Identification and characterization of genome variants associated with Gilles de la Tourette syndrome

Project implemented as part of a scientific consortium. The project leader is Mirosław Mossakowski Institute of Experimental and Clinical Medicine of the Polish Academy of Sciences and the Partner - the Medical University of Warsaw, 1st Faculty of Medicine. Gilles de la Tourette Syndrome (GTS) is a neuropsychiatric disorder of children and adults of unknown cause whose main symptoms are tics and mental disorders. The severity of tics decreases after the age of 15. Only 1/5 of people have tics persistently severe in adulthood. The cause of tics recovery in some people is unknown. There is currently no diagnostic test to confirm a clinical diagnosis of GTS. Genetic factors play a major role in the pathogenesis of the disease. Autism is an early childhood developmental disorder that causes disturbances in social functioning, speech disorders, and movement stereotypes. Some patients with GTS have autistic features, and both diseases show common symptoms. The biological basis for autism is not established. The aim of the study is to determine the genetic basis of the disease in three selected groups: 1. in families with GTS with a very clear family history of the disease; 2. in families where GTS and autism occur in closely related people; and 3. in adults with GTS and severe tics (which may indicate the presence of an additional genetic factor). In the research, we plan to use the whole genome sequencing (WGS) method that has not been used so far in the study of GTS substrate, thanks to which in the obtained raw sequencing results it will be possible to search for DNA copy number variants (CNV), regions of heterozygosity loss ( loss of heterozygosity (LOH), rare genetic variants (mutations) and identification of causative mutations by using the latest bioinformatics algorithms, comparing the genome sequences of healthy and sick family members and patients with different clinical phenotypes of GTS (including severe adult GTS vs mild form in children). Three groups will be used in the research: 1. eight families, in each of which there are at least 5 people diagnosed with GTS or other tics (40 people from each family will be tested: 3 sick people + 2 healthy people, most often parents); 2. four families with coexistence of GTS and autism (20 people will be tested: 4 people with GTS, 4 people with autism and 12 healthy family members); and 3rd group of adult patients with GTS and severe tics (30 people). The total study group will include 90 people. As the population of children with GTS in Poland amounts to 60,000 people, and adults - about 3,500 people, the size of the study groups is representative and gives a chance to determine the genetic basis of the disease, especially as groups 1 and 2 relate to family forms, and group 3 - severe forms GTS. In the research, we plan to use the whole genome sequencing (WGS) method that has not been used so far in GTS research. Both the copy number variants (CNV) and point changes of the DNA sequence will be searched for in the obtained raw genome readings. The obtained list of variants will be subject to further, in-depth bioinformatics analysis using the latest algorithms and available tools. The analysis will aim to identify potential causative variants, especially those that may affect the structure of protein products. The bioinformatic analysis will each time include a comparison of the genomes of sick and healthy people within the family, sick people between families and sick people with sequences stored in public databases. The analysis will additionally use the database of the sequence of the entire exome> 100 people from the Polish population that we had prepared as part of another project. Selected genomic variants will be confirmed by the Sangerian sequencing method or MLPA (Multiplex Ligation-dependent Probe Amplification), and their occurrence will be checked as broadly as possible in proband families. The project is the first attempt in Poland to understand the genetic basis of GTS and to establish possible relationships between the genotype and the clinical phenotype of the disease. The uniqueness of the study lies in the use of a modern method of whole genome sequencing (WGS) and advanced bioinformatics methods using data obtained from ethnically homogeneous and fully clinically described groups of patients and healthy people. One study will look at both broad genome rearrangements and point changes in DNA sequences, and in particular causative mutations. We expect that the project will lead to the identification of new genes and/or loci related to GTS, determination of common genes / loci for neuropsychiatric diseases such as autism and GTS, determination of the genetic basis determining the variable course of GTS, identification of biochemical and/or signaling pathways at the level of cellularity, and will also enable the determination of genomic markers of the disease and, in the future, the development of new methods of GTS treatment.