1 - Paediatric Endocrinology Unit, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
2 - Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Congresso internacional online
- Apresentação em forma de poster
Resumo:
Introduction: MODY prevalence in pediatric diabetes populations is variable. Many cases are misdiagnosed as type 1 (T1D) or type 2 diabetes. Moreover, diabetes types are not mutually exclusive, and it is not yet clear how they interact towards the clinical phenotype.
Objectives: To evaluate the presence of mutations in known MODY genes in a selected cohort of early onset T1D children (≤5Y, EOT1D) and to determine the genotype–phenotype associations.
Methods: This cohort is included in a study on the genetics of EOT1D versus later onset (≥8Y). DNA samples were processed for high resolution HLA II haplotyping and Single Nucleotide Polymorphisms (SNP) genotyping. T1D-Genetic Risk Score (T1D-GRS) was calculated using 36 non-HLA SNPs associated with T1D.
Results: Among EOT1D children (N=102), 12 patients (11,8%) had mutations in MODY genes. In silico evaluation of pathogenicity using 5 prediction tools was conclusive for the presence of likely deleterious mutations in HNF1A (n=1), HNF1B (n=2), HNF4A (n=1) and GATA6 (n=1) genes, in 4 of these patients (Table 1). Other mutations were located in CEL (n=3), PDX1 (n=3) and INS (n=1) genes. EOT1D patients harboring in silico predicted deleterious MODY mutations had T1D risk HLA II haplotypes (at least one DR3 or DR4 haplotype) as well as a T1D-GRS within the range displayed by the other EOT1D patients in our cohort.
Conclusions: This study shows that in silico predicted deleterious mutations in MODY genes can be found in children with EOT1D, suggesting an overlap of diabetes subtypes and beta cell dysfunction mechanisms. MODY screening may be considered in children ≤5 years old with T1D phenotype, independently of auto-antibodies status. Accurate diagnosis of diabetes in young children allows for better understanding of disease pathophysiology and for implementation of specific interventions, representing an opportunity to apply precision-medicine approaches.