McMaster researchers pinpoint genes causing complex brain disorders

Karun Singh

McMaster University Scientists have published 2 studies identifying which gene is responsible for causing brain development disorders when several genes are deleted in an individual’s genome, providing a path forward for developing new therapies.

In Ontario, there are more than 300,000 children and youth affected by a neurodevelopmental disorder such as autism spectrum disorders, attention deficit hyperactivity disorder, and intellectual disability. These disorders typically cause long-term problems and impact the day-to-day life of affected individuals and families. There are no specific treatments, and medications have side-effects that can be severe in children and young adults.

Many neurodevelopmental disorders are caused by large missing pieces of genetic material in a person’s genome that contain several genes, termed a ‘microdeletion’. Accurately diagnosing a gene microdeletion helps doctors to predict patient outcome and to determine if a novel treatment is available. However, for microdeletions associated with brain disorders, it is currently unknown which gene is causing the neurological symptoms. Identifying this critical gene is essential for developing targeted treatments.

In new research led by Karun Singh from McMaster’s Stem Cell and Cancer Research Institute (SCCRI) in collaboration with Dr. Stephen Scherer team from the Hospital for Sick Children, the team discovered the gene likely responsible for two brain disorders.

“Our studies reveal that in complex brain disorders that have a loss of many genes, a single deleted gene is sufficient to cause the patients symptoms,” says Karun Singh. “This is exciting because it focuses our research effort on the individual gene, saving us time and money, which will speed up the development of a targeted therapeutics to this gene alone.”

The team has now reported 2 studies in the scientific journals Molecular Psychiatry and the American Journal of Human Genetics. The researchers used genetically engineered models and computer algorithms to study the human genome, which allowed them to pinpoint the single disease-causing gene. This led to the identification of a gene called OTUD7A, as the gene responsible for the 15q13.3 microdeletion syndrome, and the gene TAOK2 was identified as a critical gene in the 16p11.2 microdeletion syndrome. Importantly, the work indicates that a drug able to control TAOK2 could lead to a specific treatment for the 16p11.2 microdeletion disorder where none is available, providing hope for the estimated 10,000-14,000 individuals affected by it in Canada.

Beyond these studies, the unique process used by the team has broad clinical application for other brain disorders. Singh and Scherer are now positioned to use the same successful approach to solve the genetic mystery for other brain disorders that are routinely identified in the clinic.

Singh says “our ultimate goal is to this use this strategy to develop new therapeutics for individuals to overcome symptoms and become more independent”. To enable this to patient impact, the researchers are turning to stem cell technology developed at the SCCRI that allows the conversion of patient blood into brains cells in the laboratory. With the patient’s own brain cells in a dish, Singh and his team can test specific drugs that are customized to the patient’s condition to find ones that restore normal neurological function. This demonstrated approach is also part of a larger Ontario network of scientists and clinicians working with Singh and his team, that is set up to take candidate drugs from the stem cell studies into pilot clinical trials, providing hope to treat these complex disorders.

The research was funded by the Canadian Institutes of Health Research, Ontario Brain Institute, Autism Speaks, Brain Canada, Brain and Behavioral Research Foundation and the Natural Science and Engineering Research Council.

Source of text:

McMaster University

Original Research Papers:

Richter, M. #, Murtaza, N. #, White, S., Scharrenberg, R., White, S.H., Jahanns, O., Walker, S., Yuen, R.K., Schwanke, B., Beturftif, B., Henis, M., Schart, S., Kraus, V., Dork, R., Hellmann, J., Lindenmaier, Z., Ellegood, J., Hartung, H., Kwan, V., Sedlacik, J., Fiehler, J., Schweizer, M., Lerch, J.P., Hanganu-Opatz, I.L., Morellini, F., Scherer, S.W.*, Singh, K.K.*, and De Anda, F.C.* (2018). Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Molecular Psychiatry (NPG). February 21, 2018. doi:10.1038/s41380-018-0025-5

Uddin, M. †, Unda, B.K. †, White, S., Woodbury-Smith, M., Pellecchia, G., D’Abate, L., Nalpathamkalam, T., Lamoureux, S., Wei, J., Speevak, M., Stavropoulos, J., Scherer, S.W.* and Singh, K.K.* (2018). OTUD7A contributes to neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome. American Journal of Human Genetics (Cell Press) 102, 278-295.  doi: