ESPE Abstracts

Introduction: Family history is observed in approximately 10% of the cases with type 1 diabetes mellitus (T1DM). The most important gene that determines susceptibility is the human leukocyte antigen complex (HLA) on chromosome 6. In HLA genes; specific combinations of alleles at DR3, DR4, DRB1, DQA1 and DQB1 locus either predispose or protective for T1DM. In this study, we aimed to investigate the molecular genetic etiology by whole exome sequence (WES) analysis in cases with familial T1DM who had no HLA haplotype predisposition or incomplete predisposition.

Method: Patients who had at least one first degree relatives with T1DM were included in the study. In the first step, HLA DRB1, DQA1 and DQB1 loci were investigated with polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) method. In the second step, the presence of variants that could explain the clinic in cases where both tissue types were negative in HLA typing (DQ2 (-) / DQ8 (-)) and only one of the HLA types was found positive (DQ2 (+) / DQ8 (-), and DQ2 (-) / DQ8 (+)) was investigated by WES analysis method.

Results: Four cases (16%) had consanguineous marriage between their parents out of 25 patients (female/male: 15/10). Mean age and diabetes duration of the cases were 15.77±5.89 and 8.31±5.71 years respectively. There was celiac disease in one case and Hashimato thyroiditis in 3 cases. Both HLA-DQ2 and DQ8 were positive in 17(68%) of the cases. WES analysis applied to one case with DQ2 (-) and DQ8 (-), 7 cases with DQ2 (+) and DQ8 (-), and one case with DQ2 (-) and DQ8 (+). They had no possible pathogen/pathogen variant. In the detailed analysis of genes important in DM etiology, high-scored VUS (variant with unknown efficacy) was found in 3 cases (Table 1). Segregation analysis are ongoing for variants detected in other affected individuals in the family.

Conclusion: In this study, non-HLA genes responsible for development of T1DM were detected in familial T1DM cases. It is planned that the presence of specific genes that have not yet been clarified for the pathogenesis and treatment of T1DM will continue to be investigated by increasing the number of cases without HLA tissue type predisposition with WES analysis.