Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register

Autor: Minna Harsunen, Jarno L. T. Kettunen, Taina Härkönen, Om Dwivedi, Mikko Lehtovirta, Paula Vähäsalo, Riitta Veijola, Jorma Ilonen, Päivi J. Miettinen, Mikael Knip, Tiinamaija Tuomi
Přispěvatelé: Medicum, HUS Children and Adolescents, Children's Hospital, CAMM - Research Program for Clinical and Molecular Metabolism, Institute for Molecular Medicine Finland, HUS Abdominal Center, Clinicum, Endokrinologian yksikkö, Molecular and Integrative Biosciences Research Programme, Faculty Common Matters (Faculty of Medicine), Viikki Molecular Nutrition Group, Centre of Excellence in Stem Cell Metabolism, Timo Pyry Juhani Otonkoski / Principal Investigator, Research Programs Unit, Centre of Excellence in Complex Disease Genetics, Tiinamaija Tuomi Research Group, Research Group Knip, Tampere University, Department of Paediatrics
Rok vydání: 2022
Předmět:
Zdroj: Diabetologia.
ISSN: 1432-0428
Popis: Aims/hypothesis Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. Methods The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual’s phenotype suggested monogenic diabetes. Results Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. Conclusions/interpretation More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes. Graphical abstract
Databáze: OpenAIRE