Searching for Monogenic Autoimmune Etiology in Patients With Type 1 Diabetes Onset Before 30 Months of Age.

Introduction: The most frequent form of diabetes in pediatric patients is polygenic autoimmune diabetes (type 1 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.

Methods: 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 next-generation sequencing 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.

Results: Genetic screening identified, in 2 patients with diabetes onset before 1 year of age, 2 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.

Conclusion: T1D onset in the first year of life may indicate monogenic autoimmune diabetes and molecular testing may be recommended.