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Thursday, January 21 2021
Press release

Predicting the effect of genetic mutations on neurodevelopmental disorders

MONTREAL, January 21, 2021 – An international research team at CHU Sainte-Justine and Université de Montréal has developed a statistical model to predict the effect of structural genomic mutations on cognitive abilities and risk for intellectual disability using bioinformatic models. The results of this work are presented in the journal Molecular Psychiatry.

Dr. Sébastien Jacquemont's team studied a cohort of 24,092 people from the general population (including the CARTaGENE cohort from Quebec) and individuals with a diagnosis of autism. The cognitive abilities of all participants were assessed.

The model was nearly 80% accurate in predicting the effect of genomic copy number variations (CNVs) on cognitive abilities. Models also estimate that 10000 genes (half of the coding genome) have measurable effects on cognition when deleted by CNVs.

Neurodevelopmental disorders

Approximately 2 to 5% of the general population have neurodevelopmental and neuropsychiatric disorders, including intellectual disabilities, severe learning disabilities and autism spectrum. Genetic tests routinely performed in patients referred to developmental clinics identify CNVs in 10-15% of cases. CNVs are deletions (loss) or duplications (gain) of a portion of the genome.

"However, the effects on cognition of the majority of these mutations are unknown, because they are very rare," says Dr. Jacquemont, the clinician and researcher in the genetics service at CHU Sainte-Justine who headed the study.

Without a tool to predict the effects of such mutations on cognition, it is impossible to know whether or not they contribute to a patient’s neurodevelopmental symptoms.

Assessing the effect of loss or gain of genetic material

To develop this tool, the research team analysed cognitive measures and identified the CNVs present in the genomes of more than 24,000 people from seven cohorts.

The team then explored the functional characteristics of each CNV and identified those that best characterizes the impact of deletions and duplications on cognitive traits.

To ensure the relevance of the results, the researchers validated the model by showing that it could predict with 78% accuracy the quantitative effect of 47 deletions and duplications whose impact on cognition is known.

"It’s important to note that our model does not predict the individual’s IQ. Rather, it allows us to predict the impact on cognition associated with the presence of a CNV in the genome. If the mutation has an effect in line with the patient's cognitive difficulties, we would consider that this mutation represents a major diagnostic factor for this patient," explains Guillaume Huguet, PhD, lead author of the study.

The study also shows that 10,000 genes (half the genome) influence the IQ when they are deleted by a CNV. Almost all molecular functions are involved in cognition.

Clinical application

This discovery will improve clinical interpretation of genetic testing in the neurodevelopmental disorder clinic. The results also shed light on the genetic architecture of cognition.

In addition, this study provides a framework to study very rare mutations that can’t be investigated using conventional approaches.

About the study

The article "Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability" was published on January 7, 2021, in the journal Molecular Psychiatry. The primary authors are Guillaume Huguet and Catherine Schramm, who work in Dr. Jacquemont’s laboratory. The principal author is Dr. Sébastien Jacquemont, medical geneticist and researcher at CHU Sainte-Justine and associate professor in the Department of Pediatrics, Faculty of Medicine, Université de Montréal.

The study was supported by a Canada Research Chair in Genetics of Neurodevelopmental Disorders, the Jeanne-et-J.-Louis-Levesque Chair in Genetics of Brain Diseases, the Institute for Data Valuation (IVADO), the Canadian Institutes of Health Research (CIHR), the CHU Sainte-Justine Foundation, the Network of Applied Genetic Medicine, the Fondation Bettencourt-Schueller, the Marcel and Rolande Gosselin Research Chair of Applied and Fundamental Cognitive Neuroscience in Autism Spectrum Disorders, the Brain Canada Foundation, the Heart & Stroke Foundation of Canada, the Wellcome Trust, and the National Institutes of Health (NIH). The Saguenay Youth Study (SYS) is funded by CIHR and the Heart & Stroke Foundation of Canada.

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CHU Sainte-Justine Research Centre is a leading mother-child research institution affiliated with Université de Montréal. It brings together more than 210 research investigators, including over 110 clinician-scientists, as well as 450 graduate and postgraduate students focused on finding innovative prevention means, faster and less invasive treatments, as well as personalized approaches to medicine. The Centre is part of CHU Sainte-Justine, which is the largest mother-child centre in Canada and second pediatric centre in North America.

CHU Sainte-Justine


Maude Hoffmann
Communications, CHU Sainte-Justine Research Centre

Media contact:

Florence Meney
Executive advisor – External communications
CHU Sainte-Justine
Tel.: 514-755-2516

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Updated on 2/3/2021
Created on 1/21/2021
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