ESPE Abstracts (2015) 84 P-1-33

ESPE2015 Poster Presentations Poster Category 1 Diabetes (33 abstracts)

Improved Genetic Testing for Monogenic Diabetes in the Swiss Population by Targeted Next Generation Sequencing

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

aPediatric Endocrine and Diabetes Unit, Children’s University Hospital, Geneva, Switzerland; bUniversity Medical Center, Genetic Medicine and Development, Geneva, Switzerland

Background: Monogenic diabetes is a heterogeneous group of diabetes due to a single gene mutation and includes neonatal diabetes (NDM), MODY and rare forms of syndromic diabetes. These forms of diabetes remain undiagnosed in probably more than 90% of patients. The aim of the study was to identify mutations causing monogenic diabetes using a single test.

Method: Swiss endocrinologists were proposed to participate in the study and to send blood samples of their patients with suspected monogenic diabetes. Inclusion criteria were NDM, autoantibody negative type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) diagnosed before the age of 45 without metabolic features and syndromic diabetes regardless to treatment. The analyses were performed by a targeted next-generation sequencing (NGS) assay sequencing 323 diabetes genes using the Haloplex technology. All the variants were confirmed by Sanger sequencing.

Results: So far we have analysed 142 diabetic probands by NGS. We identified 73 variants (51%) in the selected 323 genes, compatible with neonatal diabetes and MODY, we also found, variants in genes associated with T1 or T2 diabetes. 55% (40/73) of the mutations were found in one of the 13 putative MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11). The most frequent MODY mutations were found in the GCK gene (42%, 31/73). 17 different mutations of GCK could be identified and 16% (12/73) of the probands carry the p.Val203Ala mutation.

Conclusion: This study shows that monogenic diabetes can easily be diagnosed by NGS. In 51% of the probands, changes in diabetes genes were found; several variants will need functional validation. 42% of the positive patients had GCK diabetes and the Val203Ala mutation is the most prevalent in the Swiss population. Introducing the targeted next generation sequencing as a clinical diagnostic testing could clearly improve the identification of this kind of diabetes.

Funding: This work was supported by the Fond National Suisse and Schweizerische Diabetes Stiftung.

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