Whole Exome Sequencing characterization of Maturity-Onset Diabetes of the Young (MODY) and Type 2 Diabetes Mellitus patients reveals polygenic features and novel genetic variants of risk for MODY in a Latino population

IntroductionMODY misdiagnosis remains widespread, existing remarkable variability within genetic variants across populations. While diagnostic tools are based on Caucasian cohorts, Whole Exome Sequencing (WES) studies are needed to identify new genes in non-Caucasians, as up to 77% of patients do not harbor variants of significance in MODY-known genes. In Latino populations, no WES studies have addressed MODY genomic landscape beyond its canonical genes. MethodsWe carried out WES in 17 patients with MODY, 17 patients with type 2 diabetes (T2DM) and 17 healthy controls (HC). MODY diagnosis was established according to Exeter criteria (score [≥]36%) in subjects with no or minimal insulin requirements. We compared the single nucleotide variant (SNV) landscape across groups. ResultsPatients with MODY present a polygenic landscape with allelic variants in canonical and non-canonical genes. Canonical MODY genes used for routine genetic diagnosis showed low discrimination utility, having similar frequencies between MODY, T2DM and HC in the Mexican population. We propose 14 genes with variants that distinguish MODY from T2DM and HC, as we detected variants in genes as MAP2K3, SYT15, TPTE, KCNJ12, PEX5, and OR2A1 in 75-100% of MODY cases while were absent in T2DM and HC. Enrichment analysis revealed involvement in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase kinase/MAPK cascade, and insulin/IGF pathway-protein kinase B/AKT signaling cascade. DiscussionMODY presents a polygenic landscape. Besides improving our understanding of glycemic regulation pathways, the candidate genes could serve as MODY diagnostic biomarkers in Latino populations. FundingSupported by grant R-2019-785-052 from Instituto Mexicano del Seguro Social.