MON-556 Characterizing the Genomic Landscape of MODY in a Latino Population, New Candidate Genes and Insights Beyond MODY 1-14

Abstract Disclosure: A. Moscona-Nissan: None. D. Marrero-Rodríguez: None. S. Andonegui-Elguera: None. E.S. Luna-Ávila: None. F. Martínez-Mendoza: None. S. Vela-Patiño: None. I. Ramírez-Ramos: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R.A. Chavez-Santoscoy: None. S. Mercado-Medrez: None. K.S. León-Wu: None. R. De Miguel Ibanez: None. M. Mercado: None. K. Taniguchi-Ponciano: None. A. Ferreira-Hermosillo: None. MODY 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 explored MODY’s genomic landscape beyond its canonical genes. We carried WES in 51 participants: 17 patients with MODY, 17 with type 2 diabetes (T2DM) and 17 healthy controls (HC) at a Mexican tertiary care center. MODY diagnosis followed Exeter criteria (score ≥36%) in subjects with minimal or no insulin use. Clinical and genomic data were analyzed, comparing the SNV landscape across groups using Maftools in R, and performing enrichment analyses. We compared genetic variant frequencies of MODY 1-14 and additional genes associated with MODY in other populations using Chi-squared test. Canonical MODY genes used for routine genetic diagnosis showed low discrimination utility, having variants similar frequencies between MODY, T2DM and HC in the Mexican population. We propose 14 candidate genes with variants distinguishing MODY from T2DM and HC, as we detected variants in genes as MAP2K, TPTE, SYT15, PEX5, KCNJ12, KTM2C, OR2A1, RIMBP3, TRIM49C, AQP12B, OR51A4, RIMBP3B, ZNF717, and SUSD2 in 75-100% of MODY cases while absent in T2DM and HC. In MAP2K3, we detected variants c.281G>T (p.Arg94Leu), c.286C>T (p.Arg96Trp), c.304C>T (p.Gln102Ter), and c.164G>C (p.Arg55Thr) in 100% of MODY cases but in none of T2DM/HC cases. In KCNJ12, variant c.128G>A (p.Arg43His) was found in 100% of MODY but 0% of T2DM/HC cases. In TPTE, variants c.1156A>G (p.Lys386Glu) and c.1445A>C (p.Tyr482Ser) were detected in 100% and 94% of MODY cases, respectively, while absent in T2DM/HC. Regarding PEX5, a splicing variant was found in 94% of MODY cases while in 0% of T2DM/HC. Enrichment analysis revealed involvement of the mentioned genes in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase/MAPK cascade, and insulin/IGF pathway-protein kinase B/AKT signaling cascade. This is the first WES study in a MODY Latino population, analyzing beyond canonical genes. Besides improving our understanding of glycemic regulation pathways, candidate genes could serve as diagnostic biomarkers for MODY in Latinos, enabling accurate diagnosis and implementation of personalized therapies for patients. Presentation: Monday, July 14, 2025