March 30, 2026

expert reaction to identification of most common recessive neurodevelopmental disorder

Three studies published in Nature Genetics look at the identification of a common recessive neurodevelopmental disorder (NDD). 

Cornelius Gross, Head of EMBL, Rome, said: 

“This study is a significant advance in understanding neurodevelopment disorders because it identifies a set of surprisingly common recessive disease mutations in the dark genome – the 98% of our genome that is non-coding. Tracking down such mutations has been much harder than finding disease mutations in coding genes and the study is an example of how improved sequencing methods and annotations have opened a door on new disease genes.

“It can be considered a breakthrough because of the surprisingly high abundance of these variants – more than 3 times higher than the next recessive mutation causing severe neurodevelopmental disorders. This finding makes it of general medical relevance because it shows that non-coding genes are hot spots for disease and deserve greater attention in our search for the genetic basis for disease.

“The publication of three independent studies reporting highly concordant results in different clinical populations strengthens the credibility and impact of the finding.

“The study gives hope to parents with undiagnosed neurodevelopment disorders and means that genetic screening and family planning could help reduce such conditions in the future.”

Dr Núria Setó-Salvia, Senior Postdoctoral Researcher, Reta Lila Weston Institute and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, said:

“This is a very exciting discovery that will impact the diagnosis of neurodevelopmental disorders and future treatments.

“These studies provide strong genetic evidence that variants in RNU2-2 gene cause neurodevelopmental disorders and epileptic encephalopathy.

“These studies present strong evidence that variants in RNU2-2 gene can cause neurodevelopmental disorders autosomal dominantly and, even more frequently, recessively.

“The spliceosome RNA genes are promising candidate to contribute to further research into neurodevelopmental disorders.

“These studies show the importance of not underestimating the function of non-coding genes in neurodevelopmental disorders, and non-coding RNA genes should be further explored in clinical genomic testing for neurodevelopmental disorders.

“These studies provide evidence of altered RNA spliceosome function caused by variants RNU2-2 and related genes, with both dominant and recessive inheritance patterns observed, further work is required to fully understand the effects of these variants and how they impact gene expression in brain development.

“The identification of signatures in the relative expression of RNU2-2 and RNU2-1 associated with pathogenic variants could be an important biomarker to help with the interpretation of variants in these genes in a diagnostic setting, where evidence to support the pathogenicity of rare and novel variants is often lacking.”

Prof Cathy Abbott, Professor of Mammalian Molecular Genetics, University of Edinburgh, said:

“These three papers together represent a real step change in our understanding of the contribution of the RNU2-2 gene to the spectrum of neurodevelopmental disorders. Unlike the previously described dominant mutations in the gene, these recessive disorders can be inherited from unaffected parents. In many of the cases described in these studies, affected individuals have one inherited mutant copy, and one copy that has acquired a new mutation (“de novo”), but in others a mutant copy is inherited from both parents. This will be particularly significant in populations with a higher frequency of consanguineous marriages, so the worldwide frequency of this disorder may be even higher than we currently think.

“Although Greene et al describe this condition as a more general neurodevelopmental disorder, Jackson et al and Leitao et al, with bigger cohorts, are able to show that the condition can be categorised as a developmental epileptic encephalopathy, with real implications for treatment. They also pick up distinct facial features in many cases.

“These three studies together will lead to an end to the diagnostic odyssey for many families, and because this is a recessive disorder (with predictable inheritance) there are implications for genetic counselling as well as future therapeutic strategies.”

Dr Rich Scott, Chief Executive Officer of Genomics England, said:

“This discovery, which data from Genomics England’s National Genomic Research Library helped make possible, will provide much sought-after answers to families who will likely have spent years searching for a diagnosis. It shows why genomic data at a national scale can be so valuable to researchers in helping them make what can be life-changing breakthroughs for patients, and why genomics is becoming an increasingly key focus for healthcare systems around the world.

“A diagnosis means families can access support and find a community which can be incredibly significant for them, alongside sometimes having new information around any other complications associated with the condition either now or in the future. It may even be the first step towards potential treatments through future research.

“This news is a powerful example of how research linked to clinical care, powered by genomic data from patients and research participants, can change lives around the world.”

‘Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder’ by Turro et al. was published in Nature Genetics at 10:00 UK time on Monday 30th March. 

DOI: https://doi.org/10.1038/s41588-026-02539-5

‘Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy’ by Jackson et al. was published in Nature Genetics at 10:00 UK time on Monday 30th March. 

DOI: https://doi.org/10.1038/s41588-026-02551-9

‘Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies by Depienne et al. was published in Nature Genetics at 10:00 UK time on Monday 30th March. 

DOI: https://doi.org/10.1038/s41588-026-02547-5

Declared interests

Dr Núria Setó-Salvia: No conflicts of interest.

Prof Cathy Abbott: I am on the Scientific Advisory Committee of Epilepsy Research Institute UK (honorary appointment).

For all other experts, no reply to our request for DOIs was received.