New causes of hereditary blindness found

A team of researchers from Radboud University Medical Centre (Netherlands) and the University of Basel (Switzerland) has discovered previously unknown genetic causes of retinitis pigmentosa, one of the most common forms of inherited vision loss. The work is published in Nature Genetics.

The main surprise: in some cases, the disease is triggered by changes not in protein-coding genes, but in sections of DNA that produce small RNAs and help cells "correctly mount" genetic instructions.

What retinitis pigmentosa is and why it is difficult to "catch" by analyses

Retinitis pigmentosa (RP) occurs in about 1 in 5,000 people. It usually starts with impaired night vision, followed by "tunnel" vision, and some patients develop severe vision loss over time.

Although science knows more than a hundred genes associated with RP, in 30-50% of patients the cause has not been found for a long time, even after extensive DNA testing. That is, the diagnosis is there, but the "culprit" is not.

How one family helped find the key

The study started with an unusual case: an American family where the father and eight children had blindness. Scientists tested known RP genes - to no avail. Then they went wider and began to analyse the whole genome.

So they found a variant in RNU4-2 - a gene that does not produce protein, but makes RNA that participates in the process of splicing (assembling/editing RNA before creating proteins). The mutation was at a "critical point" in the molecule and disrupted a mechanism important specifically to the retina.

They tested 5,000 patients - and found dozens of families worldwide

After the discovery, the scientists, together with colleagues from different countries, examined data from 5,000 RP patients in whom the genetic cause remained unknown.

The result:

• pathogenic variants in RNU4-2 and four other similar RNA genes were found;

• this gave a molecular diagnosis of 153 patients from 67 families;

• explained about 1.4% of all previously "unsolved" RP cases.

Why this is important for more than just science

This discovery immediately yields practical things:

• more accurate diagnosis: some of the patients who for years could not be told the cause can now get a confirmed genetic version;

• genetic counselling: families will be able to assess inheritance risks;

• reproductive solutions: if desired, options like preimplantation diagnosis (to avoid passing on the mutation to children) are possible.

The main conclusion of the study is that the cause of inherited diseases should not only be looked for in "classical" protein-coding genes. Non-coding DNA regions and RNA genes can be just as critical - and they have not been "seen" by standard search strategies before.