Background: Targeted exome sequencing is widely used for genetic diagnosis of rare disease and it is replacing Sanger sequencing. In this study we investigated pathogenic variants of monogenic diabetes genes in Korean early onset diabetes patients using targeted exome sequencing.

Method: The main eligible criteria for this study was: non-type 1 diabetes patients with age of onset < 30 years old and body mass index (BMI) < 30 kg/m2. Among the 2353 patients screened from the diabetes registry of Seoul National University Hospital Diabetes Clinic, a total of 93 participants were eligible. We analyzed 30 monogenic diabetes genes using targeted exome sequencing. Identified genetic variants were evaluated by ACMG-AMP guideline for their pathogenicity.

Result: Among the 93 index patients, a total of 83 rare (minor allele frequency < 0.5%), non-silent variants were found and evaluated for its pathogenicity according to the ACMG-AMP guideline. These variants were classified as likely benign (N=8), uncertain significance (N=59), likely pathogenic (N=13), and pathogenic (N=5). Three causative mutations were identified in HNF4A (p.R136W, p.M1I, p.R89Q), four mutations in five patients were identified in HNF1A (c.G-124C, p.Y166N, p.L26Q, p.R278Q), four mutations were found in GCK (p.G410S, p.N231S, p.L164F, p.H156fs) and one mutation was identified in HNF1B (p.L168P). Other causative mutations were identified in WFS1 (p.R629W), INS (c.C-60G), ABCC8 (p.R933Q) and FOXP3 (p.Q200R). Mitochondria 3243 A>G variant was identified in two patients. Patients with pathogenic variants had higher MODY probability score and lower BMI than those without causative gene variants (p=0.015, p=0.039, respectively).

Conclusions: In this study, a total of 19 (20.4%) participants were identified to have monogenic cause of diabetes among 93 early onset diabetes patients. Further research is required to validate the clinical utility of targeted exome sequencing in early onset diabetes patients.


S. Park: None. S. Jang: None. Y. Lee: None. Y. Cho: None. H. Jang: None. K. Park: None. S. Kwak: None.

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