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Genetic Characteristics That Increase Risk of Developing TS

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  • Genetic Characteristics That Increase Risk of Developing TS

    Researchers unravel genetic characteristics that increase risk of developing Tourette syndrome
    New Medical Life Sciences
    August 10, 2017

    An international research team including Vasiliy Ramensky, a member of the Moscow Institute of Physics and Technology (MIPT) Life Sciences Center, has unraveled genetic characteristics that increase the risk of developing Tourette syndrome. Tourette's is a central nervous system disorder which is often inherited. The scientists compared the data of thousands of people with Tourette's and healthy people, and it turned out that in people with the condition there are significant modifications in two genes -- NRXN1 and CNTN6. The paper detailing their study was published in the journal Neuron.

    Why is Tourette's important?
    Tourette syndrome is characterized by motor and vocal tics, and it manifests itself in childhood. Patients often make uncontrolled movements and sounds (swear words in 10% of cases). The impulse to have a tic feels like growing tension which has to be released. It is very similar to the urge to sneeze. Tourette's is not a rare disease. It is found among 0.3-0.9% of the population, and the children of those who suffer Tourette's are 60 times more likely to have it as well. However, the syndrome can also appear in children with no family history of the syndrome. About 85% of patients suffering from Tourette's have co-occurring conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism spectrum disorders, anxiety, and depression. The fact that the mechanisms of these illnesses and Tourette syndrome converge means that Tourette's studies can shed light on the causes of other mental disorders.

    Are the genes to blame?...
    It is believed that Tourette syndrome is a developmental disorder of the brain and nervous system. This is partially proved by the fact that the symptoms start to appear in childhood and peak during adolescence. However, the exact causes are unknown. There is no doubt that the disorder is of a predominantly genetic nature, but the particular genes that increase the likelihood of developing Tourette's have not yet been identified. Candidate regions found in different research studies rarely coincide. This suggests that the condition is caused by combination of various genetic factors, in other words, it has complex genetic architecture.

    ...or their copies?
    Modern genetic studies focus on searching for point mutations and significant genetic rearrangements. Significant rearrangements in the genome, which are called copy number variation (CNV), can lead to deletion, gene fragment loss, or, on the contrary, to gene duplication with repeat chromosome regions. The number of gene copies in an individual genome affects the quantity of protein encoded by the gene: the more copies, the more protein. However, not all chromosome rearrangements affect vital gene segments and not all of them are related to diseases.

    What did the researchers do?
    The researchers studied the genetic data of 2434 people with Tourette syndrome and 4093 healthy people (the control group). The scientists cataloged all deletions and duplications in each genome and classified them according to frequency, length and whether they affect genes or not. It turned out that rare and long chromosome rearrangements affecting genes were found, on average, more often among the people with the disorder than among people from the control group. This suggests that these types of chromosome rearrangements, in particular, have clinical utility. The researchers then identified which genes suffer the most from these rearrangements. It was found that people with Tourette's frequently had significantly more deletions in the NRXN1 gene and duplications in the CNTN6 gene. Proteins encoded in these genes (neurexin 1 and contactin 6) are involved in the process of cell fusion in the nervous system.

    Deletions affecting NRXN1 have already been described in papers on other mental disorders, in particular, schizophrenia. The link between deletions in NRXN1 and Tourette syndrome has already been shown in earlier studies in a small sample of cases. It is now safe to say that this type of genome variation increases the risk of developing the condition. Duplications in CNTN6 were linked to Tourette's for the first time, though deletions affecting this gene have already been noticed in cases of autism spectrum disorders.

    Vasily Ramensky, a member of the Genome Engineering Lab of MIPT's Life Sciences Center, comments: "Gradually, step-by-step, we are gathering information about the genetic architecture of Tourette syndrome. In this paper, we have made an essential step in this direction, as it is now statistically proven which genomic changes in the genes discovered are linked to the predisposition to the condition. This gives the opportunity to provide better diagnoses. Our next step is to work out how such rearrangements in the found genes affect cell operation. Understanding these mechanisms will help in finding new therapies."

    Researchers find the genes responsible for motor and vocal tics in children Moscow Institute of Physics and Technology
    Last edited by aparente001; August 12, 2017, 12:26 PM. Reason: explained acronym at beginning
    TouretteLinks Forum

  • #2
    Re: Genetic Characteristics That Increase Risk of Developing TS

    Here is the original article:1-s2.0-S0896627317305081-main.pdf

    I don't have the scientific background to understand the article in detail, but I was able to follow some of the Discussion section, starting on page 1105, where they talk about future directions. For me, the take-away message was that for researchers to understand better the genetic component of TS, studies are needed that analyze a much, much larger set of DNA samples than was used in this particular work.

    Unfortunately, I don't think I personally can help with that. When I was at a Tourette event in New Jersey, the Rutgers researchers were there, collecting samples from families who agreed to contribute blood samples, but I was told that as the adoptive parent of a child with Tourette, our samples don't fit the requirements of this type of study.


    • #3
      Re: Genetic Characteristics That Increase Risk of Developing TS


      Dear Families and Friends,

      NJCTS has received many calls and emails from families and professionals asking for clarification on the two recent Tourette Syndrome Breakthrough research announcements, one on May 3 and the other on June 21. They are indeed different findings from two different groups of researchers. These are exciting breakthroughs in that each of the research groups has identified mutations in several different genes that cause Tourette Syndrome. We reached out to our research experts for their perspective on these recent findings and have included it below. We hope you find this information useful. NJCTS will continue to provide "perspectives" on research and all things related to TS as they occur.

      Best wishes,

      Faith Rice
      Executive Director, NJ Center for Tourette Syndrome and Associated Disorders, Inc.


      While research has consistently demonstrated a significant genetic contribution, the role of genes in Tourette Syndrome, or Tourette Disorder (TD) as it is referred to here, is not well understood. Furthermore, progress in finding TD genes has been slow relative to other neuropsychiatric disorders such as autism, mainly due to less research funding. However, two recent articles show significant progress in understanding the genetic causes of TD. We'll briefly summarize their results and implications for individuals with TD and their families.

      On May 3rd 2017, Willsey and colleagues[1] published an article in the scientific journal Neuron describing DNA sequencing of the portion of the genome that encodes proteins in children with TD and their parents. They purposely selected "simplex" families in which the child had TD and the parents did not. They were trying to find new genetic mutations that are not inherited from parents, but rather occur spontaneously in a particular egg or sperm or at conception. While TD is often inherited as a consequence of pre-existing mutant genes, in some cases it might result from newly mutated genes. These newly mutated genes provide a window into unraveling the brain pathways involved in TD. The results of this study showed that the rate of new, damaging mutations was higher in children with TD than in children without TD. They also found four damaged genes (WWC1, CELSR3, NIPBL, and FN1) in multiple unrelated families that likely cause TD in these patients. These data show genetic pathways disrupted in TD and the authors calculated that approximately 12 percent of TD cases involve new mutations in any one of about 400 different risk genes. This study included a main set of families collected by the Tourette International Collaborative Genetics Study (TIC Genetics) and a replication sample from the Tourette Association of America (TAA) International Consortium for Genetics (TSAICG). TIC Genetics is a collaboration between Rutgers University, the University of California San Francisco and other universities in the US and throughout the world and it has been supported by grants from the New Jersey Center for Tourette Syndrome (NJCTS) and a grant from the National Institute of Health's (NIH) National Institute of Mental Health.

      Afterwards, on June 21st 2017, Huang and colleagues[2] published an article in Neuron describing a different kind of mutation in TD. Instead of single gene DNA mutation as in the previous study, they looked for DNA structural variants. Structural variants involve deletions or duplications of relatively large sections of DNA - and are called copy number variants (CNVs). In this second study they found a higher occurrence of CNVs in TD cases compared to controls. They also observed two genes, NRXN1 and CNTN6, to be frequent within CNVs. Three previous studies [3-5] also found CNVs in NRXN1 and both NRXN1 and CNTN6 have been previously associated with Autism Spectrum Disorders, another neurodevelopmental disorder. Data from this study included individuals collected by TSAICG and the Gilles de la Tourette Syndrome GWAS Replication Initiative (GGR) and funding from TAA and NIH.

      Perspectives: Taken together, these two studies show that TD is not a single gene disorder like sickle cell anemia or cystic fibrosis. Instead, TD is the result of mutations in different genes that result in similar symptoms. This means that the cause of TD in one family is likely to be different from the cause in another family. So, testing individuals to determine if they have a TD risk mutation will be complicated. However, these many genetic factors likely work within a smaller number of biological pathways in the brain. The next step is to find more of these TD risk genes and determine how they interact in biological pathways during brain development and within the adult brain. Once such TD pathways are identified, it may be possible to develop drugs that correct the malfunctioning pathways, thus alleviating symptoms. These discoveries are made possible by the participation of TD families and funding from the federal government (NIH), NJCTS, TAA and other organizations.

      Gary Heiman, Ph.D., Associate Professor of Genetics, Rutgers University
      Jay A. Tischfield, Ph.D., Distinguished Professor of Genetics, Rutgers University

      1. Willsey, A.J., et al., De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron, 2017. 94(3): p. 486-499.e9.
      2. Huang, A.Y., et al., Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron, 2017. 94(6): p. 1101-1111.e7.
      3. Fernandez, T.V., et al., Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry, 2012. 71(5): p. 392-402.
      4. Nag, A., et al., CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. PLoS One, 2013. 8(3): p. e59061.
      5. Sundaram, S.K., et al., Tourette syndrome is associated with recurrent exonic copy number variants. Neurology, 2010. 74(20): p. 1583-90.