This test is for the dystrophinopathies, a spectrum of muscle diseases that are caused by pathogenic variants in the DMD gene. The DMD gene is associated with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and dilated cardiomyopathy (CMD3B).
The dystrophinopathies are similar to other muscular dystrophies in terms of age of onset and clinical presentation. Diagnostic genetic testing may obviate the need for a muscle biopsy. Identification of the underlying genetic cause may direct medical treatment, predict outcome for the patient, or clarify recurrence risk. Identification of the specific DMD pathogenic variant may also be a requirement for enrollment in clinical trials.
DMD can also be ordered as part of broader panels to test for cardiomyopathy disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Duchenne muscular dystrophy (DMD) is characterized by childhood onset, progressive proximal muscle wasting and weakness, delayed milestones, pseudohypertrophy of the calves, and elevated serum creatine kinase levels. Usually, only males are affected, although in some cases females may be affected. Becker muscular dystrophy (BMD) is a less clinically severe muscular dystrophy, characterized by later-onset skeletal muscle weakness. Despite a milder skeletal muscle involvement in BMD patients, heart failure from dilated cardiomyopathy is a common cause of morbidity. Some genotype-phenotype correlation is possible, as the majority of pathogenic variants causing DMD are truncating, whereas pathogenic variants causing BMD are usually in-frame, leading to residual DMD function. Both DMD and BMD patients are affected by cardiomyopathy. DMD-related dilated cardiomyopathy can occur in female carriers of DMD and in some cases can be the presenting finding in male individuals who have BMD and little or no evidence of skeletal muscle disease.
The gene DMD is the only known cause of Duchenne and Becker muscular dystrophies. Test sensitivity is high when quantitative analysis and gene sequencing are combined. This test includes both full-gene sequencing and deletion/duplication analysis of the DMD gene.
For DMD patients:
For BMD patients:
Relative contribution to dilated cardiomyopathy by DMD is unknown, but it is likely less than 1% of all cases of DCM.
The dystrophinopathies are inherited as X-linked recessive disorders. Female carriers are typically unaffected, although skewed X inactivation can result in symptoms.
Dystrophinopathies are fully penetrant disorders in males. Onset of symptoms in DMD typically occurs before age 5 and individuals usually lose their ability to walk independently during early adolescence. Individuals with BMD typically have a later onset of disease and greater variability in terms of the age at which assistance with walking will be required. Female carriers may also be affected,though symptoms are generally less severe than in affected males. Female carriers can present with symptoms from early childhood through adulthood and may depend in part on patterns of X-chromosome inactivation.
Approximately 1 in 3,000 to 1 in 5,000 newborn males will be affected with DMD. BMD is much less common (approximately 1 in 20,000 male births). DMD-related dilated cardiomyopathy in the absence of skeletal muscle disease is very rare; dilated cardiomyopathy, however, is a near-universal finding in males with DMD.
A diagnosis of DMD typically occurs around 5 years of age, but DMD may be suspected much earlier due to delays in the achievement of developmental milestones. Initial symptoms can include delayed walking, frequent falls, difficulty running, and difficulty climbing stairs. The presence of the Gower’s sign in a male child should trigger the diagnostic investigation of DMD. In the following scenarios, DMD should be considered, irrespective of family history:
For management recommendations, please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
DMD: Analysis guarantees del/dup detection at single-exon resolution.