Collaborative study uncovers unknown causes of blindness Genetic analysis of one family brings clarity to dozens of families worldwide

Researchers from Radboud university medical center and Institute of Molecular and Clinical Ophthalmology Basel have discovered new genetic causes of inherited blindness. Their study shows that changes in specific pieces of DNA, which play a role in processing genetic information, can lead to retinitis pigmentosa. This eye condition affects about 1 in 5,000 people worldwide, causing ‘tunnel vision’ and often leads to legal blindness. The discovery provides clarity for dozens of families globally and opens new possibilities for diagnostics and counseling in hereditary conditions.

Retinitis pigmentosa (RP) is a disorder in which the rod cells and later also the cone cells in the retina gradually die. Affected individuals first experience night blindness, followed by tunnel vision. Some eventually lose their sight completely. Although more than a hundred genes are known to cause RP, in 30 to 50 percent of patients the genetic cause remains unresolved, even after extensive DNA testing. Researchers at Radboudumc have now solved part of this puzzle.

From one family to dozens

The discovery began with an American family of a father and eight children affected by blindness and other genetic conditions. ‘They came to us asking: what’s behind this? Is there one cause explaining all these conditions, or are multiple genes involved?’ says lead researcher Susanne Roosing, molecular geneticist at Radboudumc. ‘We did not find a cause in a known RP gene. So, we analyzed the entire DNA of the parents and children. That explained the other conditions, but not the RP. We knew then we had to look for a new cause. A huge challenge, but eventually we found a variation in the gene RNU4-2.’ 

The change occurs in a special gene, RNU4-2, which does not produce a protein but only RNA. RNA from such genes associate with proteins and other RNAs and the whole resulting complex assists in editing genetic information (splicing), a step required before a cell can make proteins. Other changes in RNU4-2 were recently linked to developmental disorders. The variant in the American family with RP, however, sits at a critical hinge point in the RNA. This disrupts a regulatory mechanism which apparently important for the retina, ultimately leading to blindness.

Analysis of 5,000 patients

Together with researchers Mathieu Quinodoz and Carlo Rivolta from the Institute of Molecular and Clinical Ophthalmology Basel / the University of Basel and colleagues worldwide, the team launched a large-scale analysis of DNA from 5,000 patients whose genetic cause underlying RP was still unknown. They found, in addition to changes in RNU4-2, four similar genes, providing a molecular diagnosis for 153 individuals from 67 families. These variants now explain about 1.4 percent of all unresolved RP cases worldwide. ‘This is a huge step forward’, says Kim Rodenburg, genetic researcher at Radboudumc. ‘We’ve not only identified a new cause of blindness, but we also show that DNA segments that don’t make proteins are still crucial. Non-coding genes have never been linked to inherited retinal diseases.’   

The American family that started this search is thrilled with the breakthrough. They never expected that research into their genes would help 66 other families. ‘They now know the source of their blindness,’ Roosing explains. ‘And they can make informed choices, such as using preimplantation genetic testing to prevent passing the condition to their children. That’s incredibly valuable.’

A new chapter in genetics

This breakthrough goes beyond these specific genetic variants causing RP. It shows that we should also look beyond protein-coding genes.’ Rodenburg: ‘We’ve learned that changes in these RNA genes can be just as impactful as changes in protein-coding genes. This is fundamental knowledge that broadens our understanding of hereditary diseases.’

Genetic researcher Susanne Roosing.

About this publication

This article was published in Nature Genetics: De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa – Mathieu Quinodoz*, Kim Rodenburg*, Zuzana Cvackova, Karolina Kaminska, Suzanne E. de Bruijn […], Frans P. M. Cremers, Winston Lee, Jamie M. Ellingford, David Stanek, Susanne Roosing#, Carlo Rivolta#. DOI: 10.1038/s41588-025-02451-4. 

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