HLA Doku Tipi Yatkınlığı Saptanmayan Ailesel Tip 1 Diyabetes Mellituslu Olgularda Tüm Ekzom Dizi Analizi İle Sorumlu Yeni Genlerin Araştırılması
Project no. 22312 · Status: Kapanmış · 2021
Summary
<p>ABSTRACT Introduction: Familial transmission is observed in approximately 10% of cases with type 1 diabetes mellitus (T1DM). The most important gene determining susceptibility is the human leukocyte antigen complex (HLA) located on chromosome 6. In HLA genes; Specific combinations of alleles at the DR3, DR4, DRB1, DQA1 and DQB1 loci produce both predisposing and protective haplotypes for T1DM. More than 50 susceptible loci associated with T1DM susceptibility have been identified in genes other than HLA. In this study, it was aimed to investigate the molecular genetic etiology by whole exome sequence analysis in cases with familial T1DM with no or weakly detected HLA tissue type susceptibility. Method: Cases with at least one type 1 DM diagnosis in first-degree relatives were included in the study. In the first step, HLA DQ2 and DQ8 loci, which are known to be associated with T1DM susceptibility, were investigated by polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) method. In the second step, the presence of variants that could explain the situation was investigated by whole-exome sequence analysis in tissue typing patients who were found to be negative for both HLA DQ2 and HLA DQ8 haplotypes, HLA DQ2 negative, HLA DQ8 positive, and HLA DQ2 positive and HLA DQ8 negative patients. Results: The mean age and duration of diabetes of the 30 cases (Girl/Male: 17/13) included in the study were 14.9±6 and 7.56±3.84 years, respectively. There was consanguineous marriage between mother and father in 4 (16%). As a result of filtering all exome sequence analysis data of 2 cases with DQ2 (-) and DQ8 (-), 7 cases with DQ2 (+) and DQ8 (-), and 1 case with DQ2 (-) and DQ8 (+), 7 different variants in 7 different genes were detected in 5 cases. The pathogenicity of the detected variants were determined according to the “American College of Medical Genetics and Genomics (ACMG)” criteria. These 7 variants detected were evaluated as high-score VUS (Variants of unknown/uncertain significance). In the segregation study conducted for the mutation in the POLG gene detected in case 5, this mutation was detected in the mother of the case and his brother with T1DM. Segregation studies are ongoing for variants detected in other affected individuals in the family. Conclusion: In conclusion, in this study, 7 different variants in 7 different genes were detected in 5 patients by whole-exome sequence analysis in familial T1DM patients with no or weak HLA tissue type susceptibility. These 7 variants detected were evaluated as high-score VUS (Variants of unknown/uncertain significance). Non-HLA genes directly responsible for the development of type 1 DM were not detected in any of the cases. For the pathogenesis and treatment of T1DM, it is planned to continue to investigate the presence of unique and unexplained genes on a larger sample by whole exome sequence analysis in cases without HLA tissue type susceptibility. Keywords: Type 1 Diabetes ; Whole Exome Sequence Analysis; HLA ; non HLA Gene, Gene , Child</p>