Endocrine Abstracts

In recent years there has been significant progress in defining the genetic aetiology of neonatal diabetes with disease-causing variants identified in over 30 genes. These genes are all recognised as having a critical role in the development, function, or destruction of the pancreatic beta-cell. Targeted next generation sequencing allows for the rapid, simultaneous screening of all 30 known neonatal diabetes genes. This analysis provides an accurate genetic diagnosis for over 80% of individuals which is important as identifying the genetic subtype will inform on whether an individual will have isolated diabetes or syndromic disease where diabetes is often the presenting feature. A genetic diagnosis will also provide accurate information on recurrence risk within families, and crucially it will inform on treatment decisions leading to improved clinical outcome. A small minority of individuals without a disease-causing variant in a known neonatal diabetes gene have extreme early-onset type 1 diabetes as shown by the presence of autoantibodies in combination with a high polygenic risk score. For the remaining individuals with genetically unsolved disease, there is strong evidence from phenotyping studies and Mendelian inheritance patterns within families to support there being undiscovered genes for neonatal diabetes. Next generation sequencing technologies also provide exciting possibilities for large scale sequencing studies with whole genome sequencing allowing for a gene agnostic approach to genetic discovery. Continuing to discover new genes for neonatal diabetes is important as it will provide further insights into pancreatic beta-cell biology as well as the pathways of autoimmunity which will be important for type 1 diabetes research.