International Business Department           Liu Bojia           July 15, 2024

  In 2021, Mia, a girl of only 7 years old, was taken by her parents to a research organisation called the Undiagnosed Diseases Network (UDN).Mia suffers from a rare neurodevelopmental disorder (NDD), which leads to developmental delays and also exposes Mia to dangerous epilepsy on several occasions. In addition, the patient has facial features such as plump cheeks and drooping corners of the mouth. However, the true cause of Mia's condition was never diagnosed.

  For many patients who have difficulty getting a diagnosis, the Undiagnosed Disease Network can be the ultimate hope for finding the cause of the disease. Yet again, Mia's parents' hopes were dashed. "When the Undiagnosed Diseases Network told us there was nothing more that could be done, we accepted that we might never find out the truth." Mia's mother said.

  Now, that long-buried truth is finally being answered. A study published as an Accelerated Publication in Nature has identified a novel disease-causing mutation in non-coding DNA, a discovery that points to the true cause of the disease for thousands of patients around the world, and a first step towards the development of future therapies.

  NDD is a collective term for severely impaired brain function that can have an impact on learning, behaviour, language and motor skills. The genetic factors that contribute to NDD are also complex, and unfortunately, only about 40 per cent of people with NDD have a clear cause, with the disease-causing mutations remaining unknown in the rest of the patients, even after they have undergone comprehensive genetic sequencing - and Mia is one of them.

  In previous tests, scientists have tended to focus on the genes that code for proteins; these genetic codes are certainly important, but they make up only 1.5 per cent of the body's genes. The remaining 98.5 per cent are non-coding sequences that for a long time have gone unnoticed, and were once even called "junk DNA".

  Of course, we know that the regulatory role of these non-coding genes has been proven time and again in recent years. In the latest study, a large-scale sequencing project also aims to improve the ability to make diagnoses from non-coding genes. This international collaboration sequenced the complete genes of individuals, resulting in the discovery of mutations in RNU4-2 in the non-coding regions of 115 patients with NDD, many of whom had identical mutations.

  RNU4-2 is very active in the developing brain, and while it does not directly code for a protein, it encodes a small U4 nuclear RNA (snRNA), which is a key component of the major spliceosome complex. When an RNU4-2 mutation results in the insertion of a single base at a key position in the snRNA, this change affects the cell's processing of other RNA molecules, including those that continue to produce proteins. As a result, it is these protein changes that ultimately impair the process of brain development.

  The study estimates that mutations in the RNU4-2 gene could explain about 0.4 per cent of NDD cases worldwide and would provide a diagnosis for thousands of NDD patients. More importantly, the finding reveals the importance of non-coding genes in those with hard-to-diagnose NDD.

  The team said that most protein-coding genes associated with NDD are thousands of bases long, compared to about 1/50th of the length of RNU4-2. However, the frequency of RNU4-2 mutations that lead to NDD is almost identical to that of those protein-coding genes, and such a high frequency has raised concerns among the researchers. professor Nicola Whiffin said that the inclusion of RNU4-2 into standard clinical genetic testing will help thousands of NDD patients worldwide to achieve a diagnosis and provide long-awaited hope for these families.

  "We are so grateful to everyone on the research team who worked tirelessly to find this diagnosis," said Mia's mother, "We like to refer to RNU4-2 as a 'new birth' (renew) , because our family is renewed by these new perceptions and hope for the future."