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Whole Genome Analysis Solves Medical Mystery in One Family, Comes Nearer to Routine Use

For release: Thursday, March 11, 2010

A DNA helix.  Courtesy of NIH's National Human Genome Research Institute.

For the first time, researchers have used whole genome sequencing to achieve a molecular diagnosis in a family with a genetic disorder.  The results suggest that in the near future, genome sequencing could become a routine part of medical care, both to diagnose rare disorders and help estimate the risk of common disorders.

The effort was led by investigators at Baylor College of Medicine Houston, Texas – James R. Lupski, M.D., Ph.D., a professor in the Department of Molecular and Human Genetics, and Richard A. Gibbs, Ph.D., director of Baylor’s Human Genome Sequencing Center.

Dr. Lupski has a nerve disorder, Charcot-Marie-Tooth disease (CMT), and the researchers scanned his genome – his complete set of genes – to identify the basis of his CMT.   They found that Dr. Lupski and three other affected members of his family carried mutations in a gene previously linked to the CMT, called SH3TC2.

The study is reported in the New England Journal of Medicine*, and was funded by the National Institute of the Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health.  In 2009 and 2010, a NINDS grant supporting the continuation of Dr. Lupski’s work was funded through the American Recovery and Reinvestment Act (ARRA).

"Without the support of the stimulus money, it would be impossible for U.S. labs to continue to be among the world leaders in scientific research and innovation in genomics and genetics," Dr. Lupski said.

Dr. Lupski received a clinical diagnosis of CMT about 40 years ago.  He became a productive researcher in the field of CMT and other nerve disorders (or neuropathies), and has published more than 100 papers related to this work.

CMT runs in families, and affects the peripheral nerves that control the body’s muscles and relay sensations to the brain.  The most common symptoms are muscle weakness and wasting in the feet and hands.

CMT has been linked to mutations in more than 31 genes, with a single gene mutation typically causing a unique variant of the disorder.  The SH3TC2 gene, at the root of Dr. Lupski’s form of CMT, is known to be active in Schwann cells, which form a protective sheath (myelin) around nerve fibers (axons).  Dr. Lupski and his siblings have a demyelinating form of CMT, and all turned out to have two mutations in SH3TC2 (one mutation each from their mother and father).  For other family members, having one of those mutations was associated with signs of axon damage; the other mutation was associated with subclinical signs of carpal tunnel syndrome, which usually involves compression of a nerve in the wrist.

Besides providing a genetic diagnosis, the findings offer a window into the biology of Schwann cells.  The fact that mutations in the SH3TC2 gene can lead to axon damage points to complex interactions between Schwann cells and axons.

“This study is an impressive use of next generation genome sequencing technology to probe the underlying causes of CMT.  It also provides proof of concept for using whole genome analysis to inform the diagnosis and potentially the care of patients with a variety of disorders,” said NINDS director Story Landis, Ph.D.

The sequencing effort was done at a remarkably low cost.  When the NHGRI-funded Human Genome Project began, the cost of sequencing less than 0.1 percent of the genome was about $100,000.  Drs. Lupski and Gibbs estimate that repeating their study today would cost less than $50,000.  Eventually, researchers hope to reduce the cost of genome sequencing technology down to $1000 or less, which could bring it into routine medical practice.

The study “provide[s] a glimpse of the future for which we need to prepare,” according to an accompanying commentary by Richard P. Lifton, M.D., Ph.D., of the Department of Genetics at Yale University in New Haven, Conn.

- By Daniel Stimson, Ph.D.


NINDS ( is the nation’s leading funder of research on the brain and nervous system.  The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.

NHGRI ( develops and implements technology to understand, diagnose and treat genomic and genetic diseases through its Division of Intramural Research.  The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

*Lupski JR et al. “Whole-genome sequencing in a patient with Charcot-Marie-Tooth Neuropathy.” New England Journal of Medicine, March 10, 2010.

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Last Modified June 24, 2010