ESPE Abstracts (2021) 94 FC4.5

ESPE2021 Free Communications Diabetes (6 abstracts)

Molecular Genetic Diagnosis and Research of Candidate Genes by Targeted Next Generation Sequence Analysis and Whole Exome Sequencing Method in Monogenic Diabetes: MODY-TURK Project

Damla Gökşen 1 , Ferda Evin 1 , Esra Işık 1 , Samim Özen 1 , Tahir Atik 1 , Ferda Özkınay; 1 , Neşe Akcan 2 , Behzat Özkan 3 , Muammer Büyükinan 4 , Mehmet Nuri Özbek 5 , Şükran Darcan 1 & Hüseyin Onay 6


1Ege University, Izmir, Turkey.;2Near East University, Lefkoşa, Cyprus.;3Behçet Uz Children Hospital, Izmir, Turkey.;4Konya Hospital, Konya, Turkey.;5Diyarbakır Hospital, Diyarbakır, Turkey.;6Multigen Genetic Diseases Diagnosis Center, Izmir, Turkey


Introduction: MODY; is a rare type of diabetes that occurs clinically and genetically due to a single heterogeneous gene defect. To date, 14 different genes have been identified. In order to develop a holistic genetic diagnosis approach to monogenic DM, it is aimed to investigate molecular genetic diagnosis and responsible candidate genes with targeted new generation sequence analysis and whole exome sequencing (WES) method.

Method: With the prediagnosis of MODY, 100 subjects between 0-25 years of age, were included in the study. In the first step, a targeted new generation sequence analysis panel including ABCC8, GCK, HNF1A, HNF4A, INS, KCNJ11, PDX1, PAX4, TCF2/HNF1B, NEUROD1, KLF11, CEL, BLK and APPL1 genes analysis was done. Whole exome sequencing was planned in cases where no variant was detected in these genes. Pathogenicity of the detected variants was determined according to the criteria of “American College of Medical Genetics and Genomics” (ACMG).

Results: Thirty-three different variants in 8 different genes were detected in thirty-nine(39 %) cases with the NGS. Most common pathogen variant was found in GCK gene in 25(25%) cases. Six different variants were detected in 6(6%) patients in ABCC8 gene, but 4(4%) cases were associated with the disease and these cases were diagnosed as ABCC8 MODY. In one(1%) case, c.584G>T variant was detected in KCNJ11 gene. In two(2%) cases, 2 different variants were detected in HNF1A gene. In one(1%) case, heterozygous variants were detected in BLK, PDX1, PAX4 genes. One(1%) case was homozygous in the KLF11 gene and one(1%) case was heterozygous, homozygous variant was classified as "benign", heterozygous variant was not associated with the disease in segregation analysis. In 45 of 65 cases; WES was done. Ten different variants were detected in eight different susceptibility genes in eight (8%) cases. Nine of the variants were not related with MODY phenotype as they did not show a distribution compatible with the pedigree with segregation analysis. Heterozygous c.2635C>T(p.Gln879Ter) variant was detected in IFIH1 gene in a patient with incidental hyperglycemia. Mother carried the same variant heterozygously shown with segregation.

Conclusion: Genetic etiology was determined in 35(35%) of the 100 cases with the NGS panel. 17 new variants in MODY genes have been identified. A candidate gene determined by WES analysis in a case that could not be diagnosed with NGS in the MODY-TURK project.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

Online,
22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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