{Reference Type}: Journal Article
{Title}: Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.
{Author}: Carrera P;Marzinotto I;Bonfanti R;Massimino L;Calzavara S;Favellato Μ;Jofra T;De Giglio V;Bonura C;Stabilini A;Favalli V;Bondesan S;Cicalese MP;Laurenzi A;Caretto A;Frontino G;Rigamonti A;Molinari C;Scavini M;Sandullo F;Zapparoli E;Caridi N;Bonfiglio S;Castorani V;Ungaro F;Petrelli A;Barera G;Aiuti A;Bosi E;Battaglia M;Piemonti L;Lampasona V;Fousteri G;
{Journal}: Diabetologia
{Volume}: 66
{Issue}: 4
{Year}: 04 2023
{Factor}: 10.46
{DOI}: 10.1007/s00125-022-05865-5
{Abstract}: 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.<BR>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.<BR>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.<BR>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.