Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder that affects approximately 1:3500 to 1:5200 live male births caused by mutations in the X-linked DMD gene. DMD gene mutations result in absence of the dystrophin protein in muscle fibers, leading to myofiber necrosis, endomysial fibrosis, and fat replacement. It is a devastating disorder, leading to loss of ambulation by age 12, and historically to death by age 20. The psychological and socioeconomic effects on families are enormous;these include but are not limited to the costs of medical care, opportunity costs for career and work, and the psychological toll taken on parents and siblings. Our long-term goal is to understand which genes modify disease progression and severity of DMD. Confirming a hypothesis derived from a genetic modifier of muscular dystrophies in mice, we have recently used data from patients enrolled in the United Dystrophinopathy Project (UDP) to demonstrate that polymorphisms in the LTBP4 gene influence age at loss of ambulation. Our objective in this project is to identify additional genetic modifiers of skeletal muscle, cardiac, and ventilatory function, and our central hypothesis is that such modifiers can be identified by use of the UDP database, a unique resource that contains detailed phenotypic data and archived DNA samples from over 900 DMD patients.
Our specific aims are to 1) update and analyze phenotypic data within the UDP cohort, 2) map modifier traits by high-density single nucleotide polymorphism arrays, 3) perform exome sequencing of individuals with extreme outlier phenotypes, and 4) validate newly identified putative genetic modifiers.
These aims will be achieved by the combined expertise and efforts from a consortium of researchers at Nationwide Children's Hospital, the University of Utah and UCLA. Collaborators for validating putative modifier genes include investigators at the University of Chicago who have pioneered modifier gene discovery in dystrophic mouse models, and two collaborating networks of investigators in the US and Europe, who have additional natural history cohorts of DMD patients. At the conclusion of these Aims, we will have gained new information about modifier genes associated with the severity and progression of DMD.
The psychological and socioeconomic effects of DMD on families are enormous. These include medical care costs, opportunity costs for career and work, and the psychological toll taken on parents and siblings. The identification of genetic modifiers of DMD will allow for patient stratification in upcoming clinical trials of novel therapies, may reveal novel targets for potential therapies, and may allow patient- specific tailoring of current therapies.