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A, Breakdown of maturity-onset diabetes of the young (MODY)-gene mutations in proband patients. B, Distribution of body mass index (BMI) percentiles of the mutation-positive patients. Each bar represents the number of the patients within the 10th percentiles around the bin center
Source publication
Background
Causative mutations cannot be identified in the majority of Asian patients with suspected maturity‐onset diabetes of the young (MODY).
Objectives
To elucidate the genetic basis of Japanese patients with MODY‐like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes.
Subjects
263 Japanese pat...
Contexts in source publication
Context 1
... total, mutations in one of the major four MODY genes were identified in 103 (39.2%, Figure 1A: 57 (55.3%) in GCK, 29 (28.2%) in HNF1A, 7 (6.8%) in HNF4A, and 10 (9.7%) in HNF1B. Details of these mutations are listed in Table 1. ...
Context 2
... at diagnosis of diabetes were available for 85 of the mutation-positive patients. As shown in Figure 1B, 30 (35.3%) mutation-positive MODY patients had a BMI above average (BMI >50th percentile), and 7 (8.2%) were in the overweight range (BMI >85th percentile). Since mutation-positive patients were not necessarily underweight, we then analyzed the insulin resistance and the insulin secretory capacity of these patients using the HOMA-IR and the HOMA-β indices. ...
Citations
... other first-degree relatives, 1 but isolated cases also occur and serve as additional reference information. 2 MODY is primarily caused by pathogenic variants of specific genes involved in pancreatic beta-cell function and glucose homeostasis, and accounts for 1% to 5% of DM cases. 3 Among DM cases caused by a single gene mutation, MODY is the most common and 14 causative genes have been identified to date. 4 Of those, HNF4A-MODY (hepatocyte nuclear factor-4a, 5 Whole exome sequencing (WES) has revolutionized genetic research and is instrumental in identifying novel diseaseassociated genetic variants in MODY patients. ...
Maturity‐Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation‐dependent Probe Amplification (MLPA) and functional analyses. Twenty‐one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) – relatively high rate reported to date. Notably, one‐third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES‐only screening.
... First, we selected non-obese children clinically diagnosed with type 2 diabetes as candidates for genetic testing for MODY. However, Yorifuji et al. (41) reported that 35% of patients with MODY had a BMI above the average (BMI > 50 th percentile) and 8.2% were overweight (BMI > 85 th percentile). Therefore, genetic testing may be necessary, even for obese children with a strong family history of diabetes, to increase the In conclusion, we identified some children with MODY at an early stage of diabetes by genetic testing and urine glucose screening at schools. ...
This study aimed to examine the clinical characteristics of young children diagnosed with maturity-onset diabetes (MODY) using urine glucose screening at schools. The study participants were 70 non-obese children who were clinically diagnosed with type 2 diabetes through urine glucose screening at schools in Tokyo between 1974 and 2020. Of these children, 55 underwent genetic testing, and 21 were finally diagnosed with MODY: MODY2 in eight, MODY3 in eight, MODY1 in four and MODY5 in one. A family history of diabetes was found in 76.2% of the patients. Fasting plasma glucose levels did not differ between the different MODY subtypes, while patients with MODY 3, 1, and 5 had significantly higher levels of glycosylated hemoglobin and 2-hour glucose in an oral glucose tolerance test than those with MODY2. In contrast, most patients exhibit mild insulin resistance and sustained β-cell function. In the initial treatment, all patients with MODY2 were well controlled with diet and exercise, whereas the majority of those with MODY3, 1, and 5 required pharmacological treatment within one month of diagnosis. In conclusion, urine glucose screening in schools appears to be one of the best opportunities for early detection of the disease and providing appropriate treatment to patients.
... In a large-scale study of Asian individuals with MODY, mutations were most frequently detected in GCK (55.3%), followed by HNF1A (28.2%), HNF1B (9.7%) and HNF4A (6.8%) genes [12]. GCK--MODY, which is one of the common types of MODY, was observed with the highest prevalence in southern European countries and Türkiye where this study was conducted [13]. ...
... These results are similar to those of a comprehensive study on monogenic diabetes conducted in the United Kingdom[21]. According to a recent report from Japan, 39.2% were diagnosed with MODY; however, 18.4% showed de novo mutations contrary to the standard MODY criteria in this study[70]. Although standard MODY criteria include early onset (before age 25 to 35), absence of insulin dependence, absence of obesity and autoantibodies, and autosomal dominant inheritance for at least two generations[71], approximately 1% of MODY patients have glutamate decarboxylase antibodies, de novo mutations, and obesity, which make it challenging for the clinician to diagnose monogenic diabetes[72]. ...
Monogenic diabetes is commonly caused by single-gene mutations. This disease ranges from 1% to 5% in all cases of diabetes and is less affected by behavior and environment. Neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) account for a major proportion of monogenic diabetes, while syndromic diabetes constitutes a smaller proportion. Diagnosis of monogenic diabetes has improved from being based on clinical phenotypes to molecular genetics, with significant advancement of genome sequencing skills. Precise medication for monogenic diabetes is based on genetic testing; therefore, an accurate diagnosis is essential. Due to the basic clinical criteria (diagnosed < 6 months of age), genetic testing and precision treatment for NDM are fast and uncomplicated. The MODY probability calculator was developed; however, it remains challenging to distinguish MODY from type 1 and 2 diabetes due to the lack of a single diagnostic criteria and genetic testing. Additionally, the high cost and complicated interpretation of these genetic test results add to these challenges. This review will discuss the distinct etiology and subgroups that contribute to predicting and treating clinical phenotypes associated with monogenic diabetes. Furthermore, we will review the recent Korean studies and suggest methods of prioritizing patient screening for genetic testing.
... The prevalence of MODY varies amongst different populations [15]. The most frequent subtype in the United States, Japan and Turkey is GCK-MODY2, accounting for approximately 50% of the identified variants, followed by HNF1A-MODY3 and HNF1B-MODY5 [16][17][18][19][20]. In contrast, HNF1A-MODY3 is the most common MODY subtype among the studied populations in South Africa, South Korea and in Europe, including the United Kingdom, Germany and Poland [1,15,21,22]. ...
Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes mellitus. In this study, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar using whole-genome sequencing (WGS) of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. We focused our investigations on 14 previously identified genes ascribed to the cause of MODY and two potentially novel MODY-causing genes, RFX6 and NKX6-1. Genetic variations within the 16 MODY-related genes were assessed for their pathogenicity to identify disease-causing mutations. Analysis of QBB phenotype data revealed 72 subjects (0.5%) with type 1 diabetes, 2915 subjects (20.3%) with type 2 diabetes and 11,377 (79.2%) without diabetes. We identified 22 mutations in 67 subjects that were previously reported in the Human Genetic Mutation Database (HGMD) as disease-causing (DM) or likely disease causing (DM?) for MODY. We also identified 28 potentially novel MODY-causing mutations, predicted to be among the top 1% most deleterious mutations in the human genome, which showed complete (100%) disease penetrance in 34 subjects. Overall, we estimated that MODY accounts for around 2.2–3.4% of diabetes patients in Qatar. This is the first population-based study to determine the genetic spectrum and estimate the prevalence of MODY in the Middle East. Further research to characterize the newly identified mutations is warranted.
... To date, most studies have searched for genetic causes of MODY in Euro Caucasian patients, while only a small number of studies have been conducted in Arabia and the Middle East. [40,41] In recent years, although the relevant studies carried out in Asian populations have gradually increased, but more common in Japan and South Korea [36,42,43], and there are fewer large sample studies in Han Nationality of Chinese Population [44,45]. This study demonstrated that mutations of genes related to MODY1-14 were not the main cause of eDia3 in Chinese patients, which indicated that the pathogenic background of eDia3 needs further investigation in the future. ...
Purpose
Early-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort.
Methods
Of 6470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case–control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 early-onset T2D patients without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP, and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families.
Results
Compared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m ² , P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes ( KLF11 , GCK , ABCC8 , PAX4 , BLK and HNF1A ) of MODY.
Conclusions
eDia3 patients had unique clinical features. Known MODY genes were not common causes in these patients.
... (17) showed that the most common MODY mutation is GCK in pediatric diabetic patients in Turkey (almost 25%), whereas in the SEARCH study HNF1A mutation was found to be the most common MODY subtype among the young diabetic population in the USA (10). Almost all studies about MODY were performed in pediatric groups, and the most common MODY subtype was usually the GCK mutation in European countries, higher than in Asian countries such as Japan and Korea (35,36). In our study, pathologic GCK mutations were the most common, followed by HNF4A mutations in the adult MODY (+) group; similar to what was found in the pediatric population in Turkey. ...
... (11) reported that MODY(+) Chinese patients were younger at diagnosis, and had a longer duration of diabetes, higher fasting plasma glucose, lower C-peptides, lower BMI, lower HOMA and lower triglycerides compared with early-onset T2DM patients. A recent study on 263 Japanese patients (35) showed that mutation-positive patients had a lower BMI and insulin resistance compared to mutation-negative diabetics; and were also younger at the time of the diagnosis. Based on previous studies, Jang (39) suggests MODY genetic analysis in adult diabetic patients if they were diagnosed before the age of 30, if β-cell antibodies are negative, and if they have a family history of diabetes and BMI ≤ 30 kg/m 2 without insulin resistance. ...
Objective:
Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations.
Methods:
In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters.
Results:
In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups.
Conclusion:
According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.
... age of onset, clinical features, type of treatment) [5]. Although the traditional criteria for MODY include a family history of diabetes, sporadic de novo mutations in a number of causative genes have been reported [6][7][8]. ...
Background
A retrospective observational study was conducted to assess the prevalence of maturity onset diabetes of the young (MODY) in a large paediatric population of Southern Italy newly diagnosed with diabetes. Clinical and genetic features of the identified MODY patients were also described.
Methods
Genetic testing was performed in children and adolescents newly diagnosed with diabetes who presented autoantibody negativity and fasting C-peptide levels ≥ 0.8 ng/mL. Patients with a low insulin daily dose and optimal glycaemic control after two years from diabetes onset were also investigated for monogenic diabetes, regardless of their autoimmunity status and/or C-peptide levels.
Results
A prevalence of 6.5% of MODY was found. In particular, glucokinase-MODY was the most common type of MODY. The mean age at diagnosis was 9.1 years. Clinical presentation and biochemical data were heterogeneous also among patients belonging to the same MODY group.
Conclusions
We found a relatively high prevalence of MODY among paediatric patients with a new diagnosis of diabetes in comparison to literature data. Our findings highlight that a more detailed clinical evaluation along with easier and less expensive approachability to genetic testing may allow diagnosing an increasing number of MODY cases. A correct, prompt diagnosis is crucial to choose the most appropriate treatment and offer adequate genetic counselling.
... MODY has been suspected in the nonobese DM subjects. However, Yorifuji et al. [6] performed Sanger sequencing for the genes GCK, HNF1A, HNF4A, and HNF1B in Japanese patients with MODY-like DM and found de novo DM, overweight, and insulinresistance in some of the mutation-positive MODY. ...
Objectives
Monogenic diabetes mellitus (DM) is a single gene disorder, primarily characterized by impairment in the development or function of pancreatic beta cells.
Case presentation
A 14-year-old girl was initially diagnosed with type 2 DM. The patient did not have any anti-islet autoantibody and showed acanthosis nigricans. She was managed with long-acting insulin and oral hypoglycemic agent, but HbA 1c was still 9.3% after 1 year of management. Her mother already had type 2 DM at 46-year-old and was on medication. Under the possibility of familial monogenic DM, targeted exome sequencing was performed which included 29 genes associated with monogenic DM. Nonsense mutation of the gene RFX6 (c.2661T>A, p.Tyr887∗) was found. After adding Glucagon-like peptide-1 (GLP-1) receptor agonist, HbA 1c improved from 8.8 to 6.8% and body mass index (BMI) also improved from 31.0 to 29.2 kg/m ² .
Conclusions
It may be worth investigating genetic etiology in early-onset autoantibody-negative DM for specific genetic diagnosis and better management.
... An analysis of South Asians in the UK revealed that the genetic diagnosis rate was 12.6% [10]. Among 263 Japanese patients with suspected MODY, 39.2% had one of the four MODY gene muta-tions-GCK, HNF1A, HNF4A, and HNF1B-when tested with Sanger sequencing, and 21.6% had a GCK mutation [13]. Molecular diagnosis rate in Koreans was 21.1% for patients with clinically suspected monogenic diabetes and 1.1% for patients with overall non-T1DM in the recent largest study [14]. ...
Monogenic diabetes, including maturity-onset diabetes of the young, neonatal diabetes, and other rare forms of diabetes, results from a single gene mutation. It has been estimated to represent around 1% to 6% of all diabetes. With the advances in genome sequencing technology, it is possible to diagnose more monogenic diabetes cases than ever before. In Korea, 11 studies have identified several monogenic diabetes cases, using Sanger sequencing and whole exome sequencing since 2001. The recent largest study, using targeted exome panel sequencing, found a molecular diagnosis rate of 21.1% for monogenic diabetes in clinically suspected patients. Mutations in glucokinase (GCK), hepatocyte nuclear factor 1α (HNF1A), and HNF4A were most commonly found. Genetic diagnosis of monogenic diabetes is important as it determines the therapeutic approach required for patients and helps to identify affected family members. However, there are still many challenges, which include a lack of simple clinical criterion for selecting patients for genetic testing, difficulties in interpreting the genetic test results, and high costs for genetic testing. In this review, we will discuss the latest updates on monogenic diabetes in Korea, and suggest an algorithm to screen patients for genetic testing. The genetic tests and non-genetic markers for accurate diagnosis of monogenic diabetes will be also reviewed.
