Researchers at the University of Exeter and international collaborators have identified a previously unknown genetic cause of neonatal diabetes in babies, linked to mutations in the TMEM167A gene.

The rare, recessively inherited condition appears within the first six months of life and leads to high blood sugar as well as severe neurological complications, including epilepsy and microcephaly, by causing pancreatic beta cells to fail.

Neonatal diabetes is an uncommon disorder driven by genetic changes. Identifying its underlying cause is critical for improving diagnosis, enabling targeted treatment, and enhancing patient care.

Using stem cell models, scientists discovered that TMEM167A gene mutations trigger severe cellular stress in pancreatic cells, leading to their destruction, while also disrupting brain development.

The study found that this mutation causes a previously unrecognised form of neonatal diabetes that often presents alongside neurological abnormalities. Cases were identified in infants from several countries, raising the possibility of precision medicine approaches for affected patients.

Earlier genetic studies have focused on “coding” genes that carry instructions for making proteins. However, researchers at the University of Exeter, working with international partners, found that changes in non-coding genes, which produce functional RNA molecules, can also lead to diabetes.

RNA plays multiple roles in the body, including regulating gene activity and influencing how genetic information is interpreted.

With support from the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre and the Exeter NIHR Clinical Research Facility, the team used whole genome sequencing to analyse the complete DNA of affected individuals.

This approach revealed that mutations in two genes, RNU4ATAC and RNU6ATAC, were responsible for an autoimmune form of neonatal diabetes in 19 children. The cases were identified through the University of Exeter’s global programme, which provides free genetic testing for individuals suspected of having inherited forms of diabetes.

The findings also contribute to a broader understanding of rare diseases, which collectively affect about one in 17 people worldwide.

Lead researcher, Associate Professor, Elisa De Franco of the University of Exeter Medical School, said, “For the first time, we found that DNA changes in non-protein coding genes cause neonatal diabetes. This highlights the importance of non-coding DNA in human disease. With up to half of individuals with rare diseases still undiagnosed, exploring non-coding regions of the genome can provide answers for affected families.”

According to the study, all 19 children had an autoimmune form of diabetes in which the immune system attacks insulin-producing beta cells responsible for regulating blood sugar, a mechanism also seen in type 1 diabetes.

Using advanced laboratory techniques and computational analysis, researchers examined patient samples and found that mutations in the two non-coding genes disrupted the activity of around 800 other genes, many of which are involved in immune system function.

Co-first author Dr James Russ-Silsby said, “Combining DNA sequencing with detailed analysis of patient samples gave us a much deeper understanding of how these genetic changes operate at a cellular level. This helps explain how they lead to diabetes.”

Senior Research Fellow and co-first author Dr Matthew Johnson added that the findings could have broader implications for type 1 diabetes research.

“This discovery is important because it highlights that one or more of these 800 genes play a central role in autoimmune diabetes and could reveal new biological pathways and potential drug targets for more common forms of type 1 diabetes,” he said.

“Although this condition is rare, it offers a unique opportunity to study the mechanisms that drive autoimmune diabetes in humans and provides insight into how type 1 diabetes develops.”