Saso-Jiménez Laura, Urrutia Inés, Calvo Begona, Bilbao José Ramón, Gómez-Gila Ana Lucía, Leiva-Gea Isabel, Jiménez-Sanchis Andrea, Rica Itxaso, Castano Luis, Martínez Rosa
Biobizkaia Health Research Institute. Barakaldo, Spain.
UPV/EHU, CIBERDEM, CIBERER, Endo-ERN. Barakaldo, Spain.
J Clin Endocrinol Metab. 2025 Jan 28. doi: 10.1210/clinem/dgaf049.
The most frequent form of diabetes in pediatric patients is polygenic autoimmune diabetes (T1D), but single-gene variants responsible for autoimmune diabetes have also been described. Both disorders share clinical features, which can lead to monogenic forms being misdiagnosed as T1D. However, correct diagnosis is crucial for therapeutic choice, prognosis and genetic counseling. The aim of this study was to search for monogenic autoimmune diabetes in Spanish pediatric patients with early-onset T1D.
Among 500 Spanish pediatric patients with T1D, those with disease onset between 9 and 30 months of age were selected for screening for monogenic autoimmune diabetes (n=44). Genetic testing was performed by NGS with a customized panel that included the major causative genes for monogenic autoimmune syndromes, including early-onset diabetes: AIRE, CTLA4, FOXP3, IL2RA, ITCH, LRBA, STAT1, STAT3, STAT5B. RT-PCR and cDNA sequencing of the RNA isolated from whole blood were used to analyze splicing variants.
Genetic screening identified, in two patients with diabetes onset under one year of age, two likely pathogenic novel variants affecting canonical splicing sites: c.286-12_290del in STAT5B and c.-22-2delA in FOXP3. RNA analyses demonstrated that both variants modify mRNA splicing. The variant in STAT5B induced exon 4 skipping and the variant in FOXP3 caused a deletion of 16 nucleotides before the transcription start-site.
T1D onset in the first year of life may indicate monogenic autoimmune diabetes and molecular testing may be recommended.
儿科患者中最常见的糖尿病类型是多基因自身免疫性糖尿病（T1D），但也有导致自身免疫性糖尿病的单基因变异被描述。这两种疾病具有共同的临床特征，可能导致单基因形式被误诊为T1D。然而，正确诊断对于治疗选择、预后和遗传咨询至关重要。本研究的目的是在西班牙早发性T1D的儿科患者中寻找单基因自身免疫性糖尿病。
在500名西班牙T1D儿科患者中，选择发病年龄在9至30个月之间的患者进行单基因自身免疫性糖尿病筛查（n = 44）。通过下一代测序（NGS）使用定制的检测板进行基因检测，该检测板包括单基因自身免疫综合征的主要致病基因，包括早发性糖尿病相关基因：AIRE、CTLA4、FOXP3、IL2RA、ITCH、LRBA、STAT1、STAT3、STAT5B。使用从全血中分离的RNA进行逆转录聚合酶链反应（RT-PCR）和cDNA测序来分析剪接变异。
基因筛查在两名发病年龄在一岁以内的糖尿病患者中，发现了两个可能影响典型剪接位点的致病性新变异：STAT5B基因中的c.286-12_290del和FOXP3基因中的c.-22-2delA。RNA分析表明这两个变异均改变了mRNA剪接。STAT5B基因中的变异导致外显子4跳跃，FOXP3基因中的变异导致转录起始位点前16个核苷酸缺失。
生命第一年出现的T1D可能提示单基因自身免疫性糖尿病，可能需要进行分子检测。
