Full text
| |
| Author(s): |
Lucas Santos de Santana
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2021-11-09 |
| Examining board members: |
Milena Gurgel Teles Bezerra;
Larissa Garcia Gomes;
Regina Celia Mello Santiago Moises
|
| Advisor: | Milena Gurgel Teles Bezerra |
| Abstract | |
Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion/action. In monogenic diabetes mellitus (MDM), which corresponds to 1%-4% of DM diagnosed until the third decade of life, the phenotype is caused by genetic or epigenetic mutations in a single locus. MDM is genetically heterogeneous, with more than 40 associated genes, each one with its clinical characteristic and mendelian and no-mendelian inheritance pattern. MODY (Maturity-Onset Diabetes of the Young) is the most prevalent MDM subtype, with a remarkable genetic etiology overlapping with Neonatal Diabetes Mellitus (NDM). Clinical diagnosis confirmation must be performed by genetic test, which is important for accurate phenotype classification, prediction of clinical course, and adequate genetic counseling. MDM genetic screening, in different cohorts, has been demonstrated that currently genes associated to this phenotype still do not explain 100% of clinically diagnosed cases. This study aimed to identify novel candidate genes not yet related to MODY and Neonatal Diabetes Mellitus. Whole Exome Sequencing (WES) study was performed in clinically diagnosed MODY and NDM patients who have a previous negative genetic test for genes already associated with which phenotype. Sixteen probands, 14 MODY and 2 NDM, in addition to 5 family members, were submitted to WES. In 68.7% (11/16) of them it was possible to identify 1 or more candidate gene for phenotypic association. The discovery rate among MODY probands was 60% (3/5) in those with MODY GCK and 88.8% (8/9) in MODY not GCK. No candidate genes were identified in NDM probands. Fourteen candidate loci were prioritized, with intracohort or literature recurrence in 3 of them (KL | PTPRD | ZBED3). Additionally, we identify a possible new phenotype spectrum of the Autosomal Dominant Optical Atrophy with or without Deafness and Diabetes (OPA1). This WES study will allow not only an expansion of MDM genetic heterogeneity, but also an extension in the phenotypic spectrum of this rare subtype of dysglycemia (AU) | |
| FAPESP's process: | 17/14703-4 - Exome study in families with clinical diagnosis of MODY (Maturity-Onset Diabetes of the Young) and Neonatal Diabetes |
| Grantee: | Lucas Santos de Santana |
| Support Opportunities: | Scholarships in Brazil - Doctorate |