Diabetes Mellitus Diagnosed in Childhood and Adolescence With Negative Autoimmunity: Results of Genetic Investigation

Abstract

Monogenic diabetes is a rare form of diabetes, accounting for approximately 1% to 6% of pediatric diabetes patients. Some types of monogenic diabetes can be misdiagnosed as type 1 diabetes in children or adolescents because of similar clinical features. Identification of the correct etiology of diabetes is crucial for clinical, therapeutic, and prognostic issues. Our main objective was to determine the prevalence of monogenic diabetes in patients with diabetes mellitus, diagnosed in childhood or in adolescence, and negative autoimmunity. We retrospectively analyzed clinical data of 275 patients diagnosed with insulin-dependent diabetes at age <18yr in the last 10 years. 8.4% of subjects has negative autoimmunity. Their DNA was sequenced by NGS custom panel composed by 45 candidate genes involved in glucose metabolism disorder. Two novel heterozygous pathogenic or likely pathogenic variants (10,5% of autoantibody negative subjects) were detected: the frameshift variant c.617_618insA in NEUROD1 exon 2 and the missense change c.116T>C in INS exon 2. Our study corroborates previous results of other reports in literature. NGS assays are useful methods for a correct diagnosis of monogenic diabetes, even of rarest forms, highlighting mechanisms of pediatric diabetes pathogenesis.

From glucose sensing to exocytosis: takes from maturity onset diabetes of the young

“…NEUROD1 is highly expressed in neuroendocrine tissues and its central function in their development is evident from the mutations causing ketoacidosis-prone diabetes with microvascular sequelae and neurological abnormalities such as cerebellar hypoplasia, hearing and visual impairments, low IQ ( 125 ). Up to now, at least 26 missense and nonsense mutations found in NEUROD1 gene, which four of them were homozygous mutations ( 125 – 129 ). Homozygous inheritance shows more severe phenotype, earlier onset and higher penetrance than heterozygous state ( 130 ).…”

“Pesto” Mutation: Phenotypic and Genotypic Characteristics of Eight GCK/MODY Ligurian Patients

“…Monogenic diabetes is the second most prevailing type of diabetes after type 1 diabetes (T1D) in Italian youth, and the correct aetiological diagnosis greatly affects the treatment and likely the prognosis of diabetes complications [ 1 ].…”