University of Oulu

Harsunen, M., Kettunen, J.L.T., Härkönen, T. et al. 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. Diabetologia 66, 438–449 (2023).

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

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Author: Harsunen, Minna1,2,3; Kettunen, Jarno L. T.2,3,4,5; Härkönen, Taina3;
Organizations: 1New Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
2Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
3Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
4Abdominal Centre, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
5Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
6Department of Pediatrics, PEDEGO Research Unit, University of Oulu, Oulu, Finland
7Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
8Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
9Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
10Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
11Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
12Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Lund, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-09-08


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.

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Series: Diabetologia
ISSN: 0012-186X
ISSN-E: 1432-0428
ISSN-L: 0012-186X
Volume: 66
Pages: 438 - 449
DOI: 10.1007/s00125-022-05834-y
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. The FPDR has been supported by the Academy of Finland (grant no. 292538 to MK), the Sigrid Juselius Foundation, Finska Läkaresällskapet, and the Liv and Hälsa Fund. The Botnia and FINNMODY Study have been supported by grants from the Folkhälsan Research Foundation, the Sigrid Juselius Foundation, the Academy of Finland (grants 263401, 267882 and 312063 to LG; grant no. 312072 to TT), University of Helsinki, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS, MOSAIC FP7-600914), Ollqvist Foundation, Swedish Cultural Foundation in Finland, Novo Nordisk Foundation, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Signe and Ane Gyllenberg Foundation, Finnish Medical Society, Paavo Nurmi Foundation, State Research Funding via the Helsinki University Hospital, Perklén Foundation, Närpes Health Care Foundation and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland, Municipal Health Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, Närpes and Korsholm.
Dataset Reference: The de-identified datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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