An international consortium of scientists, with the participation of Spanish centres such as IDIBELL, CIBERER and the Germans Trias i Pujol University Hospital, has identified genetic variants in essential non-coding genes that cause previously undiagnosed neurodevelopmental disorders (NDDs) in patient cohorts. The findings have been published in the high-impact scientific journal Nature Genetics.

Beyond coding genes: How errors in RNA processing cause brain diseases

While most genetic diagnostics focus on protein-coding genes, this research applied a different strategy: It looked at 50 non-coding genes that produce snRNAs, small RNA molecules that are part of the spliceosome — a molecular machinery that edits RNA so it can be properly translated into proteins.

In large French and international (including Spanish) cohorts of people with unresolved NDD, the researchers identified pathogenic (disease-causing) variants in two key new snRNA genes: RNU5B-1, now confirmed as a new NDD-associated gene, and RNU5A-1, proposed as a strong candidate. In addition, the RNU4-2 gene, previously linked to ReNU syndrome, has been confirmed as causing disease, and this study demonstrates that the clinical presentation varies according to the position of the mutation in the gene.

These findings reveal a new category of genetic diseases: those that affect the cellular machinery responsible for processing genetic instructions, rather than the instructions themselves.

When the RNA machinery fails: from genetic discovery to diagnosis

The identified variants affect highly conserved regions of snRNAs, interfering with the ability of the spliceosome to correctly recognize and bind RNA segments. This causes subtle but widespread errors in RNA processing, which can severely impact brain development.

“These variants are mostly de novo, that is, not inherited from either parent, and cannot be detected by standard genetic tests such as exome sequencing,” explains Dr. Aurora Pujol, ICREA professor at IDIBELL, where she is leader of the Neurometabolic Diseases research group, and co-author of the study, whose scientific expertise was key to the clinical and functional characterization of the cases, in collaboration with CIBERER and IMPaCT Genomics.

Thanks to whole-genome sequencing, international collaboration, and advanced RNA-focused functional studies, the team was able to diagnose dozens of children with previously unexplained neurological disorders.

A New Frontier for Diagnosing Unresolved Rare Neurodevelopmental Disorders

The study expands the known spectrum of ReNU syndrome, showing milder or more severe forms depending on the location of the variant in the RNU4-2 gene. It also establishes RNU5B-1 as an NDD-causing gene and highlights RNU5A-1 as a key candidate.

This work also shows that non-coding genes – often ignored in standard diagnostic pathways – may be behind serious brain diseases. And he stresses that targeted analysis of RNA genes and their function can provide answers in cases that would otherwise remain undiagnosed.

“This changes the way we approach undiagnosed cases,” concludes Dr. Pujol. “If we want to provide answers to families, we need to look beyond the usual suspects and include RNA machinery in our diagnostic strategies.” Dr. Agatha Schlüter, postdoctoral researcher at IDIBELL, and Dr. Agustí Rodríguez-Palmero, neuropediatrician at the Germans Trias i Pujol Hospital in Badalona and researcher at the Badalona Neuromuscular Research Group (GRENBA) of the Germans Trias i Pujol Research Institute (IGTP).

The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, ​​and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).