Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset / P. Carrera, I. Marzinotto, R. Bonfanti, L. Massimino, S. Calzavara, M. Favellato, T. Jofra, V. De Giglio, C. Bonura, S. Stabilini, V. Favalli, S. Bondesan, M. Cicalese, A. Laurenzi, A. Caretto, G. Frontino, A. Rigamonti, C. Molinari, M. Scavini, F. Sandullo, E. Zapparoli, N. Caridi, S. Bonfiglio, V. Castorani, F. Ungaro, A. Petrelli, G. Barera, A. Aiuti, E. Bosi, M. Battaglia, L. Piemonti, V. Lampasona, G. Fousteri. - In: DIABETOLOGIA. - ISSN 0012-186X. - 66:4(2023 Apr), pp. 695-708. [10.1007/s00125-022-05865-5]

Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset

A. Petrelli;
2023

Aims/hypothesis: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. Methods: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. Results: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. Conclusions/interpretation: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.
Endotypes; Genetic risk score; HLA; Islet autoantibodies; Targeted exome sequencing; Type 1 diabetes; Whole exome sequencing;
Settore MED/13 - Endocrinologia
Settore MED/09 - Medicina Interna
apr-2023
24-gen-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1060068
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