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

Abstract MODY is a heterogeneous group of monogenic forms of diabetes which present autosomal dominant inheritance in most cases, early onset, and lack of beta-cell autoimmunity. Up to 14 types of MODY have been described in genes with key roles in beta-cell differentiation, insulin secretion, and glucose metabolism. MODY misdiagnosis remains widespread, due to overlapping clinical phenotypes and remarkable variability within genetic variants across populations. Whole Exome Sequencing (WES) studies are needed to identify new genes in non-caucasian populations, as up to 77% of non-caucasian MODY patients do not harbor variants of significance in MODY-known genes. We characterized the genetic landscape of Mexican patients with MODY through WES, comparing data with T2DM and healthy subjects and proposed a novel set of genes in MODY in a Latino population. We enrolled 51 participants divided into 3 groups, each comprising 17 subjects. Among MODY 1-14 genes, ABCC8, CEL, BLK and HNF1A genes presented the highest burden of variants across patients and found statistically significant differences in variant frequencies across groups in 5.3% of total variants. The only pathogenic variant in MODY cases that reached statistical significance (p<0.001) across all groups was c.C1226T:p.T409I in CEL gene (deleterious by SIFT and probably damaging by PolyPhen) as was present in 58.9% of MODY patients, while in 0% of T2DM and healthy subjects. We detected other frequent pathogenic, possibly/probably damaging, deleterious, or CIP variants in Mexican MODY cases in genes such as HNF1A (c.A79C:p.I27L), and APPL1 (c.A2099G:p.E700G) in 64.7% and 23.5% of MODY patients, respectively, but at similar frequencies in T2DM and healthy controls. The CEL pathogenic variants c.T2059G:p.S687A and c.G2065C:p.A689P were exclusively detected in 11.8% of MODY cases, while additional pathogenic variants in GCK, NEUROD1, PAX4, ABCC8, KCNJ11, and BLK were detected in 5.9% of cases. Upon analyzing MODY patients individually, we unveiled the presence of one or more pathogenic/likely pathogenic/deleterious/CIP variants in 15/17 (88%) patients, and no variants in 12%. However, among those 15 cases, 12 patients presented two or more concomitant pathogenic/likely pathogenic/deleterious/CIP variants, revealing polygenic features in Mexican MODY patients. WES mutational analysis revealed global and specific differences and differential enrichment in genes across groups. We propose a set of 15 candidate genes ( KCNJ2, OR2A1, RIMBP3, TRIM49C, CLEC18B, OR2T5, PEX5, AQP12B, OR51A4, SYT15, TRIM64, GSTT2B, SUSD2, TPTE, ZNF814 ) which are significantly (p<0.01) enriched in Mexican MODY patients and not in T2DM and healthy subjects, and 12 genes significantly enriched in Mexican T2DM and healthy groups, while not in MODY cases ( ABC7, ASAH2, OR2A42, RIMBP3C, NBPF6, PGA3, GOLGA8N, PABPC1, PABPC3, CNTNAP3B, POTEM, SPIN2A ). Upon analysis of exclusively high impact variants and considering a cutoff value of an adjusted p<0.01, we propose a set of 4 genes ( MAP2K3 , PEX5 , KMT2C, and ZNF717 ) enriched in the MODY group when compared to both T2DM and healthy subjects and 10 genes ( ABC7, MUC6, PLIN4, OR8U1, NBPF11 , PABPC3, RBMX, LILRA6, PABPC1, and ARHGEF5 ) enriched in both Mexican T2DM and healthy groups. MODY behaves as a genetically heterogeneous disease in the Mexican population. Although MODY 1-14 variants are frequent in Mexican patients, T2DM and healthy controls present similar frequency rates in most cases. MODY could behave as a polygenic disease in some patients and other genes may be involved in MODY Latino populations.