Molecular genetic etiology by whole exome sequence analysis in cases with familial type 1 diabetes mellitus without HLA haplotype predisposition or incomplete predisposition

Uğur Cem Yilmaz; Ferda Evin; Huseyin Onay; Samim Ozen; Sukran Darcan; Damla Goksen Simsek

doi:10.1515/jpem-2022-0295

Article

Molecular genetic etiology by whole exome sequence analysis in cases with familial type 1 diabetes mellitus without HLA haplotype predisposition or incomplete predisposition

Uğur Cem Yilmaz , Ferda Evin , Huseyin Onay , Samim Ozen , Sukran Darcan and Damla Goksen Simsek

Published/Copyright: November 7, 2022

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 36 Issue 1

Abstract

Objectives

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. More than 50 susceptible loci are 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 (WES) analysis in cases with familial T1DM with no or weakly detected HLA tissue type susceptibility. We aimed to identify new genes responsible for the development of type 1 diabetes and to reveal new genes that have not been shown in the literature before.

Methods

Cases with at least one T1DM 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. In the second step, the presence of variants that could explain the situation was investigated by WES analysis in patients who were 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) were 14.9 ± 6 and 7.56 ± 3.84 years, respectively. There was consanguineous marriage in 5 (16%) of the families. As a result of filtering all exome sequence analysis data of two cases with DQ2 (DQB1*02) (−) and DQ8 (DQB1*03:02) (−), seven cases with DQ2 (DQB1*02) (+) and DQ8 (DQB1*03:02) (−), and one case with DQ2 (DQB1*02) (−) and DQ8 (DQB1*03:02) (+), seven different variants in seven different genes were detected in five cases. The pathogenicity of the detected variants were determined according to the “American College of Medical Genetics and Genomics (ACMG)” criteria. These seven 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 variant 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.

Conclusions

In conclusion, in this study, seven different variants in seven different genes were detected in five patients by WES analysis in familial T1DM patients with no or weak HLA tissue type susceptibility. These seven variants detected were evaluated as high-score VUS. POLG might be a novel candidate gene responsible for susceptibility to T1DM. Non-HLA genes directly responsible for the development of T1DM were not detected in any of the cases.

Keywords: child; gene; HLA; non HLA gene; type 1 diabetes; whole exome sequence analysis

Corresponding author: Uğur Cem Yilmaz, MD, Department of Pediatrics, Ege University Faculty of Medicine, 35100, Izmir, Turkey, Phone: +90 232 3901230, +90 505 5959800, Fax: +90 232 3886366, E-mail: cmylmz12@gmail.com

Funding source: Ege Ãœniversitesi

Award Identifier / Grant number: Projects Number: TGA 2021-22312

Research funding: Our research was supported by Ege University Scientific Research Projects (Projects Number: TGA 2021-22312) coordinatorship.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: Approval was obtained from the Medical Research Ethics Committee (Approval Number: 19-7T/50) of Ege University Faculty of Medicine.

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Received: 2022-06-11

Accepted: 2022-09-28

Published Online: 2022-11-07

Published in Print: 2023-01-27

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https://doi.org/10.1515/jpem-2022-0295

Keywords for this article

child; gene; HLA; non HLA gene; type 1 diabetes; whole exome sequence analysis