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J Pediatr Endocrinol Metab. 2019 Sep 4. pii: /j/jpem.ahead-of-print/jpem-2019-0261/jpem-2019-0261.xml. doi: 10.1515/jpem-2019-0261. [Epub ahead of print]

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

Author information

1
Department of Paediatrics, 2Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic.
2
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
3
Department of Paediatric Haematology and Oncology, 2Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic.

Abstract

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.

KEYWORDS:

CTLA4; IPEX syndrome; STAT3; T1D-GRS; monogenic autoimmune diabetes

PMID:
31483759
DOI:
10.1515/jpem-2019-0261

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