Genetic testing for Duchenne muscular dystrophy (DMD) gene mutations may be considered medically necessary under the following conditions:
- In a male with signs and symptoms of a dystrophinopathy in order to confirm the diagnosis and direct treatment.
- For at-risk female relatives*:
- To confirm or exclude the need for cardiac surveillance.
- For preconception and/or prenatal testing to determine the likelihood of an affected offspring in a woman considering a pregnancy.
*NOTE: At risk females are defined as first- and second-degree female relatives and include the proband’s mother, female siblings of the proband, female offspring of the proband, the proband’s maternal grandmother, maternal aunts, and their offspring. (A proband is an individual being studied or reported on. A proband is usually the first affected individual in a family who brings a genetic disorder to the attention of the medical community. )
Analytic validity (refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent).
Deletions of one or more exons account for 60-70% of mutations in individuals with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). (12)
Duplications account for 5-10% of mutations in DMD and BMD. (12)
Multiplex polymerase chain reaction (PCR) may be used to amplify exons known to be most frequently deleted in DMD-affected patients. Results obtained from testing two PCR multiplex sets suggest a detection rate of approximately 98% with this methodology. (13, 14) Multiplex PCR is the most widely available testing choice but is only able to detect deletions. In addition, this method does not cover the whole gene, so a deletion might not always be fully characterized. (7) An alternative to multiplex PCR is the use of a quantitative assay (e.g. multiplex ligation-dependent probe amplification or comparative genomic hybridization [also called chromosomal microarray or CMA]) of all exons. These methods have the advantage of being able to detect whole exon deletions, as well as duplications.
Point mutations (small deletions or insertions, single-base changes, and splicing mutations) account for approximately 25-35% of mutations in males with DMD and about 10-20% of males with BMD.
If deletion/duplication detection is negative, then dystrophin gene sequencing should be done to look for point mutations or small deletions/insertions. (7)
Sequencing of the entire DMD gene to detect point mutations can be performed by traditional PCR and Sanger sequencing, or by more automated methods such as universal long PCR combined with massive pyrosequencing.
There is a lack of published studies in the peer-review literature that evaluate analytic validity. According to information from the website of a large reference laboratory, deletion/duplication analysis by CMA and point mutations by full gene sequencing detects 98-99% of mutations in both males and females. (15)
Certain types of assays may cause false-positive results if the method identifies an apparent single-exon deletion or duplication based on the absence or increased amplification, respectively, of a single PCR amplification, or hybridization; when this occurs, the result must be confirmed using an alternative assay. This different assay will verify whether the initial result could have been caused by a sequence variant preventing hybridization of a primer, probe, etc., or for duplications, if the result was an anomaly. Therefore, false positives are expected to be infrequent.
Clinical validity (refers to the diagnostic performance of the test—sensitivity, specificity, positive and negative predictive values)
Virtually all males with DMD/BMD have identifiable DMD mutations, indicating a high clinical sensitivity for genetic testing. In males with DMD and BMD, phenotypes are best correlated with the degree of expression of dystrophin, largely determined by the reading frame of the spliced message obtained from the deleted allele.
A reading frame is the way in which a messenger RNA sequence of nucleotides can be read as a series of base triplets, and affects which protein is made. In DMD, the function of the dystrophin protein is completely lost due to mutations that disrupt the reading frame. Therefore, prematurely truncated, unstable dystrophins are generated. In contrast, patients with BMD have low levels of full-length dystrophin or carry in-frame mutations that allow for the generation of partially functional proteins. This so-called reading frame rule explains the phenotypic differences between DMD and BMD patients. Since this rule was postulated in 1988, (16) thousands of mutations have been reported for DMD and BMD, of which an estimated 90% fit this rule. (17)
To establish the diagnosis of a proband with DMD or BMD in a male with clinical findings that suggest a dystrophinopathy:
- Perform DMD genetic testing for deletion/duplication analysis first.
- If a mutation is not identified, perform sequence analysis for a point mutation.
- If a disease-causing DMD mutation is identified, the diagnosis of a dystrophinopathy is established.
- In cases where a distinction between DMD and BMD is difficult, the reading frame “rule” states that the type of deletion/duplication (those that alter the reading frame [out-of-frame], which correlates with the more severe phenotype of DMD versus those that do not alter the reading frame [in-frame] which correlate with the milder BMD phenotype) can distinguish the DMD and BMD phenotypes with 91-92% accuracy.
- If no disease-causing DMD mutation is identified, skeletal muscle biopsy is warranted for western blot and immunohistochemistry studies of dystrophin.
For carrier testing in at-risk female relatives:
- When the proband’s DMD mutation is known, test for that deletion/duplication or point mutation using appropriate testing method.
- When an affected male is not available for testing, perform testing by deletion/duplication first and if no mutation is identified, by sequence analysis.
The evaluation of relatives at risk includes females who are the sisters or maternal female relatives of an affected male and females who are a first-degree relative of a known or possible carrier female.
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
The clinical utility of testing for DMD gene mutations for the index case includes:
- Establishing the diagnosis and initiating/directing treatment of the disease, such as glucocorticoids, evaluation by a cardiologist, avoidance of certain agents (e.g. botulinum toxin injections), and prevention of secondary complications (immunizations, reducing risk of fractures).
- Distinguishing between DMD and BMD.
- Avoidance of a muscle biopsy in the majority of cases.
The clinical utility of testing for DMD gene mutations for at-risk female relatives includes
- Testing to identify heterozygous females to confirm or exclude the need for cardiac surveillance.
- Preconception and /or prenatal testing in a woman considering offspring who would alter reproductive decision-making based on test results.
The analytic and clinical validity of genetic testing for DMD and BMD are high. DMD is the only gene in which mutations cause the dystrophinopathies, and molecular genetic testing can establish the diagnosis in most patients. Nearly all affected individuals will be found to have a DMD mutation, and false positives are expected to be rare.
The clinical utility of DMD gene testing can be established for the index case and for at-risk female relatives. For the index case, utility lies in confirmation of the diagnosis without a muscle biopsy, initiation of effective treatment, and in distinguishing between DMD and the less severe BMD. For at-risk female relatives, the test can confirm or exclude the need to undergo routine cardiac surveillance, and can indicate the likelihood of an affected offspring in women considering children.
Therefore, genetic testing for DMD gene mutations may be considered medically necessary to establish a diagnosis in a male with clinical signs and symptoms suggestive of a dystrophinopathy and as testing for at-risk female relatives.
Practice Guidelines and Position Statements
A meeting of 29 senior scientists from Europe, the US, India, and Australia established consensus Best Practice Guidelines for the molecular diagnosis of DMD/BMD. The recommendations for testing are, if there is a clinical suspicion of a dystrophinopathy, first screen for deletions and duplications. If no deletion or duplication is detected, but the clinical diagnosis is verified, screening for point mutations should be performed. (9)
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