Genome Sequencing Identifies Noncoding Variants Causing Neonatal Diabetes

Neonatal diabetes is a rare form of diabetes that presents in the first six months of life and is driven by genetic changes, yet many affected families still lack definitive diagnoses. Genetic studies have historically focused on protein-coding genes, leaving large portions of the genome underexamined. Understanding precise genetic causes can shape investigations and care for infants with early-onset disease. New findings demonstrate that variants in non-protein-coding genes can underlie autoimmune neonatal diabetes.

At the University of Exeter, researchers and international collaborators used genome sequencing to implicate two non-protein-coding genes, RNU4ATAC and RNU6ATAC, in autoimmune neonatal diabetes. Genome sequencing, which reads all the letters in a person’s DNA, was applied to affected children to search for disease-causing variants. The genes produce functional RNA rather than proteins and, as noted in the study title, are minor spliceosome components.

The study analyzed 19 children with autoimmune neonatal diabetes who were identified through Exeter’s global program offering free genetic testing for suspected genetic forms of diabetes. Researchers combined genomic data with state-of-the-art laboratory and computational analyses of patient samples. The work is published in The American Journal of Human Genetics and will be presented at the European Society of Human Genetics (ESHG) conference in Sweden in June.

All 19 children exhibited an autoimmune form of diabetes in which the immune system targets insulin-producing beta cells, a process also seen in type 1 diabetes. The results show that non-protein-coding genes can directly cause neonatal diabetes while illuminating immune-related pathways affected downstream. With up to half of individuals with rare diseases currently living without a diagnosis, the authors note that examining non-coding DNA can provide answers for families with rare conditions.

“For the first time, we found that DNA changes in non-protein coding genes cause neonatal diabetes. This shows the importance of non-protein coding genes and their potential to cause disease in humans,” said Elisa De Franco, Associate Professor at the University of Exeter Medical School. "With up to half of individuals with rare diseases currently living without a diagnosis, exploring the non-coding DNA can provide answers for families with rare conditions."

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