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Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?

  • Strakova, Veronika1
  • Elblova, Lenka1
  • Johnson, Matthew B.2
  • Dusatkova, Petra1
  • Obermannova, Barbora1
  • Petruzelkova, Lenka1
  • Kolouskova, Stanislava1
  • Snajderova, Marta1
  • Fronkova, Eva1
  • Svaton, Michael1
  • Lebl, Jan1
  • Hattersley, Andrew T.2
  • Sumnik, Zdenek1
  • Pruhova, Stepanka1
  • 1 Charles University in Prague, University Hospital Motol, Czech Republic , (Czechia)
  • 2 Institute of Biomedical and Clinical Science, University of Exeter Medical School, UK , (United Kingdom)
Published Article
Journal of Pediatric Endocrinology and Metabolism
Walter de Gruyter GmbH
Publication Date
Sep 04, 2019
DOI: 10.1515/jpem-2019-0261
De Gruyter


Background Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D. Methods Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions – either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS). Results We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases. Conclusions A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.

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