ESPE Abstracts (2015) 84 FC3.2

Experience with Molecular Diagnosis in 48 Cases of Neonatal Diabetes Mellitus Using Targeted Next-Generation Sequencing

Yulia Tikhonvicha, Evgeny Vasilyeva, Vasily Petrova, Oleg Malievskyd, Elena Petryaikinab, Irina Ribkinab, Olga Stotikovac & Anatoly Tiulpakova


aEndocrinology Research Center, Moscow, Russia; bMorozovskaya Children City Clinical Hospital of the Moscow Healthcare Department, Moscow, Russia; cRussian Children Clinical Hospital, Moscow, Russia; dRepublican Children’s Clinical Hospital, Ufa, Russia


Background: Neonatal diabetes mellitus (NDM) comprises a group of monogenic disorders caused by mutations in genes involved in pancreatic development or insulin secretion. Accurate and rapid molecular diagnosis of NDM is pivotal for making decision on the treatment strategy. Next-generation sequencing (NGS) allows simultaneos analysis of several candidate genes, which facilitates the diagnostic procedure in NDM.

Objective and hypotheses: To summarise our experience with molecular diagnosis of NDM using targeted NGS.

Method: 48 children with NDM were studied. Seven patients had transient NDM (TNDM), while 41 patients had permanent NDM (PNDM), five of which showed features of DEND-syndrome. In seven subjects KCNJ11, ABCC8 and INS genes were initially analysed by Sanger sequencing, and no mutations were found. ‘Diabetes panel’ genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). Bioinformatic analysis was performed using Torrent Suite (Ion Torrent) and ANNOVAR (annovar.openbioinformatics.org) Software packages.

Results: Mutations were identified in 38 of 48 patients (79.1%). Distribution of mutations was as follows: KCNJ11, n=22; INS, n=7; ABCC8, n=3; INSR, n=2; EIF2AK3, n=1; FOXP3, n=1; and HNF1B1, n=1. One patient showed digenic (HNF1A and GLIS3) mutatons. Nine mutations were novel. The patient with PNDM and EIF2AK3 defect had no features of Wolcott-Rallison syndrome at the time of diagnosis. Seventeen children with KCNJ11 defects were successfully switched from insulin to glibenclamide.

Conclusion: The study shows that targeted NGS can be successfully used in infants with NDM.

Funding: This work was supported by Alfa-Endo Program of Charities Aid Foundation (CAF) Russia.

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