Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing

Abstract

Aims: To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Methods: Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Results: Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Conclusions: Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells.

Maturity-onset diabetes of the young: update and perspectives on diagnosis and treatment

“…A possible explanation for these discrepancies is that a large proportion of the MODY cases in China have defects in unknown MODY genes [67]. The studies from Korea, Japan, and China suggest that East Asia has a high prevalence of a not yet identified form of diabetes, i.e., 'MODY X' [64,[67][68][69][70][71][72]. Next generation sequencing is one of the most powerful tools to discover unknown genetic defects [71,73], and attempts to identify new causative gene variants in MODY using whole-exome sequencing have been undertaken in Korea [72].…”

Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance

“…To identify the possible MODY‐X genes, attempts have been made using whole‐exome sequencing for multiple families . However, many times, these studies have identified mutations in known genes and, except for the APPL gene, novel genes identified in these studies are found in single families making it difficult to appreciate their real pathogenicity .…”

Identification of Maturity-Onset Diabetes of the Young Caused by Glucokinase Mutations Detected Using Whole-Exome Sequencing

“…In Korea, very few studies have focused on the discovery of patients with MODY [4]. Shim et al [10] did not find any causative alleles of known MODY 1–13 genes by WES in six Korean MODY probands and their family members. Therefore, it was believed that there is a major discrepancy in the genetic basis of the disease between Korean and Caucasian patients, despite a lack of definitive evidence.…”