Genetic coding
The research team made its discovery by uncovering variations in the genetic coding of individuals with Tourette syndrome
Jeremiah Scharf, MD, PhD

Jeremiah Scharf, MD, PhD

A team effort between genetic researchers, clinicians, a patient advocacy group and volunteer study participants has revealed new genetic insights into Tourette syndrome—a neuropsychiatric disorder that results in involuntary physical and verbal tics.

The study helps to confirm the theory that Tourette syndrome results from a complex series of genetic changes rather than a single mutated gene. It may also provide comfort for individuals with the disorder, who are often stigmatized for their uncontrollable movements and outbursts.

 “I think the challenge with neuropsychiatric disorders is that people misunderstand them. They assume somehow that the mind is different from the brain, and therefore there is an inappropriate stigma associated with them,” explains Jeremiah Scharf, MD, PhD, a behavioral neurologist and geneticist in the Center for Genomic Medicine (CGM) at Massachusetts General Hospital.

Dr. Scharf is the co-corresponding author of a study in the June edition of Neuron that identifies alterations in two genes that significantly increase an individual’s risk of developing Tourette syndrome. The other co-corresponding author is Giovanni Coppola, MD of UCLA, along with co-senior authors Carol Mathews, MD of the University of Florida and Peristera Paschou, PhD, from Purdue University.

The study compared the genomes of 2,400 individuals with Tourette syndrome against 4,100 healthy control subjects. The results revealed the first two recurrent alterations in the genome are definitively associated with the disorder.

The first alteration the team discovered was an increase in copy number deletions in the NRXN1 gene. The second was an increase in copy number duplications in the CNTN6 gene. Both changes were independently associated with an increased risk of developing the disorder.

Copy number variations—such as deletions and duplications—occur when portions of the DNA sequence in an individual’s genetic code is eliminated or repeated, which can change the way genes function.

In the long term, these discoveries could prove to be the first step in unlocking the genetic mechanisms of Tourette syndrome. In the short term, the discoveries will help to reassure individuals with Tourette syndrome that their symptoms have a biological basis.

“We’re going to help people every day with this,” says Dr. Scharf, who is also co-director of the Tourette Association of America Center of Excellence at Mass General. “Even without effective treatments, just being able to tell patients that we understand what’s going on—that it is biological—will help kids have as healthy a childhood and adolescence as they can.”

Symptoms of Tourette syndrome typically emerge in children between the ages of 5-9 years, and tend to increase in severity between the ages of 10-14.  Tics can include involuntary blinking, grimacing, head bobbing, arm or leg jerking, grunting, hooting or shouting. In limited cases, verbal tics can include outbursts of profanity or other inappropriate language, though advocates say the frequency of those symptoms is exaggerated by fictional portrayals in TV and movies.

Most affected individuals start to show improvement in late adolescence, but some have persistent, severe tics into adulthood. In either case, the disorder can create a significant amount of stress and distress for patients and their families.

While the initial results are promising, it may be possible to learn more by digging deeper into the data, Scharf says. “We can now do more specific sequencing to see where the (DNA) break points are and where they disrupt the genes, which could tell us which parts of the genes are most important.” Those insights could lead to laboratory models that could help researchers understand the impact of the genetic alterations.

Another potential next step would be comparing individuals with Tourette syndrome to their unaffected parents to see which genetic variations were inherited and which arose spontaneously during reproduction. “When you have something occur spontaneously, you need a lower threshold to prove its significance,” Scharf explains.

The study was supported through a unique partnership between the research team and the Tourette Association of America (TAA), which provided financial backing in conjunction with the NIH, and helped to connect individuals with Tourette syndrome who were interested in participating in genetic research.

Scharf hopes that the results will demonstrate that the TAA’s investment has paid off. He is also optimistic that further research could provide insights into the progression and severity of the disease in different individuals, which could help guide decisions regarding care and treatment.

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