ESPE Abstracts

Introduction: Monogenic diabetes (MD) accounts for at least 3% of all pediatric diabetes cases. MD is often misdiagnosed as type 1 or type 2 diabetes, because of its wide phenotypic spectrum. While clinical and biochemical parameters can suggest MD, a definitive diagnosis requires genetic analysis. We conducted a broad study to diagnose MD cases. Then, with the gained knowledge, we designed a new diagnostic tool to obtain a comprehensive analytical instrument for the diagnosis of MD. A correct diagnosis of MD is crucial to optimize treatment and thereby improve metabolic control.

Method: Diagnostic tool (Haloplex technology): This custom assay, designed based on liquid phase capture, allows for the trapping of all coding regions of the 42 genes and the respective splicing regions. Known enhancer regions and introns associated with diabetes were also included in the panel.

Results: Here, we developed a new diagnostic panel of 42 genes, including the genes causing Maturity onset diabetes of the Young (MODY) and neonatal diabetes. The panel was validated with independent samples of known MD patients. We have now analyzed the first 19 patients, sent in from all over Switzerland, and identified a variant in 53% of the subjects. We found three different variants in the GCK and four in the HNF1A gene, one in the EIF2AK3, ABCC8 and PAX4 genes. In nine patients the result remained negative. Interestingly, the ABCC8 variant was reported to be functionally inactivating and therefore compatible with the congenital hyperinsulinism presented by the newborn patient. This is in contrast to activating ABCC8 mutations known to cause neonatal diabetes.

Discussion and Conclusion: Our newly developed next generation diagnostic panel shows an actual pick-up rate of 53% in the 19 consecutive patients, which is above the published rates of 21% to 37% in the UK and 25% to 30% in France. The panel detects missense variants, insertions, and deletions, as well as activating or inactivating mutations, and large deletions extended from one exon to entire gene. These results indicate that the three patients with GCK diabetes didn’t need any treatment, the patients with HNF1A mutations could be switched to oral sulfonylurea or glinides. The congenital hyperinsulinism could successfully be treated by diazoxide and the neonatal diabetes due to the homozygous EIF2AK3 mutation needed insulin injections. These cases illustrate how applied precision medicine can tailor treatment to the needs of the individual patient with the aim to reduce long-term complications.