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 can 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, the Institut Pasteur, and the Université Paris-Diderot, presents a model that can predict the effect of a genetic variant on a person’s cognitive traits.

“In practical terms, our model estimates the number of lost 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,” stated Guillaume Huguet, PhD, co-lead author of the study.

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.

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 a better interpretation of genetic analyses and to better care for children at risk of developing neurodevelopmental disorders, from a very young age.