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

2024-09Artigo científico Acesso aberto
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dc.contributor.authorRibeiro, Andreia Fiúza
dc.contributor.authorFitas, Ana Laura
dc.contributor.authorPires, Marcela Oliveira
dc.contributor.authorMatoso, Paula
dc.contributor.authorLigeiro, Dário
dc.contributor.authorSobral, Daniel
dc.contributor.authorPenha-Gonçalves, Carlos
dc.contributor.authorDemengeot, Jocelyne
dc.contributor.authorCaramalho, Íris
dc.contributor.authorLimbert, Catarina
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionComprehensive Health Research Centre (CHRC) - pólo NMS
dc.contributor.pblHindawi Limited
dc.date.accessioned2024-10-21T23:22:35Z
dc.date.available2024-10-21T23:22:35Z
dc.date.issued2024-09
dc.descriptionPublisher Copyright: Copyright © 2024 Andreia Fiúza Ribeiro et al.
dc.description.abstractAims: 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent899580
dc.identifier.doi10.1155/2024/3076895
dc.identifier.issn2314-6753
dc.identifier.otherPURE: 101079622
dc.identifier.otherPURE UUID: 66c3fa91-aadf-49a0-93c0-28b6b09a717b
dc.identifier.otherScopus: 85205605241
dc.identifier.otherPubMed: 39364395
dc.identifier.urihttp://hdl.handle.net/10362/173834
dc.identifier.urlhttps://www.scopus.com/pages/publications/85205605241
dc.language.isoeng
dc.peerreviewedyes
dc.subjectearly-onset
dc.subjectMODY
dc.subjecttype 1 diabetes
dc.subjectwhole exome sequencing
dc.subjectβ-cell dysfunction
dc.subjectEndocrinology, Diabetes and Metabolism
dc.subjectEndocrinology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleWhole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneityen
dc.typejournal article
degois.publication.titleJournal of diabetes research
degois.publication.volume2024
dspace.entity.typePublication
rcaap.rightsopenAccess

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