28-OR: Genetic Landscape of Diabetes in the Swiss Population

Background/Introduction: Diabetes represents a heterogeneous group of metabolic disorders and monogenic diabetes is thought to affect 1- 5% of the diabetes population. Monogenic diabetes causes neonatal diabetes (ND), maturity-onset diabetes of the young (MODY), and syndromic diabetes. The identification of the gene underlying diabetes remains crucial. In many cases, it will instruct a personalized treatment regime, thus improving metabolic control. The aim of the study was to identify mutations causing genetic diabetes.

Methods: Inclusion criteria for testing were ND, autoantibody negative type 1 diabetes (T1D), presumed MODY, type 2 diabetes (T2D) diagnosed before the age of forty-five without metabolic features and syndromic diabetes. Haloplex technology was used to perform targeted next-generation sequencing (NGS) for 323 genes known to be involved in glucose homeostasis.

Results: We have analyzed 234 diabetic individuals (137 females, 97 males) living in Switzerland by NGS. The mean age at diabetes diagnosis was 27.7 ±15.4 years. We identified variants in the MODY genes 1-13 in 41% (95/234) of the patients, of which 7 had variants in two, and one in three genes. The most frequent variants involved GCK in 58% (55/95), followed by HNF1A 19%, HNF4A 7%, ABCC8 6%, HNF1B/KCNJ11/KLF11 3%, NEUROD1 2% and PAX4 1%. When mapped to age at diabetes onset, MODY variants were most frequent in the neonatal group (50%, 2/4), and declined with age to reach 36% (13/36) in the >45 year group. In the group with variants in other than MODY genes (n=111) diabetes onset was 30 ±16 years; in 39% of the individuals we identified one genetic variant with a maximum of up to six in 1.8% of the probands.

Conclusion: NGS is now a feasible method to diagnose monogenic diabetes, as we identified variants in MODY genes in 41% of probands in our cohort. We detected potential digenic and oligogenic diabetes forms in 61% of the probands with variants in other than MODY genes. The discovery of additional diabetes genes may lead to novel, rational treatment strategies.