Delineation of the genetic and clinical spectrum, including candidate genes, of monogenic diabetes: a multicenter study in South Korea

Abstract

ObjectivesMonogenic diabetes includes a group of heterogeneous diabetes types. We aimed to identify the frequency, clinical and molecular features of monogenic diabetes in a Korean pediatric cohort.MethodsA retrospective cohort and multicenter study of Korean children suspected to have monogenic diabetes, managed by four pediatric endocrine centers in the southeast region of South Korea, from February 2016 to February 2020. We recruited 27 pediatric Korean patients suspected to have monogenic diabetes who had at least two of the following three criteria (age at diagnosis, family history, and clinical presentation). Targeted exome sequencing was conducted in these patients. The functional consequences of the variants were predicted by bioinformatics and protein structure analysis.ResultsMolecular genetic analysis identified 16 patients (59.3%) with monogenic diabetes. We identified a total of eight unique variants, including five novel variants (HNF4A c.1088C>T, CEL c.1627C>T and c.1421C>T, PAX4 c.538+8G>C, INS c.71C>T). We also identified two potential candidate gene variants for monogenic diabetes, namely c.650T>C in the SLC2A2 gene and c.629G>A in the PTF1A gene. Other variants were identified in the WFS1and NPHP3 genes in two rare genetic disorders. Variant-positive individuals had a lower presence of autoantibody positivity at the time of diagnosis and higher glycosylated hemoglobin levels at last follow-up when compared to variant-negative patients (p<0.001 and p=0.029, respectively).ConclusionsThese results further expand the spectrum of known variants as well as potential candidate gene variants associated with monogenic diabetes in Korea.

Co-segregation analysis and functional trial in vivo of candidate genes for monogenic diabetes

“…Even after testing for pancreatic beta-cell autoimmune markers, and performing comprehensive targeted NGS, in 8.4% (102/1209) of the total cohort precise diabetes etiology was not identified. As expected, high-throughput sequencing brought several novel variants (11/102) in potential diabetes genes, in agreement with other authors reporting candidate gene variants in up to 10% of sequenced cohorts 26–28. Genomic individualized medicine not only brings the accurate molecular diagnosis and the most effective treatment plan for the patient but also delivers surveillance plan for family members; furthermore, it has proven cost-effectiveness for the healthcare system 29.…”

“…As expected, high-throughput sequencing brought several novel variants (11/102) in potential diabetes genes, in agreement with other authors reporting candidate gene variants in up to 10% of sequenced cohorts. [26][27][28] Genomic individualized medicine not only brings the accurate molecular diagnosis and the most effective treatment plan for the patient but also delivers surveillance plan for family members; furthermore, it has proven cost-effectiveness for the healthcare system. 29 Therefore, with this study, we also present our selection of potential genes for MD for further functional analysis in vitro.…”

Two New Mutations in the CEL Gene Causing Diabetes and Hereditary Pancreatitis: How to Correctly Identify MODY8 Cases

“…Moreover, when examining Iranian families with diabetes, Sarmadi et al ( 20 ) concluded that the CEL variant p.Ile488Thr causes MODY, even if present at an allele frequency of 0.01 in various Middle Eastern populations. Other single cases or families proposed to carry pathogenic CEL mutations outside the VNTR have been published from India ( 21 ), Siberia ( 22 ), China ( 23 ), and South Korea ( 24 ).…”