Identification of novel subtype of monogenic diabetes by excluding Type 1 diabetes using a polygenic risk score (360G-Wellcome-110082_Z_15_Z)

Background: Finding the genetic aetiology of monogenic diabetes has had profound scientific and clinical implications. Currently, novel subtypes of monogenic diabetes are identified by studying patients who have a clinical phenotype of known subtypes of monogenic diabetes but lack mutations in the known genes. This approach is biased: lacking ability to identify previously undescribed phenotypes. In non-obese children, Type 1 diabetes (T1D) is the only alternative diagnosis to monogenic diabetes . Therefore potential novel monogenic subtypes can be found by excluding T1D by presence of autoantibodies, but this approach is limited as autoantibodies are absent in 10-20% of T1D patients. Preliminary Data: I showed a T1D-genetic risk score (T1D-GRS), based on T1D associated common genetic variants, in the neonatal period( < 6months) identifies individuals with monogenic diabetes by robustly excluding T1D. Key goals: I will genotype the T1D-GS in large cohorts of slim patients with childhood -onset diabetes from the UK (n=5000), and Turkey (n=700) to identify patients in whom T1D is highly unlikely (T1D-GS < 1st centile of T1D) so monogenic diabetes highly likely. I will perform whole-genome-sequencing on these patients to find novel genetic aetiologies. I will perform detailed phenotyping of the individuals with confirmed novel genetic aetiologies to understand the associated biology.