ESPE Abstracts (2016) 86 P-P1-197

Diagnosis of Non-Autoimmune Paediatric Diabetes by Targeted Next Generation Sequencing (NGS): Findings in Two Families with Rare Mono- and Digenic forms of Diabetes

Amélie Poidvina, Xavier Donathc, Cécile Saint-Martinc, Sylvie Loisona, Jean-Claude Carela,b, Christine Bellanné-Chantelotc & Nadia Tubiana-Rufia

aService d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France; bUniversity Paris Diderot, Sorbonne Paris Cité, Paris, France; cDépartement de Génétique, Hôpital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France

Background: Nearly 10% of paediatric onset diabetes are auto-antibodies negative. Among them monogenic diabetes are frequently under-diagnosed. The major increase in the prevalence of childhood obesity is misleading with a risk of confusion between type 2 diabetes (T2D) and monogenic causes of diabetes.

Objective and hypotheses: To report on two informative families with negative auto-antibodies childhood-onset diabetes cases.

Method: Next generation sequencing (NGS) analysis of a panel of genes with a role in insulin secretion was applied to two index cases. Segregation analysis was subsequently performed by Sanger sequencing and quantitative PCR (MLPA) in relatives.

Results: In the first family, with three cases of diabetes diagnosed between the ages of 10 and 15 years, and a family history of T2D, diabetic subjects carried either a large deletion of the glucokinase gene (father inheritance), a variant of the ABCC8 gene (mother inheritance), or both (digenic inheritance). These genetic findings are likely associated with the variation in clinical presentation and evolution of diabetes in the family. In the second family, the onset of diabetes at the age of 15 years in an overweight but non-obese girl (HbA1c=14%, non-ketotic) with a father diagnosed as T2D at the age of 44 years, lead to the diagnosis of a novel pathogenic missense mutation of the insulin gene.

Conclusion: The identification of these rare causes of monogenic diabetes was made possible by the NGS approach. The paediatric community should be aware of these new technical possibilities for the etiological diagnosis of atypical forms of diabetes, to allow an accurate diagnosis and an appropriate management.