Duchenne Muscular Dystrophy (OMIM #310200)
Becker Muscular Dystrophy (OMIM #300376)

Background and Standard Service Information

DMD is an X-linked recessive disorder, and is the most common form of muscular dystrophy, occurring in about 1 in 3,500 males. BMD is a milder allelic form, with a lower prevalence of 1 in 18,500 live male births. Typical clinical indications include elevated Creatine Kinase (CK) levels, calf pseudohypertrophy, absence or reduction of Dystrophin protein in immunohistochemistry of muscle biopsy, and Gower’s sign (a characteristic manner of rising from a sitting to standing position).

DMD and BMD result from mutations in the DMD gene, which encodes the protein Dystrophin. Approximately 65% of DMD and 85% of BMD males have a deletion within the DMD gene. Duplications are found in around 5-10% of affected patients.

Essential referral information

In addition to supplying standard patient identification and referral information, the following should be clearly indicated:

  1. Patient’s symptoms.
  2. Any family history, including names, dates of birth, relationship and genetic test results if available.

Please note: It is the responsibility of the referring clinician to ensure consent has been obtained for testing and storage.

Samples required

Generally 5-10ml of EDTA blood (FBC bottle) is required. Blood specimens must be appropriately packaged, and preferably sent by courier to arrive as soon as possible. Do not freeze prior or during postage.

Please note that extracted DNA is stored from patient’s samples at the National Centre for Medical Genetics, and kept indefinitely unless a written request for its disposal is received from the patient or their parent/guardian.

Restrictions on Testing

Tests offered

Diagnostic testing:
Molecular confirmation of a suggested clinical diagnosis is possible, using a multiplex ligation-dependent probe amplification (MLPA) assay which tests for copy number changes in each exon of the DMD gene.
Carrier testing:

Carrier testing may be possible for females with a family history of DMD/BMD.

  1. In general, the index case must have a diagnosis of DMD/BMD, which has been confirmed by identification of the causative mutation. Carrier testing is then based on direct analysis of the DMD gene.
  2. Carrier testing (using linked markers) may also be possible in cases where a causative mutation has not been identified, as long as a firm diagnosis can be established by other means. Please contact the laboratory in advance to discuss the possibility of testing for such families.
Prenatal testing:

Prenatal testing must be arranged in advance with the laboratory, through a Clinical Genetics department if possible. As fetal sexing from a maternal blood specimen is possible, this test is generally requested to establish gender prior to an invasive prenatal DMD/BMD test being requested. Regarding prenatal testing specifically for DMD/BMD:

  1. In general, the index case must have a diagnosis of DMD/BMD, which has been confirmed by identification of the causative mutation. Prenatal testing is then based on direct analysis of the DMD gene.
  2. It may be possible to also offer prenatal diagnosis (using linked markers) in families where a causative mutation has not been identified, as long as a firm diagnosis can be established by other means. Please contact the laboratory in advance to discuss the possibility of testing for such families.

Diagnostic sensitivity of tests

Like most molecular genetic tests, the diagnostic sensitivity of the DMD/BMD tests is less than 100%.

Diagnostic testing:
The MLPA assay detects all whole exon deletions and duplications, but approximately 5% to 10% of boys with BMD, and 25% to 30% of boys with DMD, do not have whole exon deletions or duplications, but have other small insertions/deletions/point mutations etc. which are not detected by this test.
Carrier testing:
  1. Where the causative mutation is known, carrier status can be determined at an accuracy of >99%.
  2. If the mutation has not been identified in the index, it may be possible to use linkage analysis to modify the estimated risk of carrier status. However, the diagnostic sensitivity of such analysis is dependent on factors which are unique to each family assessed.
Prenatal testing:
  1. Where the causative mutation is known, a diagnostic prediction can be made at an accuracy of >99%.
  2. If the mutation has not been identified, and prenatal diagnosis by linkage analysis is appropriate, the diagnostic sensitivity is dependent on factors which are unique to each family assessed.

Interpretation

Results are given in the form of a written interpretative report to the referring clinician. For example, for diagnostic tests a diagnosis is confirmed where a deletion or duplication within the DMD gene is detected. The absence of a deletion and/or duplication does not exclude a diagnosis of DMD/BMD, since a proportion of cases result from other types of mutation.

Target reporting times

As reporting times are constantly evolving, please refer to molecular genetics, or contact the molecular genetics laboratory, to receive up-to-date information on anticipated reporting times for your referral.

Further tests

Diagnostic testing: Where MLPA does not identify a causative mutation, for a patient in whom a clinical diagnosis of DMD/BMD is considered likely, it is possible to screen for other types of mutations. This service is available through an external laboratory, using a method predicted to detect greater than 98% of all DMD/BMD mutations, and at a cost of up to stg£700.

Please contact us to make arrangements for such testing, if required.

The NCMG Molecular Genetics laboratory participates in external QA schemes run by the UK NEQAS for Molecular Genetics, the European Molecular Genetics Quality Network (EMQN), and the Cystic Fibrosis European Network. Results of assessments are available for inspection upon request.

Document Number: DOC1347, Revision Number 4