Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?
-
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.
Funding source: Ministry of Health of the Czech Republic
Award Identifier / Grant number: NV18-01-007
Funding statement: The study was funded by the Grant Agency of Charles University in Prague (no. GAUK 216217), the Ministry of Health of the Czech Republic (funder Id: http://dx.doi.org/10.13039/501100003243) (no. NV18-01-0078) and the Welcome Trust Senior Investigator Award (no. 098395/Z/12/Z).
Acknowledgments
We would like to thank M. Slamova for technical assistance with the next-generation sequencing and all paediatricians for help with clinical data collection.
Author contributions: VS analysed the data and wrote the manuscript; SP designed the study and reviewed/edited the manuscript; LE analysed the data and wrote the manuscript; MBJ researched data and reviewed/edited the manuscript; ATH reviewed/edited the manuscript; PD designed the study and reviewed/edited the manuscript; BO investigated the patients; LP investigated the patients and reviewed/edited the manuscript; SK investigated the patients and reviewed/edited the manuscript; MaS investigated the patients; JL reviewed/edited the manuscript; ZS reviewed/edited the manuscript; EF analysed the data and reviewed/edited the manuscript; MiS analysed the data and reviewed/edited the manuscript. All authors made substantial contributions to the acquisition and interpretation of data, revised the manuscript critically for important intellectual content and approved the final version to be published. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Pociot F, Lernmark Å. Genetic risk factors for type 1 diabetes. Lancet 2016;387:2331–9.10.1016/S0140-6736(16)30582-7Search in Google Scholar PubMed
2. De Franco E, Flannagan SE, Houghton JA, Lango Allen H, Mackay DJ, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015;386:957–63.10.1016/S0140-6736(15)60098-8Search in Google Scholar PubMed
3. Johansson BB, Irgens HU, Molnes J, Sztromwasser P, Aukrust I, et al. Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetologia 2017;60:625–35.10.1007/s00125-016-4167-1Search in Google Scholar PubMed
4. Delvecchio M, Mozzillo E, Salzano G, Iafusco D, Frontino G, et al. Monogenic diabetes accounts for 6.3% of cases referred to 15 Italian pediatric diabetes centers during 2007 to 2012. J Clin Endocrinol Metab 2017;102:1826–34.10.1210/jc.2016-2490Search in Google Scholar PubMed
5. Shields BM, Shepherd M, Hudson M, McDonald TJ, Colclough K, et al. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients. Diabetes Care 2017;40:1017–25.10.2337/dc17-0224Search in Google Scholar PubMed
6. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, et al. Positional cloning of the APECED gene. Nat Genet 1997;17:393–8.10.1038/ng1297-393Search in Google Scholar PubMed
7. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20–1.10.1038/83713Search in Google Scholar PubMed
8. Johnson MB, Hattersley AT, Flanagan SE. Monogenic autoimmune diseases of the endocrine system. Lancet Diabetes Endocrinol 2016;4:862–72.10.1016/S2213-8587(16)30095-XSearch in Google Scholar PubMed
9. Sediva H, Dusatkova P, Kanderova V, Obermannova B, Kayserova J, et al. Short stature in a boy with multiple early-onset autoimmune conditions due to activating mutation: could intracellular growth hormone signalling be compromised? Horm Res Paediatr 2017;88:160–6.10.1159/000456544Search in Google Scholar PubMed
10. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 2007;119:482–7.10.1016/j.jaci.2006.10.007Search in Google Scholar PubMed
11. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 2014;46:812–4.10.1038/ng.3040Search in Google Scholar PubMed PubMed Central
12. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014;345:1623–7.10.1126/science.1255904Search in Google Scholar PubMed PubMed Central
13. Johnson MB, De Franco E, Lango Allen H, Al Senani A, Elbarbary N, et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes 2017;66:2316–22.10.2337/db17-0040Search in Google Scholar PubMed PubMed Central
14. Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016;127:3154–64.10.1182/blood-2015-11-679902Search in Google Scholar PubMed PubMed Central
15. Okada Y, Wu D, Trynka G, Raj T, Terao C, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506:376–81.10.1038/nature12873Search in Google Scholar PubMed PubMed Central
16. Hughes JW, Riddlesworth TD, DiMeglio LA, Miller KM, Rickels MR, et al. Autoimmune diseases in children and adults with type 1 diabetes from the T1D Exchange clinic registry. J Clin Endocrinol Metab 2016;101:4931–7.10.1210/jc.2016-2478Search in Google Scholar PubMed PubMed Central
17. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 2015;349:436–40.10.1126/science.aaa1663Search in Google Scholar PubMed
18. Horino S, Sasahara Y, Sato M, Niizuma H, Kumaki S, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant 2014;18:25–30.10.1111/petr.12184Search in Google Scholar PubMed
19. Huopio H, Miettinen PJ, Ilonen J, Nykänen P, Veijola R, et al. Clinical, genetic, and biochemical characteristics of early-onset diabetes in the Finnish population. J Clin Endocrinol Metab 2016;101:3018–26.10.1210/jc.2015-4296Search in Google Scholar PubMed
20. Johnson MB, Patel KA, De Franco E, Houghton JA, McDonald TJ, et al. A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes. Diabetologia 2018;61:862–9.10.1007/s00125-018-4551-0Search in Google Scholar PubMed PubMed Central
21. Schweiger DS, Mendez A, Jamnik SK, Bratanic N, Bratina N, et al. High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease. Autoimmunity 2016;49:240–7.10.3109/08916934.2016.1164144Search in Google Scholar PubMed
22. Oram RA, Patel K, Hill A, Shields B, McDonald TJ, et al. A type 1 diabetes genetic risk score can aid discrimination between type 1 and type 2 diabetes in young adults. Diabetes Care 2016;39:337–44.10.2337/dc15-1111Search in Google Scholar PubMed PubMed Central
23. Patel KA, Oram RA, Flanagan SE, De Franco E, Colclough K, et al. Type 1 diabetes genetic risk score: a novel tool to discriminate monogenic and type 1 diabetes. Diabetes 2016;65:2094–9.10.2337/db15-1690Search in Google Scholar PubMed PubMed Central
24. Petruzelkova L, Ananieva-Jordanova R, Vcelakova J, Vesely Z, Stechova K, et al. The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus. Diabet Med 2014;31:165–71.10.1111/dme.12308Search in Google Scholar PubMed
25. Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136–60.10.1097/MPG.0b013e31821a23d0Search in Google Scholar PubMed
26. Andrews S. FastQC a quality control tool for high throughput sequence data. https://www.bioinformatics.babraham.ac.uk/projects/fastqc/. Accessed: 25 Aug 2017.Search in Google Scholar
27. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:1754–60.10.1093/bioinformatics/btp324Search in Google Scholar PubMed PubMed Central
28. Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, et al. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatr Diabetes 2010;11:529–35.10.1111/j.1399-5448.2010.00646.xSearch in Google Scholar PubMed
29. Romanos J, Wijmenga C. Comment on: Barker et al. (2008) Two single nucleotide polymorphisms identify the highest-risk diabetes HLA genotype: Diabetes 57:3152-3155, 2008. Diabetes 2009;58:e1.10.2337/db08-1312Search in Google Scholar PubMed
30. Adzhubei IA, Jordan DM, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9.10.1038/nmeth0410-248Search in Google Scholar PubMed PubMed Central
31. Parackova Z, Kayserova J, Danova K, Sismova K, Dudkova E, et al. T regulatory lymphocytes in type 1 diabetes: impaired CD25 expression and IL-2 induced STAT5 phosphorylation in paediatric patients. Autoimmunity 2016;49:523–31.10.1080/08916934.2016.1217998Search in Google Scholar PubMed
32. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, et al. Phenotype, penetrance, and treatment of 133 CTLA-4-insufficient individuals. J Allergy Clin Immunol 2018;142:1932–46.10.1016/j.jaci.2018.02.055Search in Google Scholar PubMed PubMed Central
©2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Original Articles
- Ghrelin and leptin levels in children with anxiety disorders
- The effectiveness of enzyme replacement therapy on cardiac findings in patients with mucopolysaccharidosis
- Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty
- Changes in body mass index in children on gonadotropin-releasing hormone agonist therapy with precocious puberty, early puberty or short stature
- Psychological effects of gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty
- The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort
- Zinc deficiency in Japanese children with idiopathic short stature
- Psychometric performance of the Quality of Life in Short Stature Youth (QoLISSY) questionnaire in a randomized open-label comparator trial in idiopathic short stature
- Findings of metabolic bone disease in infants with unexplained fractures in contested child abuse investigations: a case series of 75 infants
- Effect of home-based strength training program on IGF-I, IGFBP-1 and IGFBP-3 in obese Latino boys participating in a 16-week randomized controlled trial
- Adiposity and attained height in adolescents: a longitudinal analysis from the LabMed Physical Activity Study
- Providing quality care for children and adolescents with diabetes from lower-income families in Mexico
- Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?
- Validation of a risk screening tool for pediatric type 1 diabetes patients: a predictor of increased acute health care utilization
- Triglyceride/glucose index is a reliable alternative marker for insulin resistance in South American overweight and obese children and adolescents
- Micro-RNA 196a2 expression and miR-196a2 (rs11614913) polymorphism in T1DM: a pilot study
- Case Reports
- Successful treatment of infantile-onset ACAD9-related cardiomyopathy with a combination of sodium pyruvate, beta-blocker, and coenzyme Q10
- Short stature: making a crystal clear diagnosis
- Severe arterial hypertension and hyperandrogenism in a boy: a rare case of catecholamine- and β-HCG-secreting pheochromocytoma
Articles in the same Issue
- Frontmatter
- Original Articles
- Ghrelin and leptin levels in children with anxiety disorders
- The effectiveness of enzyme replacement therapy on cardiac findings in patients with mucopolysaccharidosis
- Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty
- Changes in body mass index in children on gonadotropin-releasing hormone agonist therapy with precocious puberty, early puberty or short stature
- Psychological effects of gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty
- The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort
- Zinc deficiency in Japanese children with idiopathic short stature
- Psychometric performance of the Quality of Life in Short Stature Youth (QoLISSY) questionnaire in a randomized open-label comparator trial in idiopathic short stature
- Findings of metabolic bone disease in infants with unexplained fractures in contested child abuse investigations: a case series of 75 infants
- Effect of home-based strength training program on IGF-I, IGFBP-1 and IGFBP-3 in obese Latino boys participating in a 16-week randomized controlled trial
- Adiposity and attained height in adolescents: a longitudinal analysis from the LabMed Physical Activity Study
- Providing quality care for children and adolescents with diabetes from lower-income families in Mexico
- Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?
- Validation of a risk screening tool for pediatric type 1 diabetes patients: a predictor of increased acute health care utilization
- Triglyceride/glucose index is a reliable alternative marker for insulin resistance in South American overweight and obese children and adolescents
- Micro-RNA 196a2 expression and miR-196a2 (rs11614913) polymorphism in T1DM: a pilot study
- Case Reports
- Successful treatment of infantile-onset ACAD9-related cardiomyopathy with a combination of sodium pyruvate, beta-blocker, and coenzyme Q10
- Short stature: making a crystal clear diagnosis
- Severe arterial hypertension and hyperandrogenism in a boy: a rare case of catecholamine- and β-HCG-secreting pheochromocytoma
