Is it time for genetic modifiers to predict prognosis in Duchenne muscular dystrophy?

Patients with Duchenne muscular dystrophy (DMD) show clinically relevant phenotypic variability, despite sharing the same primary biochemical defect (dystrophin deficiency). Recently, a series of genetic modifiers have been identified, mostly involving genes and proteins that regulate inflammation and fibrosis — processes increasingly recognized as being causally linked with physical disability. This article reviews genetic modifier studies in DMD to date. It discusses the effect of genetic modifiers on predicting disease trajectories (prognosis), clinical trial design and interpretation (inclusion of genotype-stratified subgroup analyses) and therapeutic approaches. The genetic modifiers identified to date underscore the importance of progressive fibrosis, downstream of dystrophin deficiency, in driving the disease process.