Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age

Abstract

Background. Maturity-onset diabetes of the young (MODY) is commonly misdiagnosed as type 1 or type 2 diabetes. Common reasons for misdiagnosis are related to limitations in genetic testing. A precise molecular diagnosis is essential for the optimal treatment of patients and allows for early diagnosis of their asymptomatic family members. Objective. The aim of this study was to identify rare monogenic variants of common MODY genes in Japanese pediatric patients. Methods. We investigated 45 Japanese pediatric patients based on the following clinical criteria: development of diabetes before 17 years of age, a family history of diabetes, testing negative for glutamate decarboxylase-65 (GAD 65) antibodies and insulinoma-2-associated autoantibodies (IA-2A), no significant obesity, and evidence of endogenous insulin production. Genetic screening for MODY1 (HNF4α), MODY2 (GCK), MODY3 (HNF1α), and MODY5 (HNF1β) was performed by direct sequencing followed by multiplex ligation amplification assays. Results. We identified 22 missense variants (3 novel variants) in 27 patients (60.0%) in the GCK, HNF4α, and HNF1α genes. We also detected a whole exon deletion in the HNF1β gene and an exon 5–6 aberration in the GCK gene, each in one proband (4.4%). There were a total of 29 variations (64.4%), giving a relative frequency of 53.3% (24/45) for GCK, 2.2% (1/45) for HNF4α, 6.7% (3/45) for HNF1α, and 2.2% (1/45) for HNF1β genes. Conclusions. Clinicians should consider collecting and assessing detailed clinical information, especially regarding GCK gene variants, in young antibody-negative patients with diabetes. Correct molecular diagnosis of MODY better predicts the clinical course of diabetes and facilitates individualized management.

Clinical Characters of Egyptian children with Maturity Onset of Diabetes Type 3

“…The cases group included 9 males and 11 females, this was in line with the findings of Katashima et al (13) in Japan, who enrolled 45 (17 males and 28 females) unrelated diabetic persons who were clinically diagnosed as cases of MODY. They investigated the presence of HNF4 and GCK genetic variants in juvenile study population with onset of DM before the age of seventeen years old.…”

“…In the current study, the mean age was 13.63±2.74 years, this was in the same way with Al-Kandari et al, (15), who conducted research on mutations among patients diagnosed with MODY in a nation where DM is an epidemic disease. Similarly, in the study by Katashima et al (13), the mean age at the time of diagnosis was 10.5±3.3 years. In contrast to Trhanint et al (14), who noted that the individuals' ages ranged anywhere from 13 to 19 years on average (range: 5-31 years old).…”

Mutations in GCK May Lead to MODY2 by Reducing Glycogen Synthesis

“…More than 600 GCK mutations have been reported that distributed throughout the gene, [27] but only some of them have been identified by functional studies, most of them have only been predicted by online software without experimental verification. [28][29][30][31][32] In addition, most previous studies identified pathogenic mutations in GCK by functional analysis in which enzyme kinetics and thermal stability were most commonly used as evaluation standard. [33][34][35] Analysis of enzyme kinetics and thermal stability of mutant GCK can directly reveal the function of mutant GCK, but the experiment was rather complicated.…”

A Systematic Review of the use of Precision Diagnostics in Monogenic Diabetes

“…Recent studies show that people with monogenic diabetes are often misdiagnosed as type 1 diabetes or type 2 diabetes 19 . Given the currently prohibitive cost and low yield of universal genetic testing in the vast majority with clinically classified type 1 and type 2 diabetes 14,[20][21][22] , there is therefore a need for more knowledge on who to test for monogenic diabetes using various clinical and biomarker based criteria that increase the yield for this diagnosis, thereby, making such genetic testing more cost-effective.…”