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Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.

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  • معلومة اضافية
    • المصدر:
      Publisher: Wiley Country of Publication: United States NLM ID: 101605237 Publication Model: eCollection Cited Medium: Internet ISSN: 2314-6753 (Electronic) NLM ISO Abbreviation: J Diabetes Res Subsets: MEDLINE
    • بيانات النشر:
      Publication: 2024- : [Hoboken, NJ] : Wiley
      Original Publication: Nasr City, Cairo : Hindawi Publishing Corporation, [2013]-
    • الموضوع:
      Diabetes Mellitus, Type 1*/genetics ; Exome Sequencing* ; Genetic Predisposition to Disease*; Humans ; Child, Preschool ; Female ; Male ; Hepatocyte Nuclear Factor 1-beta/genetics ; Trans-Activators/genetics ; Homeodomain Proteins/genetics ; Hepatocyte Nuclear Factor 4/genetics ; Germinal Center Kinases/genetics ; Polymorphism, Single Nucleotide ; Infant ; C-Peptide/blood ; Autoantibodies ; Child ; Haplotypes ; Diabetes Mellitus, Type 2/genetics ; Glucokinase/genetics ; Regulatory Factor X Transcription Factors
    • نبذة مختصرة :
      Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK ( n = 1), HNF1B ( n = 2), HNF4A ( n = 1), PDX1 ( n = 2), and RFX6 ( n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β -cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.
      Competing Interests: The authors declare no conflicts of interest.
      (Copyright © 2024 Andreia Fiúza Ribeiro et al.)
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    • Contributed Indexing:
      Keywords: MODY; early-onset; type 1 diabetes; whole exome sequencing; β-cell dysfunction
    • الرقم المعرف:
      0 (pancreatic and duodenal homeobox 1 protein)
      0 (HNF1B protein, human)
      0 (Rfx6 protein, human)
      138674-15-4 (Hepatocyte Nuclear Factor 1-beta)
      0 (Trans-Activators)
      0 (HNF4A protein, human)
      0 (Homeodomain Proteins)
      0 (Hepatocyte Nuclear Factor 4)
      0 (Germinal Center Kinases)
      0 (MAP4K2 protein, human)
      0 (C-Peptide)
      0 (Autoantibodies)
      EC 2.7.1.2 (Glucokinase)
      0 (Regulatory Factor X Transcription Factors)
    • الموضوع:
      Date Created: 20241004 Date Completed: 20241004 Latest Revision: 20241005
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC11449554
    • الرقم المعرف:
      10.1155/2024/3076895
    • الرقم المعرف:
      39364395