Estimating the effect of genetic mutations on neurodevelopmental disorders more accurately

March 29, 2018

About 3% to 7% of the general population have neurodevelopmental and psychiatric disorders, including intellectual disabilities, autism spectrum disorder and schizophrenia. Genetic tests commonly performed in these patients identify in 10-15% of cases, mutations contributing to neurodevelopmental disorders. However, the effect of 90% of these mutations is not known because they are very rare. How the effects of these rare and unknown variants on a person's cognitive development be assessed?

A recent study published in the science journal JAMA Psychiatry, co-edited by researchers at CHU Sainte-Justine, the Université de Montréal and the Institut Pasteur in France, presents a model that can predict the effect of a genetic variant on a person's cognitive traits. This discovery opens the way to a better interpretation of genetic analyzes and better care for children at risk of developing neurodevelopmental disorders, from a very young age.

"Our bodies are made up of billions of cells that each contain a nucleus. That nucleus contains genetic information recorded in DNA molecules that are made up of our 23 pairs of chromosomes, encoding more than 25,000 genes. Since we have pairs of chromosomes, we have two copies of the majority of our genes, each inherited from one parent. In this study, we studied deletions that are losses of genomic fragments and that can lead to the loss of one or more genes. Deletions can result in an alteration of the person's cognitive development," stated Guillaume Huguet, PhD, co-lead author of the study.

"In practical terms, our model estimates the number of lost intellectual quotient (IQ) points induced by a deletion, wherever its location, in the patient's genome. It relies on the fact that each gene defines a piece of biological information. When a gene is modified, its biological function risks being affected. If that function is related to cognition, the patient is exposed to a risk of having a neurodevelopmental disorder. Furthermore, these effects are cumulative, leading to an increased risk," Huguet added.

To reach these conclusions, the research team worked on two cohorts of the general population, with a total of 2,711 people. Initially, they identified variations (deletions and duplications) in the number of copies of genes in the subjects' DNA. The research team explored the intrinsic characteristics of each deletion, such as the size, the number of genes lost or the haploinsufficiency score, that is, the organism's intolerance for losing a copy of the gene and the resulting alteration of its biological function. The team then classified the results based on their "predictive power," defining the genetic information that best characterizes the impact of deletion on the IQ.

To ascertain the relevance of the model, the researchers tested it against recurring deletions with a well-known impact on IQ. The rate of agreement between the observations in the literature and the model was 75%.

"We should point out that our model cannot predict the IQ of an individual, but rather the loss of IQ points associated with the presence of a deletion in the genome. If the mutation has a significant effect and is consistent with the cognitive impairment of the patient, we can consider that this mutation represents a major diagnostic factor in the patient," explained Sébastien Jacquemont, MD, a clinician-scientist at CHU Sainte-Justine and a professor in the Department of Pediatrics at the Université de Montréal. "In short, in every statistical analysis, there is a percentage of uncertainty surrounding the results. To mitigate this, you have to take into account not only the predicted value, but the confidence associated with that value," said Catherine Schramm, PhD, co-lead author of the study.

This discovery proposes a new method for the study of mutations whose rarity does not make it possible to use conventional approaches. It paves the way to better clinical care for children at risk of developing a neurodevelopmental disorder.

"Our model will help clinicians estimate the cognitive impact of rare and undocumented genetic variants. This information will allow appropriate care to be put in place to try to compensate for the impact of these deleterious variants," concluded Thomas Bourgeron, PhD, professor at the Université Paris-Diderot and researcher at the Institut Pasteur, France.

The team is pursuing its research to explore other behavioural phenotypes using this same genetic analysis approach.
About the study

The article titled "Measuring and predicting the effect of copy number variants on general intelligence in community-based samples" was published in the journal JAMA Psychiatry in March 2018. The co-lead authors are Guillaume Huguet, PhD, and Catherine Schramm, PhD, both postdoctoral fellows under the direction of Sébastien Jacquemont at the CHU Sainte-Justine. The co-principal authors are Sébastien Jacquemont, MD, a doctor, geneticist and researcher at the CHU Sainte-Justine, associate professor in the Department of Pediatrics at the Université de Montréal and the scientific director of CARTaGENE, and Thomas Bourgeron, PhD, researcher at the Institut Pasteur, France, and assistant professor at the Université Paris-Diderot.

This research was enabled by support provided by Calcul Quebec and Compute. Dr Bourgeron is supported by the Institut Pasteur, the University Paris Diderot, and the Bettencourt-Schueller Foundation. Dr Jacquemont is a recipient of a Bursary Professor fellowship of the Swiss National Science Foundation, a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Dr Huguet is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. Dr Schramm is supported by the Institute for Data Valorization fellowship. Dr Loth is supported by European Autism Interventions, which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115300, the resources of which are composed of financial contributions from grant FP7/2007-2013 from the European Union's Seventh Framework Programme, the European Federation of Pharmaceutical Industries and Associations companies' in-kind contributions, and Autism Speaks. This work is supported by a grant from the Brain Canada Multi Investigator initiative (Dr Jacquemont). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study. Funding for the project was provided by the Wellcome Trust.

About the CHU Sainte-Justine Research Center

The CHU Sainte-Justine Research Center is a leading mother-child research institution affiliated with Université de Montréal. It brings together more than 200 research investigators, including over 90 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 Center is part of the CHU Sainte-Justine, which is the largest mother-child center in Canada and second pediatric center in North America. More at

About the Institut Pasteur

The Institut Pasteur, a public interest organization set up by Louis Pasteur in 1887 and inaugurated on November 14, 1888, has been an internationally renowned biomedical research center for 130 years, with a network of 33 institutes on five continents. In the pursuit of its mission to prevent and fight against diseases in France and throughout the world, the Institut Pasteur operates in four main areas: scientific and medical research, public health and health monitoring, teaching, and business development and technology transfer. More than 2,500 people work on its Paris campus. The Institut Pasteur is a globally recognized leader in infectious diseases, microbiology, and immunology. It also focuses its research on certain cancers, genetic and neurodegenerative diseases, genomics and developmental biology. This research aims to expand our knowledge of living organisms in a bid to lay the foundation for new prevention strategies and novel therapeutics. Since its inception, ten Institut Pasteur scientists have been awarded the Nobel Prize for Medicine, including two in 2008 for the 1983 discovery of the human immunodeficiency virus (HIV) that causes AIDS.

Institut Pasteur

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