Diagnosis Of Maturity-onset Diabetes Of The Young Research Articles

Clinical characteristics, treatment, and treatment switch after molecular-genetic classification in individuals with maturity-onset diabetes of the young: Insights from the multicenter real-world DPV registry.

Individuals with maturity-onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real-world setting. Individuals with MODY from the diabetes prospective follow-up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. A total of 1640 individuals were identified with GCK-MODY (n = 941) and HNF1A-MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow-up: 4.2 years [2.6-6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK-MODY (Q1-Q3: 6.2-13.1 years) and INS-MODY (2.7-13.7 years) to 14.3 years (5.0-17.1) in KCNJ11-MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A-MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A-MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8-MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and "insulin only" treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY.

MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants.

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.

The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.

Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic β-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype-phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.

Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes.

Double whammy: Coexistence of Mature onset diabetes of the young and autoimmune diabetes: A case report

Maturity-Onset Diabetes of the Young (MODY)encompasses genetic disorders caused by mutations in single genes associated with beta cell dysfunction, constituting 1-6% of all diabetes cases. Mutations in ATP binding cassette transporter subfamily C member 8 (ABCC8) causes MODY 12 which accounts for 1% among MODY cases. It can present in childhood, adolescence or adulthood. Despite growing awareness, accurate MODY diagnosis remains challenging, often leading to misclassification as type 1 or type 2 diabetes. Correct identification is crucial for tailored treatment and implications for family members. The coexistence of MODY and autoimmune related diabetes is a very rare phenomenon with only a handful of cases reported. We describe a unique case where the index patient was initially diagnosed with type 1 diabetes at age 8 due to antibody positivity, leading to insulin treatment. After 15 years, he presented with evidence of all microvascular complications. Interestingly, his brother also developed diabetes at age of 14 years but with out antibody positivity. Due to a strong family history, both siblings underwent genetic testing, revealing a heterozygous mutation in the ABCC8 gene (C.4799630 G>A; P-Arg 1600His).

Evaluation of variants in maturity onset of diabetes young related genes in Balıkesir region

Aims: Maturity-onset diabetes of the young (MODY) is an early-onset, monogenic diabetes with an autosomal dominant inheritance pattern. Single gene mutations that cause dysfunction in pancreatic beta cells are responsible for MODY etiology. In this study, we investigated the genetic variants involved in the etiopathogenesis of MODY in our region.
 Methods: Between May 2018 and April 2023, 40 pediatric patients (n=25 females, n=15 males) with a clinical diagnosis of MODY were evaluated by targeted genome sequencing.
 Results: Among the 40 pediatric patients included in this study, variants in MODY-associated genes were detected in 21 patients (52.5%), eight (38.09%), of which were pathogenic (38.09%), five (23.8%) were probable pathogenic, and eight (38.09%), were of uncertain significance.
 Conclusion: In this study, genetic diagnostic yield (including pathogenic and likely pathogenic variants) was detected in 32.5% (13/40) patients with MODY using targeted genome sequencing analysis. This rate is consistent with other studies. However, unlike other similar studies, the MODY12 subtype was the second most frequent in our study. In addition, nine novel variants were reported, including ABCC8 (n=3), CEL (n=2), KLF11 (n=1), GCK (n=1), HNF1A (n=1), and HNF1B (n=1) genes. We have presented clinical findings to improve genotype-phenotype correlation in the literature for novel variants.

Prevalence, clinical features and complications of common forms of Maturity Onset Diabetes of the Young (MODY) seen at a tertiary diabetes centre in south India

BackgroundMaturity Onset Diabetes of the Young (MODY) is a form of monogenic diabetes caused by mutations in single genes, affecting adolescents or young adults. MODY is frequently misdiagnosed as type 1 diabetes (T1). Though several studies from India have reported on the genetic aspects of MODY, the clinical profile, complications and treatments given have not been reported so far, nor compared with T1D and type 2 diabetes (T2D). AimTo determine the prevalence, clinical features, and complications of common forms of genetically proven MODY seen at a tertiary diabetes centre in South India and compare them with matched individuals with T1D and T2D. MethodsFive hundred and thirty individuals identified as ‘possible MODY’ based on clinical criteria, underwent genetic testing for MODY. Diagnosis of MODY was confirmed based on pathogenic or likely pathogenic variants found using Genome Aggregation Database (gnomAD) and American College of Medical Genetics (ACMG) criteria. The clinical profile of MODY was compared with individuals with type 1 (T1D) and type 2 (T2D) diabetes, matched for duration of diabetes. Retinopathy was diagnosed by retinal photography; nephropathy by urinary albumin excretion > 30 µg/mg of creatinine and neuropathy by vibration perception threshold > 20 v on biothesiometry. ResultsFifty-eight patients were confirmed to have MODY (10.9%). HNF1A-MODY (n = 25) was the most common subtype followed by HNF4A-MODY (n = 11), ABCC8-MODY (n = 11), GCK-MODY (n = 6) and HNF1B-MODY (n = 5). For comparison of clinical profile, only the three ‘actionable’ subtypes - defined as those who may respond to sulphonylureas, namely, HNF1A, HNF4A and ABCC8-MODY, were included. Age at onset of diabetes was lower among HNF4A-MODY and HNF1A-MODY than ABCC8-MODY, T1D and T2D. Prevalence of retinopathy and nephropathy was higher among the three MODY subtypes taken together (n = 47) as compared to T1D (n = 86) and T2D (n = 86). ConclusionThis is one of the first reports of MODY subtypes from India based on ACMG and gnomAD criteria. The high prevalence of retinopathy and nephropathy in MODY points to the need for earlier diagnosis and better control of diabetes in individuals with MODY.

C.487C>T mutation in PAX4 gene causes MODY9: A case report and literature review.

Maturity-onset diabetes of the young (MODY) is a group of autosomal dominant monogenic diabetes mellitus with a wide range of clinical manifestations that require distinct treatment strategies. MODY9 (OMIM # 612225) is a rare type of MODY, caused by a mutation in the Paired box gene 4 (PAX4). A 19-months boy was admitted to the department of endocrinology at Beijing Children's Hospital due to excessive water drinking, polyuria for over half a month, and wheezing for 3 days. The whole-exon sequencing analysis demonstrated that the child carried the heterozygous missense mutation of c.487>T in the 7th exon region of PAX4 gene and diagnosed MODY9. The patient was treated with fluid therapy, ketosis correction, insulin, and anti-infection treatment. After 17 days in the hospital, the blood glucose levels remained stable and the patient was discharged. In Chinese children, the heterozygous mutation of c.487C>T in the PAX4 gene can lead to the occurrence of MODY9.Gene sequencing analysis is of great significance in the diagnosis and classification of MODY.

Maturity-onset diabetes of the young in a large Portuguese cohort.

Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.

Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.

Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established. Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population. Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics. Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.

Maturity-Onset Diabetes of the Young (MODY)

Precision medicine, which optimizes diagnosis and treatment of diseases according to individualized characteristics, is becoming a reality in the field of diabetes, especially for monogenic diabetes. Maturityonset diabetes of the young (MODY) is a type of monogenic diabetes characterized by early onset, relative non-obesity, non-insulin dependence, and autosomal dominant inheritance. With the trend toward precision medicine and improvement in genetic testing, there have been advances in the classification, diagnosis, and treatment of MODY. MODY accounts for about 1% of diabetes in Korea, with GCK (glucokinase)-MODY, HNF1α (hepatocyte nuclear factor-1 alpha)-MODY, and HNF4α (hepatocyte nuclear factor-4 alpha)-MODY being most common. In the diagnosis of MODY, applying guidelines for interpretation of variant pathogenicity is important. For the treatment of MODY, individualized treatment strategies according to the causative gene of MODY should be applied when available. Still, the majority of MODY is misdiagnosed and more genetic testing is required in Korea. We review updates regarding the classification, diagnosis, and treatment of MODY.

The coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY): a case series.

SummaryThe coexistence of autoimmune diabetes and maturity-onset diabetes (MODY) is rare. The absence of pancreatic autoantibodies is a key factor prompting MODY genetic testing. In this study, we report three cases of young-onset diabetes with progressive beta-cell dysfunction, strongly positive glutamic acid decarboxylase (GAD) antibodies, and genetic confirmation of pathogenic gene variants of HNF-1A, HNF-4A, and ABCC8-MODY. The first case is a woman diagnosed with HNF-1A-MODY diabetes more than 30 years after her diagnosis of adult-onset diabetes at 25 years. She required insulin after her fourth pregnancy. She became ketotic on oral hypoglycaemic agents (OHAs) and subsequently, her GAD antibodies tested positive. The second case is a woman diagnosed with diabetes at 17 years who was subsequently diagnosed with HNF-4A-MODY after many hypoglycaemic episodes on low-dose insulin. GAD antibodies were strongly positive. The last case is a man diagnosed with diabetes at 26 years who was well controlled on OHAs and required insulin years later due to sudden deterioration in glycaemic control. His ABCC8-MODY was diagnosed upon realisation of strong family history and his GAD antibodies tested positive. All subjects are now treated with insulin. Less than 1% of subjects with MODY have positive autoantibodies. These cases highlight individuals who may have two different types of diabetes simultaneously or consecutively. Deterioration of glycaemic control in subjects with MODY diabetes should highlight the need to look for the emergence of autoantibodies. At each clinic visit, one should update the family history as MODY was diagnosed in each case after the development of diabetes in their offspring.Learning pointsThese cases highlight the rare coexistence of autoimmune diabetes and MODY.Deterioration of glycaemic control in subjects with MODY diabetes should highlight the emergence of autoantibodies.One should revise and update the family history as the diagnosis of MODY was made after the development of diabetes in offspring.Understanding the spectrum of diabetes allows for precision medicine.

Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel.

Maturity-onset diabetes of the young (MODY), which is the most common cause of monogenic diabetes, has an autosomal dominant pattern of inheritance and exhibits marked clinical and genetic heterogeneity. The aim of the current study was to investigate molecular defects in patients with clinically suspected MODY using a next-generation sequencing (NGS)-based targeted gene panel. Candidate patients with clinical suspicion of MODY and their parents were included in the study. Molecular genetic analyses were performed on genomic DNA by using NGS. A panel of ten MODY-causal genes involving GCK, HNF1A, HNF1B, HNF4A, ABCC8, CEL, INS, KCNJ11, NEUROD1, PDX1 was designed and subsequently implemented to screen 40 patients for genetic variants. Ten different pathogenic or likely pathogenic variants were identified in MODY-suspected patients, with a diagnostic rate of 25%. Three variants of uncertain significance were also detected in the same screen. A novel pathogenic variant in the gene HNF1A (c.505_506delAA [p.Lys169AlafsTer18]) was described for the first time in this report. Intriguingly, we were able to detect variants associated with rare forms of MODY in our study population. Our results suggest that in heterogenous diseases such as MODY, NGS analysis enables accurate identification of underlying molecular defects in a timely and cost-effective manner. Although MODY accounts for 2-5% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment and prognosis as well as for effective genetic counseling.

Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY).

Maturity‐onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1–6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK‐MODY, HNF1A‐MODY, and HNF4A‐MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK‐MODY), some others are highly responsive to oral agents (i.e., HNF1A‐MODY). The risk of micro‐ and macro‐vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50–90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision‐making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.

1290-P: A Rare Case of HNF1A-MODY

Introduction: Maturity onset diabetes of the young (MODY) is a monogenic nonimmune type of diabetes mellitus. It is rare and sometimes misdiagnosed as type 1 or type 2 diabetes (T2DM) . The age of onset is usually below 25 years. It is more common in the European population. Hepatocyte nuclear factor 1-alpha (HNF1A) is one of the most common mutations and is associated with cardiovascular and renal complications.1 Genetic testing in patients with strong hereditary factors results in definitive diagnosis and subsequent appropriate treatment.2 The aim of this report is to emphasize the importance of distinguishing MODY by considering the family history of diabetes and relative clinical features. Case presentation: A 58-year-old Filipino woman was diagnosed with T2DM at age 15. Her mother, 5 of 8 siblings and her daughter all had diabetes. They all died in the 2nd or 3rd decades of their life due to diabetes complications. Her grandfather was European. She has renal insufficiency, coronary heart disease and heart failure. Treatment included glimepiride 2 mg daily and sitagliptin 25 mg daily. The physical exam was unremarkable. Body mass index (BMI) was 21. GAD 65 antibody and Islet cell antibody were negative, C peptide: 3.6 ng/mL, blood sugar: 1mg/dL, HbA1c: 7.3%, creatinine: 2.15 mg/dL and GFR: 25 mL/min/1.73m2. A diagnosis of MODY was considered due to strong family history of diabetes, young age at the onset of diabetes and normal BMI. DNA sequencing demonstrated positive HNF1A mutation compatible with HNF1A-MODY. Due to post prandial hyperglycemia, glimepiride was replaced with pre-meal lispro. Conclusion: This is a rare case of HNF1A-MODY found in a Filipino patient. MODY should be included in the differential diagnosis of diabetic patients with an extensive family history of diabetes, young age of onset of diabetes and negative pancreatic antibodies. Early diagnosis with genetic profiling can guide therapy and hopefully decrease the vascular complications of long-term poor glycemic control. Disclosure S.Velayati: None. M.Shanik: Consultant; Bigfoot Biomedical, Inc., Proteomics International, Research Support; Better Therapeutics, Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Novo Nordisk, Xeris Pharmaceuticals, Inc. I.J.Romao: None.

How do I diagnose Maturity Onset Diabetes of the Young in my patients?

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria‐based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.

IDF21-0348 Incidence and risk of diabetic retinopathy in Emirati patients with maturity onset diabetes of the young (MODY)

Background: Diabetic retinopathy (DR) is a potentially sight-threatening complication of diabetes mellitus. The incidence and associated risk factors of DR has been studied in primary forms of diabetes but little is known with regards to maturity onset diabetes of the young (MODY), particularly in Middle Eastern populations Aim: We aimed to study the incidence of DR in Emirati patients with MODY and to identify clinical and biochemical risk factors associated with its occurrence. Method: Patients with diabetes mellitus underwent digital retinal photography at Imperial College London Diabetes Centre, United Arab Emirates (UAE). Retinal photographs were graded according to the NHS Diabetic Eye Screening Programme for severity of DR and presence or absence of maculopathy. Forty-eight patients highly suspected to have MODY were tested for mutations in all known monogenic diabetes genes using targeted next generation sequencing. Clinical and biochemical parameters were reviewed. Results: Pathogenic MODY mutations were identified in a total of 30 cases, with HNF1A, GCK, HNF4A, HNF1B, and CEL in 50%, 26.7%, 16.7%, 3.3% and 3.3%, respectively. Retinal disease of any grade was found in 26.7% (n=8) of individuals with a genetic diagnosis of MODY, with 75% (n=6) of HNF1A-MODY patients having background (n=4), proliferative (n=1), or stable-proliferative DR (n=1), and 25% (n=2) of HNF4A-MODY patients having background (n=1) or stable-proliferative (n=1) retinopathy. Maculopathy occurred in half (50%) of the HNF1A-MODY cases and all (100%) with HNF4A-MODY. Overall, the incidence rate of any degree of DR in patients with MODY was 880 (270-1490) cases per 10,000 person-years. Significant differences were found in univariate analysis in mean duration of diabetes (14.2±5.3 vs 5.4±6.3years, p=0.002), HbA1c (9.5±1.8% vs 7.1±1.3%, p=<0.001), total cholesterol (TC) (5.3±1.7 vs 4.1±1.0mmol/L, p=0.030), and triglycerides (1.8±1.1 vs 1.0±0.6mmol/L, p=0.018) between individuals with any degree of retinopathy and those without retinal disease. Treatment modality was significantly different in cases with and without any retinopathy (p=0.001), with 50% vs 9.1% receiving insulin. No significant difference in age at onset of diabetes (p=0.640), LDL (p=0.225), albumin-creatinine ratio (p=0.208) were observed. Mean age at examination, blood pressure (BP), estimated glomerular filtration rate, and BMI in individuals with or without retinopathy were 32.2±9.9 vs 19.9±10.9years, 114.5±9.8/69.4±7.4 vs 112.9±12.1/67.1±10.5mmHg, 122±31.6 vs 120.3±25mL/min/1.73m2, 24.1±2.4 vs 22.5±5.3kg/m2, respectively. In multivariate Cox regression incorporating TC:HDL ratio, systolic BP and HbA1c, increased TC:HDL was independently associated with significantly increased hazard of any degree of retinopathy (HR 3.96 (1.08-14.5)). Discussion: The incidence rate of any degree of retinopathy in Emirati patients with primarily HNF1A and HNF4A MODY appears increased in comparison to recently published incidence rates for Type 2 Diabetes (200 to 300 per 10,000 person-years) and comparable with rates reported in Type 1 Diabetes (500 to 660 cases per 10,000 person-years). The high incidence of retinal disease in HNF1A MODY highlights the importance of retinal screening from the time of diagnosis, along with early identification of potential MODY cases in order to optimise blood glucose quickly and effectively.

Precision Diagnosis of Maturity-Onset Diabetes of the Young with Next-Generation Sequencing: Findings from the MODY-IST Study in Adult Patients.

Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.

A stochastic DNA walker electrochemiluminescence biosensor based on quenching effect of Pt@CuS on luminol@Au/Ni-Co nanocages for ultrasensitive detection of I27L gene

The common I27L mutations of the hepatocyte nuclear factor-1α (HNF1A) significantly increase the incidence of maturity-onset diabetes of the young (MODY). Hence, the establishment of an ultrasensitive detection strategy for I27L gene is crucial for the diagnosis and treatment of MODY. Herein, a signal-off electrochemiluminescence resonance energy transfer (ECL-RET) biosensor with effective target-induced stochastic DNA walker amplification was fabricated for I27L detection. In this biosensor, Prussian blue analogues (Ni-Co) nanocages/Au-supported luminol (luminol@Au/Ni-Co) were used as ECL donors and exhibited excellent luminous efficiency. On the other hand, Pt nanoparticles-grown on copper sulphide (Pt@CuS) were used as energy acceptors to quench the initial signal based on RET between luminol and CuS. Moreover, the autonomous locomotion of I27L assisted by Exo III is the key in this DNA walker biosensor, as it continually induces new digestion processes on the electrode surface and quenches signals caused by the introduction of numerous acceptors. The efficient donor/acceptor pairs and DNA walker amplification system of the ECL-RET allowed the proposed biosensor to effectively detect I27L with a wide linear range of 0.0001 to 100 nM and a limit of detection as low as 23 fM. Thus, the ECL-RET biosensor provides a promising sensing platform for the diagnosis and typing of diabetes.

Метод секвенирования нового поколения в дифференциальной диагностике сахарного диабета у детей

In addition to type 1 and 2 diabetes mellitus (DM), endocrine disorders in children include hereditary forms of diabetes, such as maturity onset diabetes of the young (MODY). Since pathogenic mechanisms of chronic hyperglycemia in MODY are different from those in DM1 and DM2, it requires other therapeutic approaches. The diagnosis of MODY is confirmed by expensive molecular testing, such as next generation sequencing (NGS). Therefore, the strategy of choosing candidates for NGS is very important. Objective. To optimize the algorithm of choosing patients for NGS testing for DM type verification. Patients and methods. This study included 97 patients aged 1–18 years suspected of having MODY. We used NGS to confirm the diagnosis and identify polymorphisms in MODY-associated genes. Results. Fifty-three patients were found to have polymorphisms in MODY-associated genes, including GCK gene (MODY2) (n = 44), NHF1A gene (MODY3) (n = 8), and PAX4 gene (MODY9) (n = 1). Comparison of family histories of patients with MODY-associated polymorphisms and those in whom clinical diagnosis of MODY was not confirmed by NGS demonstrated significant differences: children with verified MODY were more likely to have first-degree relatives with some carbohydrate metabolism disorder (CMDs). Clinical, laboratory, and anthropometric parameters, as well as levels of insulin secretion and carbohydrate metabolism were similar in both groups. However, patients with non-confirmed MODY received insulin therapy more frequently than those with verified MODY as the majority of them were on a diet. Conclusion. NGS confirms the diagnosis of MODY in patients with different CMDs. A tailored approach should be used to choose patients for NGS to confirm MODY. Key words: monogenic diabetes mellitus in children, diabetes mellitus, next generation sequencing, GCK, HNF1A, MODY