ESPE Abstracts (2016) 86 FC9.1

Next Generation Sequencing for the Diagnosis of Monogenic Diabetes in Switzerland

Philippe Klee, Mirjam Dirlewanger, Jean-Louis Blouin, Montserrat Castellsague-Perolini, Federico Santoni & Valérie Schwitzgebel


University Hospital of Geneva, Geneva, Switzerland


Background: Monogenic diabetes (MD) remains undiagnosed in more than 90% of the cases. However, precise, quick and cost-effective diagnosis is important to choose an adequate treatment and to avoid long-term complications.

Objective and hypotheses: To develop and validate a diagnostic tool to improve diagnosis rate of MD in Switzerland, as well as to open new research directions.

Method: Targeted next-generation sequencing (NGS) of 323 known or potential diabetes genes using the Haloplex technology on patients with neonatal diabetes (ND), anti-antibody negative type 1 (T1DM) and type 2 diabetes (T2DM) diagnosed before the age of 45 years without metabolic features.

Results: In this ongoing study, 178 probands have been analyzed. A single mutation/variant was found in 41.6%, while two or more mutations/variants were found in 41.5% of the probands. 16.9% of the patients showed no anomaly. For the whole cohort, excluding ND, glucokinase (GCK) mutations were most frequent (19.6%), followed by HNF1A (5.6%) mutations and mean age at diagnosis was 27.7 years. For childhood onset diabetes (>6 months to < 18 years), GCK mutations were found in 16.9% and HNF1A mutations in 10.2% of the probands. Mean age at diagnosis was 11.2 years.

Conclusion: Using NGS in a selected population, we found a mutation or gene variant in 83.1% of the cases. Most patients were found to have GCK mutations. 7.9% of the probands had either HNF1A or HNF4A mutations for which oral antidiabetic drugs can replace insulin. These results highlight the importance of genetic analysis in patients with antibody-negative T1DM, ND or atypical T2DM. The identification of previously unknown variants in genes involved in beta-cell development or function opens the possibility to improve current knowledge about beta-cell physiology.

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