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Identification of m...
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Harsunen, MinnaHelsinki University Central Hospital,University of Helsinki,Folkhälsan Research Center
(author)
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
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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2022-11-23
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Springer Science and Business Media LLC,2023
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LIBRIS-ID:oai:lup.lub.lu.se:e2f243f0-1b86-4662-870f-6b1646dce6f6
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https://lup.lub.lu.se/record/e2f243f0-1b86-4662-870f-6b1646dce6f6URI
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https://doi.org/10.1007/s00125-022-05834-yDOI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
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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: [Figure not available: see fulltext.]
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Kettunen, Jarno L.T.University of Helsinki,Folkhälsan Research Center,Helsinki University Central Hospital
(author)
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Härkönen, TainaUniversity of Helsinki
(author)
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Dwivedi, OmFolkhälsan Research Center,University of Helsinki
(author)
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Lehtovirta, MikkoUniversity of Helsinki
(author)
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Vähäsalo, PaulaUniversity of Oulu,Oulu University Hospital
(author)
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Veijola, RiittaOulu University Hospital,University of Oulu
(author)
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Ilonen, JormaUniversity of Turku
(author)
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Miettinen, Päivi J.Helsinki University Central Hospital,University of Helsinki
(author)
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Knip, MikaelTampere University Hospital,Helsinki University Central Hospital,University of Helsinki
(author)
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Tuomi, TiinamaijaLund University,Lunds universitet,Diabetiska komplikationer,Forskargrupper vid Lunds universitet,Diabetic Complications,Lund University Research Groups,Folkhälsan Research Center,Helsinki University Central Hospital,University of Helsinki(Swepub:lu)ti8736tu
(author)
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Helsinki University Central HospitalUniversity of Helsinki
(creator_code:org_t)
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In:Diabetologia: Springer Science and Business Media LLC66:3, s. 438-4490012-186X1432-0428
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Härkönen, Taina
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Vähäsalo, Paula
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Veijola, Riitta
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Diabetologia
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