International Research Team Finds Two Genetic Flaws Behind Third Most Common Form of Inherited Muscular Dystrophy

The team, co-led by Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division, discovered that a rare variant of FSHD, called type 2, which accounts for about 5 percent of cases, is caused by two genetic mutations that together cause the production of muscle-damaging toxins responsible for causing symptoms of this progressive muscle disease.

Specifically, the researchers found that a combination of genetic variants on chromosomes 4 (called DUX4) and 18 (called SMCHD1) can cause type 2 FSHD. The DUX4 variant was first described by the research team in 2010 as a mechanism behind the more common, type 1, version of the disease.

“Many diseases caused by a single gene mutation have been identified during the last several decades, but it has been more difficult to identify the genetic basis of diseases that are caused by the intersection of multiple genetic flaws,” Tapscott said. “Recent advances in DNA sequencing made this study possible and it is likely that other diseases caused by the inheritance of multiple genetic variants will be identified in the coming years.”

Understanding the genetic mechanisms of type 2 FSHD could lead to new biomarker-based tests for diagnosing the disease and could lead to the development of future treatments, Tapscott said.

FSHD affects about half a million people worldwide. Symptoms usually first appear around age 20 and are characterized by a progressive, gradual loss of muscle strength, particularly in the upper body.

In addition to Tapscott and other Hutchinson Center researchers, other key members of the research team included Daniel G. Miller, M.D., Ph.D., an associate professor of pediatrics at the University of Washington; Rabi N. Tawil, M.D., a professor of neurology at the University of Rochester Medical Center; and Silvère van der Maarel, Ph.D., a professor of medical epigenetics at Leiden University Medical Center in The Netherlands; plus investigators from Raboud University Nijmegen Medical Centre in The Netherlands and Nice University Hospital in France.

Funding for the research came from multiple institutions at the National Institutes of Health (National Institute of Neurological Disorders and Stroke, Clinical and Translational Science Awards Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Human Genome Research Institute and the National Genetics Institute), Friends of FSH Research, the Muscular Dystrophy Association, and the University of Rochester Medical Center Fields Center for FSHD and Neuromuscular Research.

Editor’s note: To obtain an embargoed copy of the Nature Genetics paper, “Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2,” please contact press@nature.com. Once the paper is published electronically, the abstract (available to everyone) and full text (available only to subscribers) can be retrieved by visiting http://dx.doi.org/10.1038/ng.2454

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