Going ‘outside the box’ to explain different symptoms in people with the same DNA deletion syndrome

Even when genetic conditions can be clearly traced to a root cause in the DNA, how those conditions present in different individuals can vary widely. This is certainly the case for 22q11.2 deletion syndrome (22q11DS). This multisystem disorder results from a missing segment of DNA on one copy of chromosome 22 including approximately 45 genes (a copy number variant, or CNV). The disorder is often described as “rare”, but in fact, occurs in up to 1/3,000 births making it the most common CNV syndrome observed worldwide. People with 22q11DS are all at increased risk to develop intellectual disability and schizophrenia. Yet some are severely affected while others have much milder symptoms. A team of investigators from the International 22q11.2 Deletion Syndrome Brain Behavior Consortium (IBBC), led by The Hospital for Sick Children (SickKids), discovered they needed to look outside the genetic root cause of the disorder to find out why. 

Genome-wide data could explain the difference 

In a new study published in Nature Medicine on November 9, 2020, the team co-led by Dr. Jacob Vorstman, Child and Adolescent Psychiatrist and Clinical Scientist in the Genetics & Genome Biology Program at SickKids, found they could predict who would be at higher risk for developing intellectual disability or schizophrenia by using the information hidden in other parts of the genome. To do this, they used a novel analytical tool called polygenic risk scores, which summarize the cumulative effect of thousands of small common genetic variations. 

“Everyone’s genomes have their own unique variations. Some are high-impact, such as a 22q11.2 deletion, but more commonly these variants confer little to no risk of developing a disease when looked at individually,” says Vorstman, who also holds the SickKids Psychiatry Associates Chair in Developmental Psychopathology and is an Associate Professor in the Department of Psychiatry at the University of Toronto. “Using genome-wide data, we can combine information from many common genetic variants to arrive at the likelihood an individual will develop a certain condition in their lifetime.” 

Predicting risk on an individual basis 

The team evaluated health and genetic data from 965 individuals with 22q11DS (previously also known as Velocardiofacial syndrome or DiGeorge syndrome) and analyzed associations with polygenic risk scores for schizophrenia and cognitive ability derived from previous studies in the general population. Applying these scores to patients with 22q11DS, the research team found they could substantially improve individual risk predictions for the probability of a given patient growing up with cognitive challenges or developing schizophrenia later in life. 

“With genetic disorders, there’s a tendency to only look at the main genetic variant causing the condition,” says Dr. Carrie Bearden, a Professor in the Department of Psychiatry and Biobehavioral Sciences and Psychology at UCLA who co-led the work. “But you have to literally think outside the box and dive into the wealth of information hidden in the rest of the genome. That’s where we can start to explain why two children who have the same genetic variant may be affected in entirely different ways.” 

Their findings also explain the genetic bases for the wide variation of neuropsychiatric symptoms in patients with 22q11DS. For example, some patients show a significant cognitive decline between the ages of 8 and 24 and a previous study by the IBBC had already demonstrated that this subgroup is also at an increased risk for schizophrenia. Through their research, the team found this cognitive decline shares some of the same genetic underpinnings as schizophrenia. 

Understanding genetic variations and corresponding symptoms crucial for precision medicine 

The researchers say their findings are a key step towards a future of precision medicine and will pave the way for further work on targeted early intervention strategies. They hope their genomic analyses will be used to distinguish different risk groups within the 22q11DS patient population, enabling each individual to receive tailored treatment specific to their care needs. Leading experts in psychiatry say this kind of approach is sorely needed. 

“The importance of a precision medicine approach for brain and mental health cannot be understated,” says Dr. Peter Szatmari, Chief of the Child and Youth Mental Health Collaborative between SickKids, The Centre for Addiction and Mental Health and the University of Toronto. “We’re talking about some of the most complex human disorders that can look completely different in patients who have the same diagnosis. The better we can individualize our care, the better outcomes our patients will have.” 

The team is now looking at replicating their findings and examining the use of polygenic risk scores for prediction in patient populations with other high-impact genetic variants. Other members of the research team include Dr. Robert Davies, co-first author of the paper and inaugural recipient of the Lap-Chee Tsui Scholarship at SickKids, who is now at the University of Oxford, and Ania Fiksinski, co-first author and a PhD student in Vorstman’s lab, as well as Drs. Elemi Breetvelt, Stephen Scherer and Greg Costain. 

This work was supported by the National Institute of Mental Health (NIMH), the Lap-Chee Tsui Fellowship for Research Excellence, the Canadian Institutes of Health Research (CIHR), the Brain and Behavior Research Foundation and SickKids Foundation.