Duchenne muscular dystrophy, usually shortened to DMD, sits at the severe end of a group of related conditions called the dystrophinopathies, a spectrum of muscle disease that ranges from an isolated blood marker of muscle breakdown with no other symptoms, all the way through Becker muscular dystrophy, DMD, and a form that mainly affects the heart, known as DMD-associated dilated cardiomyopathy. All of these conditions are caused by changes, called pathogenic variants, in a single gene, DMD, which sits on the X chromosome and is one of the largest genes in the human genome. It provides instructions for a protein called dystrophin, which sits just beneath the outer membrane of muscle cells and links the internal skeleton of the cell to structural proteins outside it, stabilizing the membrane during the repeated stretching and contracting of muscle activity.

Whether a genetic change in DMD produces the severe Duchenne phenotype or the milder Becker phenotype generally comes down to whether the change disrupts what is called the reading frame, the sequence in which genetic instructions are read three letters at a time to build a protein. Changes that throw off the reading frame usually prevent any usable dystrophin from being made at all, leading to the more severe, rapidly progressive Duchenne presentation. Changes that preserve the reading frame usually still allow a shortened but partially working dystrophin protein to be produced, which generally leads to the later-onset, more slowly progressive Becker presentation. This general pattern, called the reading frame rule, predicts the phenotype correctly in the large majority of cases, though exceptions occur, so genetic findings are always interpreted together with the clinical picture.

Because the gene lies on the X chromosome, the condition follows an X-linked pattern, and it is males, who carry only one X chromosome, who are almost always affected with the full clinical picture. About two-thirds of pathogenic changes in the gene are deletions removing one or more of its many building blocks, called exons, with smaller genetic changes and duplications accounting for the remainder.