: 1/3,500 male births worldwide
BMD: 1/19,000 male births worldwide

Genetics

Gene: DMD

Inheritance: X-linked

Penetrance

Males: 100%
Females: varies with X-chromosome inactivation

De novo variants: approximately 1/3 cases

Typical Diagnostic Testing Strategy

Initial testing for DMD/BMD
- Serum creatine kinase (CK) concentration
- Muscle biopsy with dystrophin studies
Molecular testing
- Deletion/duplication analysis
- Sequencing analysis

Typical Carrier Testing Strategy

For a known familial DMD variant, targeted testing is recommended.
If there is a family history of DMD/BMD but the causative familial variant is unknown, test an affected relative then perform targeted testing for the identified variant in at-risk relatives.
If an affected relative cannot be tested, at-risk relatives should be tested by deletion/duplication analysis first because most DMD variants are large deletions and duplications.
- If negative, consider DMD sequencing.

Recommended Follow-Up Testing

Cardiac evaluation for affected individuals and carriers

Test Description

Clinical Sensitivity

DMD
- Deletion/duplication: 55-75%
- Sequencing: 20-35%
BMD
- Deletion/duplication: 75-90%
- Sequencing: 10-20%

Results

Positive
- One pathogenic variant detected in DMD gene
  - Causative for DMD/BMD in males
  - Female carriers are variably affected
Negative
- No pathogenic variants identified
  - Risk for being affected with, or a carrier of, DMD/BMD, is reduced but not excluded.
Inconclusive
- Variants of uncertain clinical significance detected
- Whether variants are benign or pathogenic is unknown

Limitations

A negative result does not exclude a heritable form of muscular dystrophy.
Diagnostic errors can occur due to rare sequence variations.
Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted gene(s)
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Noncoding transcripts
The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants

Analytic Sensitivity

For MLPA: greater than 99%
For massively parallel sequencing:

Variant Class	Analytic Sensitivity (PPA) Estimate^a (%)	Analytic Sensitivity (PPA) 95% Credibility Region^a (%)
SNVs	99.2	96.9-99.4
Deletions 1-10 bp	93.8	84.3-98.2
Deletions 11-44 bp	100	87.8-100
Insertions 1-10 bp	94.8	86.8-98.5
Insertions 11-23 bp	100	62.1-100
DMD gene is a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

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