Rare Genetic Variants in Childhood Diabetes: Improving Diagnostics and Treatment of Childhood Diabetes by Next-Generation Sequencing

Diabetes is a major health burden (WHO). Diabetes is currently classified in four types; type 1 diabetes, type 2 diabetes, gestational diabetes, and monogenic/other types of diabetes. Mutations in around 20 genes cause monogenetic forms of diabetes. With the new genetic technology in which the whole exome and even genome of a person can be investigated in a high throughput manner, there is accumulating data indicating that rare, genetic variants may play a role in the pathogenesis of many diseases. The role of rare genetic variants in diabetes is so far not known. In this project, we speculate that rare variants have an important role for several forms of diabetes, based on our recent collaborative studies showing that rare variants in the ZNT8 gene can protect from type 2 diabetes, and that a rare variant in the monogenic gene HNF1A is a risk factor for type 2 diabetes. In our research plan, we will investigate to which extent rare variants can cause (misclassified) type 1 diabetes, and how rare variants can play a role for the pathogenesis of type 1 diabetes in children. The outcome of the study may open up new research fields in which it is possible to find new targets for drug treatment so it is possible to install personalized treatment. Last years have been excellent for the project. The scientific achievements have been outstanding with more than 50 papers published in solid international journals. We led an international study on long-term treatment of neonatal diabetes with sulfonylurea that was published in the Lancet Diabetes and Endocrinology. Due to this, interviews in NRK Dagsrevyen 21. The project has led to the involvement of a number of international studies last year using genetic data from our cohorts published in Nature (and Nature Genetics, all with scientific contribution from our lab. Mechanistic insight into effect of rare diabetes gene variants have been published in the top special journals Diabetes and JBC. Moreover, new mechanistic insight in the development of birth weight published in Nature Genetics, and development of growth and weight in children published in Nature Communication, Nature Metabolism and Nature Genetics with group members as first and last authors.

development of expertise, for trade and industry and society as a whole). Our results already have a large effect on diagnosis and treatment of childhood diabetes. Hence, we have contributed population-based data for the prevalence of pathogenic and variants of uncertain significance in several monogenic diabetes in childhood diabetes. Screening these children for mutations in monogenic genes is now in international guidelines of pediatric diabetes. I have contributed to writing these guidelines. The important findings from our lab, that some children with neonatal diabetes and certain variants in HNF1A can switch from insulin injections to sulfonylurea tablets, are also part of the international guidelines today. On a scientific-political level, I have been central for establishing the Nordic Society of Human Genetics and Precision Medicine, coordinating a paper in Nature Genetics (Njølstad et al., 2019) suggestion this idea and being on the scientific board (https://nshg-pm.org/). I stayed at the Broad Institute of Harvard and MIT, Boston, 12 months 2018-19 (Prof. D Altshuler). This had a large effect on the project leading directly to many of the best studies and new networks in this project. My PhD student Marie Solheim was sent to the Joslin Diabetes Center, Harvard Medical School, Boston, 3 years 2014-17 to study the mouse model we made in one of the best labs (Prof. CR Kahn) on insulin signalling. This led to the many studies on PIK3R1. Solheim has since been at the Max Planck Inst., Köln.

Following the success of genome-wide association studies of common variants, the focus now is to study the effect of rare variants. We suggest an ambitious project to unravel the role of rare genetic variants for diagnosis, pathogenesis and treatment of childhood diabetes. We have access to all children newly diagnosed with diabetes in Norway 2002-2014 (n=4000). Studies indicate 2-3% of children with apparent type 1 diabetes are misclassified and have a monogenic form of diabetes. Most often, monogenic diabetes in this age group can be treated with sulfonylurea tablets. We will therefore do a systematic screen of genes associated with monogenic diabetes using targeted sequencing in the 4000 cases with childhood diabetes looking for pathogenic mutations. Furthermore, we will perform whole-genome sequencing in antibody negative cases, and their healthy parents, aiming to identify novel diabetes genes caused by de novo mutations. If unclear whether variants are pathogenic or not, functional studies in cell models will be performed in our laboratory. Children with pathogenic mutations in monogenic genes may then be able to switch treatment from insulin injections to sulfonylurea tablets. The targeted sequencing will also include genes encoding type 1-associated antibodies. We will look for rare variants in these genes and relate those to clinical phenotypes such as antibody positivity at diagnosis and residual insulin production one year after diagnosis. These findings can shed new light on the mechanisms of type 1 diabetes as well. The study includes all pediatric departments in Norway with collaboration with Broad Institute of Harvard and MIT, Cambridge, USA; Lund University, Sweden; and Peninsula Medical School, Exeter, UK. Our studies may lead to improved quality of life for those that we can diagnose, and reveal novel mechanisms for diabetes development, opening a possibility of finding new targets for drug treatment and installment of personalized treatment.