Dystrophinopathy via the DMD Gene

The dystrophinopathies include Duchenne muscular dystrophy (DMD, OMIM 310200), Becker muscular dystrophy (BMD, OMIM 300376), and dilated cardiomyopathy, type 3B (CMD3B, OMIM 302045).

Duchenne muscular dystrophy is the most common form of congenital muscular dystrophy in all ethnic groups. DMD presents in affected boys in early childhood with difficulty walking and climbing stairs, progressive proximal weakness, pseudohypertrophy of the calves, and greatly elevated serum creatine phosphokinase (CK) levels (Darras et al. 2011). Patients become wheelchair dependent by age 13. Dilated cardiomyopathy and congestive heart failure occur in nearly all patients by their late teens or early 20s. DMD muscle biopsies show a dystrophic process with fibrosis and fatty infiltration. Dystrophin protein content in DMD patients is less than 5% of controls when measured by Western blot or immunohistochemistry (Hoffman et al. 1988).

Becker muscular dystrophy is a relatively mild form of dystrophinopthy with later onset of proximal weakness and preservation of ambulation into the third decade of life. The minimum age for wheelchair dependency in BMD is age 16. As in DMD, cardiomyopathy is a significant cause of morbidity, however, serum CK levels are less elevated than in DMD (Zatz et al. 1991). Dystrophin protein content in BMD patients varies from 20% of control levels to normal levels when measured by Western blot or immunohistochemistry (Hoffman et al. 1988).

Both DMD and BMD can be associated with intellectual deficits, specifically involving working memory and executive function (Darras et al. 2011).

DMD-related cardiomyopathy in the absence of skeletal muscle disease is a less common form of dystrophinopathy which presents in affected males between 20 and 40 years of age and later in carrier females (Beggs 1997). In some mild BMD patients, cardiomyopathy can be the presenting feature (Towbin 1998).

Females who are heterozygous for a DMD causative mutation are at risk for dilated cardiomyopathy and 70% have slightly elevated CK (Schade van Westrum et al. 2011). Carriers may also present with a myopathy resembling limb-girdle muscular dystrophy (Moser and Emery 1974).

The dystrophinopathies are inherited as X-linked recessive disorders, and approximately one-third of mothers who have a son with dystrophinopathy have no family history. Heterozygous female carriers are at increased risk for dilated cardiomyopathy. The extent of skeletal muscle involvement in carriers is dependent upon the level of skewed X-chromosome inactivation.

The DMD gene is located at Xp21 and occupies about 1.5% of the entire X chromosome. Approximately two-thirds of the mutations in DMD patients are deletions of one or more exons in the DMD gene. The occurrence of deletions is slightly higher in BMD patients. Duplications are found in approximately 10% of DMD patients and 20% of BMD patients. In general, in-frame deletions, which preserve partial functional dystrophin protein, are correlated with a milder (BMD) clinical phenotype (Monaco et al. 1988; Aartsma-Rus et al. 2006).

Mutations detectable by sequence analysis are found in approximately one-third of DMD cases and in approximately 20% of BMD cases. In DMD cases, the vast majority of these mutations result in premature protein termination whereas missense mutations are rare (http://www.LOVD.nl/DMD).

DMD (OMIM 300377) encodes dystrophin, a large structural protein that binds sarcoplasmic actin at its amino end and beta dystroglycan at its carboxyl end, thus bridging the cytoskeleton to the dystroglycan-associated glycoprotein complex at the sarcolemma (Barresi and Campbell 2006).

Mutations detectable by sequence analysis are found in approximately one-third of DMD cases and in approximately 20% of BMD cases. In DMD cases, the vast majority of these mutations result in premature protein termination whereas missense mutations are rare (http://www.LOVD.nl/DMD).

Approximately two-thirds of the mutations in DMD patients are deletions of one or more exons in the DMD gene. The occurrence of deletions is slightly higher in BMD patients. Duplications are found in approximately 10% of DMD patients and 20% of BMD patients. In general, in-frame deletions, which preserve partial functional dystrophin protein, are correlated with a milder (BMD) clinical phenotype (Monaco et al. 1988; Aartsma-Rus et al. 2006).

This test provides full coverage of all coding exons of the DMD gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.