Intellectual development disorders: two new genes under the microscope

Intellectual development disorders (IDDs) or intellectual disabilities are a “significantly reduced ability to understand new or complex information and learn to apply new skills (impaired intelligence)” according to the World Health Organization (WHO). This impairment of adaptive functioning is visible in skills areas including communication, school learning, autonomy, individual responsibility, social life, work, leisure, health, and even safety.

These disorders affect around 1% of the general population, according to the Ministry of Health. They can be linked to the patient’s environment or to genetics (more than 1,680 genes involved have already been identified), but in many cases their cause is still unknown.To advance our understanding of these complex diseases, and identify new genes associated with these disorders, whole genomes needed to be studied.

Thanks to the roll-out of the 2025 France Genomic Medicine initiative led by Inserm, whole genome sequencing is now offered to patients with rare diseases or cancers to guide diagnosis, genetic advice or the management of their condition. Since its launch in 2016, more than 100,000 sequencing procedures have been carried out for more than 40,000 patients and their relatives, providing scientists with a repository of genetic data.

“This initiative has made it possible to reach a diagnosis for around 30% of the people affected, sometimes after years of diagnostic deadlock, explains Frédérique Nowak, coordinator of the 2025 France Medicine Genomic initiative at Inserm. But another aim of this initiative was to back up research with the data resulting from these sequencing procedures” .

Almost 24,000 French genomes

This second objective has already been achieved, according to the results of a new study supervised by a Franco-German international research team. Based on studies of 23,649 genomes of French patients with rare diseases, together with other genomes from international collaborations, the scientists were able to collect a very large sample of cases, confirming that two genes were heavily involved in severe neurodevelopmental disorders. These genes code for small RNAs, molecules with a structure close to DNA, but which belong to the “major spliceosome”. This mechanism makes it possible to “prepare” what is known as messenger RNA, a sort of copy of genes, before they are translated into proteins.

“This work identified 145 patients with de novo mutations (in other words, mutations not passed down by parents) in the RNU4-2 gene, and 18 patients with de novo mutations in the RNU5B-1 gene, an unprecedented number of patients with similar symptoms, including developmental delays, intellectual development disorders, microcephaly and treatment-resistant epilepsies, says Julien Thevenon (Inserm), a Paris Brain Institute researcher working on the advancement of biosciences at Grenoble university hospital, and co-author of the study.

By carrying out blood tests, the research teams also succeeded in developing two new types of test to diagnose ReNU syndrome, the rare disease linked to RNU4-2 gene mutations that presents, among other things, as intellectual and motor development delays or language disorders.

These tests will be useful if a diagnosis with a conventional DNA test proves difficult. The first, called a “transcriptomic” study, identifies the quantity and characteristics of messenger ribonucleic acids (or RNA) produced during the copying—or transcription—of a genetic sequence. The second, called an epigenetic study, studies molecular changes that occur on DNA without modifying its sequence. In both cases, the objective is to observe whether these characteristics are close to those considered hallmark characteristics of Renu syndrome.

The research involved a high number of French researchers affiliated with the SeqOIA and AURAGEN laboratories, the only two laboratories in France authorized to carry out whole genome sequencing (i.e. all chromosomes and genes of each patient) in a diagnostic setting. “This is collective work and an excellent research organization. It should help maintain the momentum of the France Medicine Genomics initiative”, says Caroline Nava (AP-HP Paris Public Hospital Network, Sorbonne University), researcher at Paris Brain Institute and the study’s first author. 

“It is thanks to the sheer amount of data and the collaborations with researchers all around the world that we have been able to make these discoveries”, continues Christel Depienne, researcher at Essen University and co-last author of the study.

The focus was on providing a diagnosis for as many people as possible and ending the diagnostic odyssey that is so arduous for families, improving genetic counseling by informing parents about the risk of having more children with the same disease and, finally, helping to develop therapies that target the mechanisms of disease.