ESPE Abstracts

Background and aims: The introduction of next-generation sequencing (NGS) as an essential tool for the routine molecular diagnosis of DM has highlighted the under-diagnosis of monogenic diabetes mellitus (MonDM). Accurate molecular diagnosis of the MonDM subtype has important implications for prognosis and choice of treatment, family counseling and health management, enabling precision medicine. The main objective was to clinically and molecularly characterize the different forms of MonDM in pediatric patients referred by pediatric endocrinologist in Spanish tertiary hospitals during the period from January 2009 to December 2021.

Materials and methods: Multicenter cross-sectional study that included 131 pediatric patients with suspected MonDM analyzed by targeted NGS with a custom panel including up to 482 genes implicated in or associated with dysglycemia. The variants detected were classified according to ACMG rules and prioritized using criteria of confidence and quality, coverage (20x/pb >95%), allele frequency in control population (<1%, gnomAD) and predicted deleteriousness (CADD>15). Quantitative data were expressed as mean±standard deviation and qualitative data as absolute frequencies and percentages

Results: Variants in known MODY genes were identified in 95/121 patients (78.5%). We identified variants in 13/14 MODY genes, excepting the APPL1-MODY subtype. The most prevalent form was GCK-MODY (43.8%) followed by HNF1a-MODY (9%) and HNF4a-MODY (5%). There were 4 digenic MODY forms, 5 novel variants, 3 de novo, and two patients with positive pancreatic autoimmunity. 17.3% (n=21) of the cases presented with predicted deleterious variants in candidate genes (MODY-X), suggesting a potential role for NR4A3, RFX6, PCK1, PCK2, SERPINB3, SERPINB4, GLUD1, FOXA1, FOXA2 and PPARG in the etiology of MonDM; 28% (n=34) presented >1 deleterious variant in dysglycemia-related genes; 6.6% (n=8) had neonatal DM (NMD) with variants in ABCC8, KCNJ11, RFX6 or HNF1b, and 1 case transient NDM (disomy of chromosome 6). Lastly, 5.7% (n=7) presented syndromic forms of diabetes: four cases compatible with Wolfram Syndrome 1 (WFS1, AR), two with Wolfram-like Syndrome (WFS1, AD) and four cases with Martínez-Frías/Mitchell-Riley syndrome (RFX6, AR).

Conclusions: The study of MonDM by NGS reveals a greater genetic complexity than initially expected. The clinical heterogeneity classically described for MonDM may be due to the oligogenic combination of variants in different relevant genes. The identification of new genes involved in its etiology will make it possible to establish genotype-phenotype correlations to guide diagnostic suspicion, predict the evolution, prognosis and transmission of MonDM and optimize/personalize treatment.