SickKids researchers identify rare genetic variants linked to immune system regulation

Two weeks after she was born, Madelynn Schwartz and her family started a seven-month journey at The Hospital for Sick Children (SickKids) to find a diagnosis for an unknown illness that was already threatening her young life. Madelynn, now almost two years old, spent 91 days in hospital at SickKids with intermittent fevers, skin rashes, early onset inflammatory bowel disease and additional inflammation throughout her body. With many unanswered questions and having exhausted all other testing options, Madelynn underwent whole exome sequencing to investigate if a genetic mutation could be causing her illness.

Even after Dr. Aleixo Muise, one of Madelynn’s doctors and Staff Gastroenterologist at SickKids, analyzed her results, the search was far from over.

“Finding the answer to Madelynn’s mysterious illness was like searching for a needle in a genetic haystack,” says Muise, who is also a Senior Scientist in the Cell Biology program at SickKids.

Through ongoing conversations with Madelynn’s parents, her clinical team learned her father, Glen, also experienced many of the same issues as an infant. With this information, the SickKids team’s search could be narrowed, and Madelynn’s family and her doctors had an answer a month later – an incredibly rare mutation in the gene encoding spleen tyrosine kinase (SYK), a critical molecule for the immune system.

International group of researchers uncover rare genetic mutation affecting immune system activity

SickKids’ discovery of this novel genetic mutation became the focus of a study co-led by SickKids, Children’s Hospital of Fudan University, East China Normal University, University of Vienna and Oxford University. The international team of researchers, including labs in Hong Kong and Israel, used this new information to screen for additional genetic variations in SYK across many different patient registries and understand the role of these variants in the development of disease. In total, the team found six patients, including Madelynn and her father, who experienced similar clusters of symptoms linked to SYK variants.  

Published in Nature Genetics on March 29, 2021, the study concluded that the patients all shared a gain-of-function variant in the SYK gene – meaning that the genetic mutation was causing the gene to always be “on”.  

“SYK plays a complex role in a number of cellular processes in the human body including regulating major aspects of the immune system. The discovery of this variant is a significant step forward in both identifying and treating these rare diseases that have remained a mystery and challenged our ability to provide care,” says Muise, Co-Principal Investigator of the study.

After finding the variant, the researchers then set out to determine how exactly it impacted immune system processes and how it could be treated. To do this, Dr. Dali Li at East China Normal University developed a mouse model of the SYK variant to recreate the major aspects of the condition. The research team found that the variant caused enhanced activity that affected various immune responses associated with the SYK gene, leading to inflammation throughout the body. They also found that the SYK gene could be targeted with medication.

Using precision child health to find treatments for Madelynn

While her medical journey is still ongoing, this information has given Madelynn’s medical team more treatment options as they learn more about this rare illness. The first treatment for Madelynn targeted her B cells – the cells responsible for antibody-mediated immunity – and led to initial remission of her inflammation symptoms. The treatment’s effectiveness was short term, but armed with enhanced knowledge about her illness, Madelynn’s medical team is actively seeking alternative options for her.

“With this information and the ability to test therapies on an animal model in the lab, we can take a precision child health approach to treating patients like Madelynn by targeting specific pathways that will reduce or even eliminate their symptoms. As we learn more about this variant, we will be able to further investigate novel treatment options that can be tailored to each individual patient,” adds Muise, who is also a Professor in the Departments of Paediatrics, Biochemistry and Institute of Medical Sciences at the University of Toronto.

Not only has this discovery helped Madelynn, but it has also given answers to her father, Glen, who experienced health challenges of his own without a diagnosis for many years.

“This information probably saved his life and without it, he could have had serious health complications. Now, Glen is receiving more targeted and improved treatment from his own doctors,” notes Erin Nadler, Madelynn’s mom and Glen’s wife.

Erin adds, “These findings give our family hope that more people who didn’t know what they had will come forward. As more research is done on a broader group, we will have better understanding of this disease and hopefully, more treatment options for Madelynn as she grows older.”

This work was supported by the National Key R&D Program of China, JiuJiu Charitable Trust, German Research Foundation, Care-for-Rare Foundation, National Institute for Health Research Biomedical Research Centre, Crohn’s and Colitis Canada, Canadian Association of Gastroenterology, Canadian Institutes of Health Research, European Research Council, Germany's Excellence Strategy, ERA-Net E-Rare, German Ministry of Education, Wellcome Trust, The Leona M. and Harry B. Helmsley Charitable Trust, National Institutes of Health, Government of Canada and SickKids Foundation.