Estimating the effect of genetic mutations on neurodevelopmental disorders more accurately

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.