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Maturity Onset Diabetes of the Young (MODY) remains an underdiagnosed condition with remarkable genetic variability 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. No WES studies have addressed the genomic landscape of MODY beyond its canonical genes in Latino populations. We aimed to characterize the genomic landscape of MODY through WES in a Mexican cohort, comparing cases with type 2 diabetes mellitus (T2DM) patients and healthy controls (HC).

WES was performed in 17 patients with MODY, 17 with T2DM and 17 HC. We compared the single nucleotide variant landscape across groups in MODY-known genes and searched for genetic variants with differential enrichment across groups.

MODY genes used for routine diagnosis showed low discrimination utility, as patients with MODY, T2DM and HC harbored genetic variants in MODY-known genes at similar frequencies in most cases. We found 14 genes with variants capable of distinguishing MODY from T2DM and HC. Variants in genes such as MAP2K3, SYT15, KCNJ12, PEX5, and TPTE were found in 75-100% of MODY cases while absent in T2DM and HC. Enrichment analysis revealed involvement in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase kinase/MAPK, and insulin/IGF pathway-protein kinase B/AKT signaling.

MODY presents a complex genetic architecture in the Mexican population. Besides improving our understanding of glycemic regulation pathways, identified genes may serve as diagnostic biomarkers.