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Background: 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. Methods: 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. Results: 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%. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m2. Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1(p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it.

Abstract Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m2. Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1 (p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionMonogenic diabetes often occurs as a result of single-gene mutations. The illness is minimally affected by environmental and behavioral factors, and it constitutes around one to five percent of all cases of diabetes.Newborn diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the predominant causes of monogenic diabetes, accounting for a larger proportion of cases, while syndromic diabetes represents a smaller percentage. MODY, a group of inherited non-autoimmune diabetes mellitus disorders, is quite common. However, it remains frequently misdiagnosed despite increasing public awareness. The condition is characterized by insulin resistance, the development of diabetes at a young age (before 25 years), mild high blood sugar levels, inheritance in an autosomal dominant pattern, and the preservation of natural insulin production.Currently, there are 14 distinct subtypes of MODY that have been identified. Each subtype possesses distinct characteristics in terms of their frequency, clinical symptoms, severity of diabetes, related complications, and response to medicinal interventions. Due to the clinical similarities, lack of awareness, and high expense of genetic testing, distinguishing between type I (T1D) and type II diabetes mellitus (T2D) can be challenging, resulting in misdiagnosis of this type of diabetes. As a consequence, a significant number of individuals are being deprived of adequate medical attention. Accurate diagnosis enables the utilization of novel therapeutic strategies and enhances the management of therapy in comparison to type II and type I diabetes.This article offers a concise overview of the clinical subtypes and characteristics of monogenic diabetes. Furthermore, this article discusses the various subtypes of MODY, as well as the process of diagnosing, managing, and treating the condition. It also addresses the difficulties encountered in detecting and treating MODY. [ABSTRACT FROM AUTHOR]

The editorial discusses personalized therapies for monogenic diabetes, focusing on three main clinical forms: Maturity Onset Diabetes of the Young (MODY), Neonatal Diabetes Mellitus (NDM), and Severe Insulin Resistance syndromes. The article highlights the genetic basis of these conditions and treatment options, such as oral hypoglycemic agents for MODY and NDM, and human recombinant IGF1 for Severe Insulin Resistance syndromes. Additionally, the editorial emphasizes the importance of precision medicine in managing monogenic diabetes and explores potential therapeutic targets through Mendelian randomization. [Extracted from the article]

BACKGROUND. Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, usually diagnosed before the age of 30 years in non-obese patients with a family history of diabetes mellitus (DM). MODY is relatively rare compared to type 1 and type 2 DM, with various literature estimates affecting only 1-2 % of people with diabetes, but because it is rare, clinicians may misdiagnose it as type 1 or type 2 DM, which happens in most cases. Unlike type 1 DM patients, patients with MODY have preserved pancreatic β-cell function, so lifestyle modification in combination with glucose-lowering therapy, which in some cases may include insulin, may be sufficient interventions as treatment. OBJECTIVE. With the help of literary sources, familiarize yourself with the classification, clinical manifestations, aspects of treatment and prognosis of the main forms of MODY diabetes. MATERIALS AND METHODS. Object: MODY diabetes as an orphan disease. Research method: a review of literary sources. RESULTS. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on genetic mutation. Subtypes 1-3 are the most common, accounting for 95 % of cases. Treatment usually includes diet, exercise, and, in some cases, insulin or oral hypoglycemic drugs. In general, the prognosis can be quite favorable, provided that carbohydrate metabolism is compensated. CONCLUSIONS. MODY diabetes is a complex genetically determined pathology, and understanding the features of this disease, diagnosis and treatment are of great importance for patients and their families. The development of modern methods of treatment and monitoring of glucose, such as insulin pumps, 24-hour glycemic monitoring and other technologies, may improve the prognosis for patients with MODY. Each patient with MODY diabetes has individual characteristics, which leaves an imprint on the prognosis of the disease and approaches to treatment. The main goal is to maintain a normal level of glucose in the blood to avoid complications.

Monogenic diabetes (MD) represents a cluster of different types of diabetes produced by a mutation of a single gene. The commonest type of MD is maturity-onset diabetes of the young (MODY) which has several subtypes, and neonatal diabetes mellitus (NDM). With improved diagnostic facilities, more cases of monogenic diabetes are being described, and pregnancy is being reported in different forms of monogenic diabetes as these patients enter the reproductive age group. The treatment of monogenic diabetes may change once pregnancy sets in. For example, some forms of monogenic diabetes which respond to oral antidiabetic drugs (OHA), particularly the sulfonylurea agents (SUs), may need insulin during pregnancy. However, this depends on the fetal inheritance of mutation from the mother. This review attempts to put together published reports of pregnancy in various types of monogenic diabetes focussing on the most frequently seen forms of MD. [ABSTRACT FROM AUTHOR]

Purpose: Monogenic diabetes (MD) is caused by a mutation in a single gene and accounts for approximately 2.5–6% of all diabetes cases. Maturity-onset diabetes of the young (MODY) is the most common form of MD. To date, 14 different genes have been identified and associated with the presence of MODY phenotype. However, the number of potential candidate genes with relevance to beta cell function and glucose metabolism is increasing as more research is published. The aim of the study was to identify potentially causative variants in selected candidate genes in patients with a clinical diagnosis of MD. Methods: Targeted Next-Generation Sequencing (tNGS) on Illumina NextSeq 550 platform involving Agilent SureSelectQXT Target Enrichment protocol for 994 patients with suspected MD was performed. In the next step, the sequencing data of 617 patients with no pathogenic variants in main MD-related genes were reanalysed for the presence of causative variants in six candidate genes (MTOR, TBC1D4, CACNA1E, MNX1, SLC19A2, KCNH6). The presence of the selected variants was confirmed by Sanger sequencing. Results: Seven heterozygous possibly damaging variants were identified in four candidate genes (MTOR, TBC1D4, CACNA1E, MNX1). Five changes were assessed as novel variants, not previously described in available databases. None of the described variants were present among patients previously diagnosed with MODY diabetes due to causative, pathogenic variants in known MODY-related genes. Conclusions: The results obtained seem to confirm the effectiveness of the NGS method in identifying potentially causative variants in novel candidate genes associated with MODY diabetes. [ABSTRACT FROM AUTHOR]

Background: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. Methods: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. Results: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. Conclusion: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods: We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea. Results: In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation: Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY. [ABSTRACT FROM AUTHOR]

The etiological diagnosis of diabetes conveys many practical consequences for the care of patients, and often of their families. However, a wide heterogeneity in the phenotypes of all diabetes subtypes, including Type 1 diabetes, Type 2 diabetes, and monogenic diabetes, has been reported and contributes to frequent misdiagnoses. The recently revised WHO classification of diabetes mellitus includes two new classes, namely “hybrid forms” and “unclassified diabetes”, which also reflect the difficulties of this etiological diagnosis. During the last years, many studies aiming at identifying homogenous subgroups on refined phenotypes have been reported. Ultimately, such subtyping may improve the diagnosis, prognosis, and treatment of patients on a pathophysiological basis. Here, we discuss the concepts of typical vs. atypical diabetes in the context of autoimmune Type 1 diabetes, Type 2 diabetes, and its monogenic forms. We discuss the contributions of clinical markers, biological tests, particularly islet cell auto-antibodies, and genetics to improving accurate diagnoses. These data support a systematic evaluation of all newly diagnosed diabetes cases.

Maturity 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). To 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. Five 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. Fifty-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). This 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. • Prevalence, clinical features of common MODY forms from south India are presented. • MODY cases were confirmed by ACMG and gnomAD criteria. • The pick-up rate for MODY was 10.9% among clinically suspected MODY. • HNF1A -MODY is the most common subtype of MODY followed by HNF4α MODY. • The prevalence of retinopathy & nephropathy was higher among MODY than T1D and T2D. [ABSTRACT FROM AUTHOR]

Objective. This study aimed to evaluate the utility of C-peptide levels in the differentiation of monogenic forms of diabetes from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in clinical practice. Subjects and Methods. A total of 104 patients aged >16 who visited the Dicle University's Faculty of Medicine between April 2011 and December 2020 and were diagnosed with monogenic diabetes by genetic analysis or with T1DM and T2DM were randomly selected for retrospective evaluation. The C-peptide levels of these patients at the time of diagnosis of diabetes were compared. Results. Of the 104 patients, 24 (23%) were diagnosed with maturity-onset diabetes of the young (MODY), 40 (38.5%) with T1DM, and 40 (38.5%) with T2DM. Median C-peptide levels (ng/mL) (interquartile range) were 1.78 (1.24-2.88) in MODY group, 0.86 (0.34-1.22) in T1DM group, and 2.38 (1.58-4.27) in T2DM group. Conclusions. There was a difference in C-peptide levels between MODY and T1DM groups but not between MODY and T2DM groups. As per clinical evaluations, although C-peptide levels of patients with MODY are similar to those of patients with T2DM patients, the possibility of C-peptide levels being similar to those required for T1DM diagnosis should also be considered. [ABSTRACT FROM AUTHOR]

Objective: This study was aimed to determine the genetic background of pediatric patients with a clinical diagnosis of maturity-onset diabetes of youth (MODY). Materials and methods: In this study, MODY-related genes of 80 pediatric patients diagnosed with MODY in Türkiye between January 2016 and January 2022 were investigated using three different large gene panels and next-generation sequencing. Results: Causal variants were detected in the genes investigated in 16 (20%) of 80 patients included in the study. The GCK gene was responsible for the clinical findings in 13 (82%) of 16 patients with a molecular diagnosis, and the HNF1A, HNF1B, and ABCC8 genes in the remaining three patients. This study identified six of the detected genomic variants for the first time in the literature. Conclusions: MODY is a group of diseases that differ from each other in terms of clinical findings, treatment, progression, genetic etiopathogenesis and incidence. For this reason, genetic analyses using multigene panels will enable accurate identification of MODY subtypes, genetic counseling of patients, guidance to optimal treatment options, and screening of carrier relatives. [ABSTRACT FROM AUTHOR]

The etiological diagnosis of diabetes conveys many practical consequences for the care of patients, and often of their families. However, a wide heterogeneity in the phenotypes of all diabetes subtypes, including Type 1 diabetes, Type 2 diabetes, and monogenic diabetes, has been reported and contributes to frequent misdiagnoses. The recently revised WHO classification of diabetes mellitus includes two new classes, namely "hybrid forms" and "unclassified diabetes", which also reflect the difficulties of this etiological diagnosis. During the last years, many studies aiming at identifying homogenous subgroups on refined phenotypes have been reported. Ultimately, such subtyping may improve the diagnosis, prognosis, and treatment of patients on a pathophysiological basis. Here, we discuss the concepts of typical vs. atypical diabetes in the context of autoimmune Type 1 diabetes, Type 2 diabetes, and its monogenic forms. We discuss the contributions of clinical markers, biological tests, particularly islet cell auto-antibodies, and genetics to improving accurate diagnoses. These data support a systematic evaluation of all newly diagnosed diabetes cases. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) has revolutionized the field of genomics and created new opportunities for basic research. We described the strategy for the NGS validation of the "dysglycaemia panel" composed by 44 genes related to glucose metabolism disorders (MODY, Wolfram syndrome) and familial renal glycosuria using Ion AmpliSeq technology combined with Ion-PGM. Anonymized DNA of 32 previously genotyped cases with 33 different variants were used to optimize the methodology. Standard protocol was used to generate the primer design, library, template preparation, and sequencing. Ion Reporter tool was used for data analysis. In all the runs, the mean coverage was over 200×. Twenty-nine out of thirty three variants (96.5%) were detected; four frameshift variants were missed. All point mutations were detected with high sensitivity. We identified three further variants of unknown significance in addition to pathogenic mutations previously identified by Sanger sequencing. The NGS panel allowed us to identify pathogenic variants in multiple genes in a short time. This could help to identify several defects in children and young adults that have to receive the genetic diagnosis necessary for optimal treatment. In order not to lose any pathogenic variants, Sanger sequencing is included in our analytical protocol to avoid missing frameshift variants. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young is the most common monogenic diabetes form affecting between 1% and 5% of all diabetes cases. Clinical characteristics include young onset (usually before 45 years), autosomal dominant inheritance, absence of autoantibodies and metabolic syndrome, and impaired glucose-dependent insulin secretion. To date, at least 14 maturity-onset diabetes of the young subtypes have been identified, harboring numerous mutations that contribute to highly heterogeneous clinical phenotypes. While much is known about the common subtypes of maturityonset diabetes of the young linked to mutations in HNF4A, GCK, HNF1A, and HNF1B; little is known about relatively rare mutations in IPF1/PDX1, NEUROD1, KLF11, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1 genes. However, with the advent of next-generation sequencing, rare maturity-onset diabetes of the young subtypes are being increasingly reported worldwide. Although nearly 6 decades have passed since the first cases were identified, maturity-onset diabetes of the young is often misdiagnosed as type 1 or type 2 diabetes mellitus due to overlapping clinical features, limited use of genetic testing, and lack of awareness of this type of diabetes. Although there are many clinical characteristics suggesting the diagnosis of maturity-onset diabetes of the young, there is no single criterion. Identifying clinical features of different maturity-onset diabetes of the young subtypes can reduce the number and cost of genetic testing; On the other hand, early diagnosis will reduce the risks of inappropriate treatment and related side effects. The aim of this review is to highlight the role of clinical features, demonstrate the effectiveness of clinical biomarkers in the differential diagnosis of maturity-onset diabetes of the young subtypes, and identify the most suitable candidates for genetic testing. [ABSTRACT FROM AUTHOR]

Aims: To evaluate (a) the diagnostic yield of genetic testing for monogenic diabetes when using single gene and gene panel-based testing approaches in the New Zealand (NZ) population, (b) whether the MODY (Maturity Onset Diabetes of the Young) pre-test probability calculator can be used to guide referrals for testing in NZ, c) the number of referrals for testing for Maori/Pacific ethnicities compared to NZ European, and (d) the volume of proband vs cascade tests being requested. Methods: A retrospective audit of 495 referrals, from NZ, for testing of monogenic diabetes genes was performed. Referrals sent to LabPlus Auckland) laboratory for single gene testing or small multi-gene panel testing, or to the Exeter Genomics Laboratory, UK, for a large gene panel, received from January 2014 -- December 2021 were included. Detection rates of single gene, small multi-gene and large gene panels (neonatal and non-neonatal), and cascade testing were analysed. Pre-test probability was calculated using the Exeter MODY probability calculator and ethnicity data was also collected. Results: The diagnostic detection rate varied across genes, from32% inGCK, to 2% in HNF4A, with single gene or small gene panel testing averaging a 12% detection rate. Detection rate by type of panel was 9% for small gene panel, 23% for nonneonatal monogenic diabetes large gene panel and 40% for neonatal monogenic diabetes large gene panel. 45% (67/147) of patients aged 1-35 years at diabetes diagnosis scored <20% on MODY pre-test probability, of whom 3 had class 4/5 variants in HNF1A, HNF4A or HNF1B. Ethnicity data of those selected for genetic testing correlated with population diabetes prevalence for Māori (15% vs 16%), but Pacific People appeared under-represented (8% vs 14%). Only 1 in 6 probands generated a cascade test. Conclusions: A new monogenic diabetes testing algorithm for NZ is proposed, which directs clinicians to choose a large gene panel in patients without syndromic features who score a pre-test MODY probability of above 20%. [ABSTRACT FROM AUTHOR]

Yosef Tsegaye Dabi,1,2 Sisay Teka Degechisa1,3 1Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Medical Laboratory Science, Wollega University, Nekemte, Ethiopia; 3Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Arba Minch University, Arba Minch, EthiopiaCorrespondence: Yosef Tsegaye Dabi, Email yoseftsegaye01@gmail.comAbstract: Diabetes is a metabolic disease characterized by chronic hyperglycemia. Polygenic diabetes, which encompasses type-1 and type-2 diabetes, is the most prevalent kind of diabetes and is caused by a combination of different genetic and environmental factors, whereas rare phenotype monogenic diabetes is caused by a single gene mutation. Monogenic diabetes includes Neonatal diabetes mellitus and Maturity-onset diabetes of the young. The majority of our current knowledge about the pathogenesis of diabetes stems from studies done on animal models. However, the genetic difference between these creatures and humans makes it difficult to mimic human clinical pathophysiology, limiting their value in modeling key aspects of human disease. Human pluripotent stem cell technologies combined with genome editing techniques have been shown to be better alternatives for creating in vitro models that can provide crucial knowledge about disease etiology. This review paper addresses genome editing and human pluripotent stem cell technologies for in vitro monogenic diabetes modeling.Keywords: monogenic diabetes, MODY, NDM, genome editing, pluripotent stem cell

AimsTo evaluate (a) the diagnostic yield of genetic testing for monogenic diabetes when using single gene and gene panel-based testing approaches in the New Zealand (NZ) population, (b) whether the MODY (Maturity Onset Diabetes of the Young) pre-test probability calculator can be used to guide referrals for testing in NZ, (c) the number of referrals for testing for Māori/Pacific ethnicities compared to NZ European, and (d) the volume of proband vs cascade tests being requested.MethodsA retrospective audit of 495 referrals, from NZ, for testing of monogenic diabetes genes was performed. Referrals sent to LabPlus (Auckland) laboratory for single gene testing or small multi-gene panel testing, or to the Exeter Genomics Laboratory, UK, for a large gene panel, received from January 2014 – December 2021 were included. Detection rates of single gene, small multi-gene and large gene panels (neonatal and non-neonatal), and cascade testing were analysed. Pre-test probability was calculated using the Exeter MODY probability calculator and ethnicity data was also collected.ResultsThe diagnostic detection rate varied across genes, from 32% in GCK, to 2% in HNF4A, with single gene or small gene panel testing averaging a 12% detection rate. Detection rate by type of panel was 9% for small gene panel, 23% for non-neonatal monogenic diabetes large gene panel and 40% for neonatal monogenic diabetes large gene panel. 45% (67/147) of patients aged 1-35 years at diabetes diagnosis scored

Aims: 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. Methods: 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. Results: 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 23 years, 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

We aimed to identify the origin of atypical diabetes in a family with four generations of diabetes from South Asia. The family members showed different clinical phenotypes. Members of generation one to three were presumed to have type 2 diabetes and generation four to have type 1 diabetes. We performed a genetic analysis of the family using targeted high throughput sequencing. We identified a novel nonsense variant in the neurogenic differentiation 1 (NEUROD1) gene, co-segregating with diabetes. The variant was located in the DNA-binding domain, altering a protein residue that was very well conserved among different species. [ABSTRACT FROM AUTHOR]

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A , HNF4A , and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%–97%). We highlight that pathogenic variants in HNF1A , HNF4A , and GCK are not ultra-rare in the population. For HNF1A and HNF4A , we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list. The prevalence of pathogenic variants in common MODY-associated genes are ∼1:1,500 in the population. The penetrance of pathogenic HNF1A and HNF4A variants, but not of GCK variants, is substantially lower when found incidentally. Our findings are important for incidental reporting of pathogenic variants in MODY and other monogenic disorders. [ABSTRACT FROM AUTHOR]

Background: Although monogenic diabetes accounts for a small proportion of diabetes cases, accurate diagnosis may significantly change treatment. This study aimed to contribute to knowledge about the genotype-phenotype relationship in monogenic diabetes. Methods: This study used data from a tertiary centre in Turkey. Genetic analysis outcomes for 36 patients were evaluated. The panel included 23 genes related to maturity-onset diabetes of the young (MODY), neonatal diabetes, and some genes related to hyperglycemic hypoglycemia. The next-generation sequencing method was used after DNA isolation from the peripheral blood. Results: Mutations were identified in 19 (52.8%) of 36 patients. Of the 19 mutations, 7 (36.8%) were new mutations. A total of 20 cases met the MODY clinical criteria, and mutations were identified in 11 (55%) of them. In total, nine patients had more than one mutation. Mutations were identified on the ABCC8 (n = 7), PDX1 (n = 6), GLIS3 (n = 6), ZFP57 (n = 5), GCK (n = 4), HNF1A (n = 3), GLUD (n = 3), and HNF4A, KLF11, NKX2-2, and INSR genes (n = 1 each). Conclusion: Our findings highlight a broad clinical and genetic spectrum of MODY, and genetic analysis may provide a better understanding of diabetes and improve the individualised treatment approach. [ABSTRACT FROM AUTHOR]

Aims: Correct genetic diagnosis of maturity-onset diabetes of the young (MODY) is beneficial for person's diabetes management compared to no genetic testing. Aim of the present study was a search for optimal time- and cost-saving strategies by comparing two approaches of genetic testing of participants with clinical suspicion of MODY. Methods: A total of 121 consecutive probands referred for suspicion of MODY (Group A) were screened using targeted NGS (tNGS), while the other 112 consecutive probands (Group B) underwent a single gene test based on phenotype, and in cases of negative findings, tNGS was conducted. The study was performed in two subsequent years. The genetic results, time until reporting of the final results and financial expenses were compared between the groups. Results: MODY was confirmed in 30.6% and 40.2% probands from Groups A and B, respectively; GCK-MODY was predominant (72.2% in Group A and 77.8% in Group B). The median number of days until results reporting was 184 days (IQR 122–258) in Group A and 91 days (44–174) in Group B (p < 0.00001). Mean costs per person were higher for Group A (639 ± 30 USD) than for Group B (584 ± 296 USD; p = 0.044). Conclusions: The two-step approach represented a better strategy for genetic investigation of MODY concerning time and costs compared to direct tNGS. Although a single-gene investigation clarified the diabetes aetiology in the majority of cases, tNGS could reveal rare causes of MODY and expose possible limitations of both standard genetic techniques and clinical evaluation. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective:The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey.Methods:A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses.Results:In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel.Conclusion:This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.

BackgroundDiagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes.MethodsWe utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls.ResultsA total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome.ConclusionTargeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.

Monogenic forms of diabetes mellitus may affect a significant number of patients of this disease, and it is an important molecular cause to be investigated. However, studies of the genetic causes of monogenic diabetes, especially in populations with mixed ethnic backgrounds, such as the one in Brazil, are scarce. The aim of this study was to screen several genes associated with monogenic diabetes in fifty-seven Brazilian patients with recurrence of the disease in their families and thirty-four relatives. Inclusion criteria were: Age of onset ≤ 40 years old, BMI < 30 kg/m², at least two affected generations and negative anti-GAD and anti-IA2 antibodies. MODY genes HNF4A , GCK , HNF1A , HNF1B , NEUROD1 , KLF11 , PAX4 , INS , KCNJ11 , and MT-TL1 were sequenced by Sanger sequencing. We identified a total of 20 patients with variants, 13 GCK-MODY, four HNF1A-MODY, and one variant in each of the following genes, HNF4A , HNF1B and MT-TL1. Segregation analysis was performed in 13 families. Four variants were novel, two in GCK (p.(Met115Val) [c.343A>G] and p.(Asp365GlufsTer95) [c.1094_1095insGCGA]) and two in HNF1A (p.(Tyr163Ter) [c.489C>G] and p.(Val380CysfsTer39) [c.1136_1137insC]). Here we highlight the importance of screening for monogenic diabetes in admixed populations. [ABSTRACT FROM AUTHOR]

Monogenic forms of diabetes mellitus may affect a significant number of patients of this disease, and it is an important molecular cause to be investigated. However, studies of the genetic causes of monogenic diabetes, especially in populations with mixed ethnic backgrounds, such as the one in Brazil, are scarce. The aim of this study was to screen several genes associated with monogenic diabetes in fifty-seven Brazilian patients with recurrence of the disease in their families and thirty-four relatives. Inclusion criteria were: Age of onset ≤ 40 years old, BMI < 30 kg/m², at least two affected generations and negative anti-GAD and anti-IA2 antibodies. MODY genes HNF4A, GCK, HNF1A, HNF1B, NEUROD1, KLF11, PAX4, INS, KCNJ11, and MT-TL1 were sequenced by Sanger sequencing. We identified a total of 20 patients with variants, 13 GCK-MODY, four HNF1A-MODY, and one variant in each of the following genes, HNF4A, HNF1B and MT-TL1. Segregation analysis was performed in 13 families. Four variants were novel, two in GCK (p.(Met115Val) [c.343A>G] and p.(Asp365GlufsTer95) [c.1094_1095insGCGA]) and two in HNF1A (p.(Tyr163Ter) [c.489C>G] and p.(Val380CysfsTer39) [c.1136_1137insC]). Here we highlight the importance of screening for monogenic diabetes in admixed populations.

Aims/hypothesis: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. Methods: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). Results: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. Conclusions/interpretation: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria. [ABSTRACT FROM AUTHOR]

Tandi E Matsha,1,* Shanel Raghubeer,1,* Abegail M Tshivhase,1 Saarah FG Davids,1 Gloudina M Hon,1 Lise Bjørkhaug,2 Rajiv T Erasmus1 1SAMRC/Cardiometabolic Health Research Unit, Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, Bellville Campus, Cape Town 7530, South Africa; 2Department of Safety, Chemistry, and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway*These authors contributed equally to this workCorrespondence: Shanel RaghubeerSAMRC/CPUT/Cardiometabolic Health Research Unit, Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, Bellville Campus, Cape Town 7530, South AfricaTel +27 21 959 6015Email shanelraghubeer@gmail.comBackground and Aim: Maturity-onset diabetes of the young (MODY) is the result of single gene variants. To date, fourteen different MODY subtypes have been described. Variants in genes coding for glucokinase (GCK, MODY2) and hepatic nuclear factor 1 alpha (HNF1A, MODY3) are most frequently encountered. MODY patients are often misdiagnosed with type 1 or type 2 diabetes, resulting in incorrect treatment protocols. At the time of reporting, no data are available on MODY prevalence in populations from Africa. Our study aimed to investigate and report on the incidence of MODY-related variants, specifically HNF1A variants, in a population from the Western Cape.Methods: Study participants were recruited (1643 in total, 407 males, 1236 females) and underwent anthropometric tests. Thereafter, blood was collected, and real-time PCR was used to screen for specific variants in HNF1A and GCK genes.Results: Ninety-seven individuals (5.9%) were identified with a specific HNF1A gene polymorphism (rs1169288) and twelve (0.9%) with a GCK polymorphism (rs4607517).Conclusion: In total, 6.6% of the study population expressed MODY variants. To our knowledge, we are the first to report on MODY incidence in Africa. This research provides the basis for MODY incidence studies in South Africa, as well as data on non-Caucasian populations.Keywords: MODY, HNF1A, GCK, diabetes mellitus, monogenic diabetes, South Africa

Faiza Bouldjennet,1,* Anette P Gjesing,2,* Malha Azzouz,3 Samir Ait Abderrahman,4 Amina El Guecier,5 Said Ali,6 Brahim Oudjit,4 Farida Mennadi-Lacete,7 Lyèce Yargui,6 Aissa Boudiba,3 Ahcène Chibane,5 Chafia Touil-Boukoffa,1 Torben Hansen,2 Rachida Raache1 1Laboratory of Cellular and Molecular Biology, Cytokine and NO Synthase Team, University of Science and Technology, Houari Boumediene (USTHB), Algiers, Algeria; 2The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 3Diabetology Department of Mustapha Pacha Hospital, Algiers, Algeria; 4Diabetology Department of Mohamed Seghir Nekkache Hospital, Algiers, Algeria; 5Internal Medicine Department of Djillali Bounaâma Hospital, Algiers, Algeria; 6Laboratory of Biochemistry, Mustapha Pacha, Algiers, Algeria; 7Pediatric Department of Parnet Hospital, Algiers, Algeria*These authors contributed equally to this workCorrespondence: Anette P Gjesing; Rachida Raache Email anette.gjesing@sund.ku.dk; raache_ipa@yahoo.frAim: To investigate the prevalence of variants within selected maturity-onset diabetes of the young (MODY)-genes among Algerian patients initially diagnosed with type 1 diabetes (T1D) or type 2 diabetes (T2D), yet presenting with a MODY-like phenotype.Methods: Eight unrelated patients with early-onset diabetes (before 30 years) and six relatives with diabetes were examined by targeted re-sequencing for variants in genes known to be involved in MODY (HNF1A, GCK, HNF4A, HNF1B, INS, ABCC8, KCNJ1). Clinical data for probands were retrieved from hospital records.Results: A total of 12 variants were identified, of which three were classified as pathogenic and one as a variant of uncertain clinical significance (VUS). Two of the pathogenic variants were found in GCK (p.Gly261Arg and p.Met210Lys, respectively) in one proband each and the remaining pathogenic variant was found in HNF1B (p.Gly76Cys) in a proband also carrying the VUS in HNF1A (p.Thr156Met).Conclusion: Variants in known MODY-genes can be the cause of early-onset diabetes in Algerians diagnosed with T1D or T2D among patients presenting with a MODY-like phenotype; thus, genetic screening should be considered.Keywords: MODY, type 1 diabetes, early-onset, monogenic diabetes, genes

Abstract Background The most common type of monogenic diabetes is maturity-onset diabetes of the young (MODY), a clinically and genetically heterogeneous group of endocrine disorders that affect 1–5% of all patients with diabetes mellitus. MODY is characterized by autosomal dominant inheritance but de novo mutations have been reported. Clinical features of MODY include young-onset hyperglycemia, evidence of residual pancreatic function, and lack of beta cell autoimmunity or insulin resistance. Glucose-lowering medications are the main treatment options for MODY. The growing recognition of the clinical and public health significance of MODY by clinicians, researchers, and governments may lead to improved screening and diagnostic practices. Consequently, this review article aims to discuss the epidemiology, pathogenesis, diagnosis, and treatment of MODY based on relevant literature published from 1975 to 2020. Main body The estimated prevalence of MODY from European cohorts is 1 per 10,000 in adults and 1 per 23,000 in children. Since little is known about the prevalence of MODY in African, Asian, South American, and Middle Eastern populations, further research in non-European cohorts is needed to help elucidate MODY’s exact prevalence. Currently, 14 distinct subtypes of MODY can be diagnosed through clinical assessment and genetic analysis. Various genetic mutations and disease mechanisms contribute to the pathogenesis of MODY. Management of MODY is subtype-specific and includes diet, oral antidiabetic drugs, or insulin. Conclusions Incidence and prevalence estimates for MODY are derived from epidemiologic studies of young people with diabetes who live in Europe, Australia, and North America. Mechanisms involved in the pathogenesis of MODY include defective transcriptional regulation, abnormal metabolic enzymes, protein misfolding, dysfunctional ion channels, or impaired signal transduction. Clinicians should understand the epidemiology and pathogenesis of MODY because such knowledge is crucial for accurate diagnosis, individualized patient management, and screening of family members.

Gabriella de Medeiros Abreu,1,* Camila de Almeida Pereira Dias Soares,1,* Roberta Magalhães Tarantino,2,3 Ana Carolina Proença da Fonseca,1 Ritiele Bastos de Souza,1 Maria de Fátima Carvalho Pereira,4 Pedro Hernan Cabello,1,5 Melanie Rodacki,2 Lenita Zajdenverg,2 Verônica Marques Zembrzuski,1 Mário Campos Junior1 1Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 2Diabetes and Nutrology Section, Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Ambulatory of Diabetes, State Institute for Diabetes and Endocrinology Luiz Capriglione, Rio de Janeiro, Brazil; 4Clinical Pathology Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 5Laboratory of Genetics, School of Health Science, University of Grande Rio, Rio de Janeiro, Brazil*These authors contributed equally to this workCorrespondence: Mário Campos Junior JuniorHuman Genetics Laboratory,Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilhão Leônidas Deane, Sala 615, Avenida Brasil 4365, Rio de Janeiro 21040-360, RJ, BrazilTel +55 21 3865 8192Email mario.junior@ioc.fiocruz.brPurpose: The aim of this study was to sequence the coding region of the PAX4 gene in a Brazilian cohort with clinical manifestations of monogenic diabetes.Patients and Methods: This study included 31 patients with autosomal dominant history of diabetes, age at diagnosis ≤ 40 years, BMI < 30 kg/m2, and no mutations in GCK or HNF1A, HNF4A, and HNF1B. Screening of the PAX4 coding region was performed by Sanger sequencing. In silico algorithms were used to assess the potential impact of amino acid substitutions on protein structure and function. Additionally, PAX4-MODY family members and 158 control subjects without diabetes were analyzed for the identified mutation.Results: The molecular analysis of PAX4 has detected one missense mutation, p.Arg164Gln (c.491G>A), segregating with diabetes in a large Brazilian family. The mutation was absent among the control group. The index case is a woman diagnosed at 32 years of age with polyneuropathy and treated with insulin. She did not present diabetic renal disease or retinopathy. Family members with the PAX4 p.Arg164Gln mutation have a heterogeneous clinical manifestation and treatment response, with age at diagnosis ranging from 24 years to 50 years.Conclusion: To the best of our knowledge, this is the first study to report a PAX4-MODY family in Brazil. The age of PAX4-MODY diagnosis in the Brazilian family seems to be higher than the classical criteria for MODY. Our results reinforce the importance of screening large monogenic diabetes families for the understanding of the clinical manifestations of rare forms of diabetes for the specific and personalized treatment.Keywords: diabetes mellitus, monogenic diabetes, MODY, PAX4, mutation

Aims: Monogenic diabetes is responsible for 1–5% of all cases of diabetes. A previous Australian study estimated a prevalence of 89 cases per million adults, or one in 280 people with diabetes. Approximately 80% of monogenic diabetes is misdiagnosed as type 1 or type 2 diabetes. Our aims were: 1. To estimate the incidence of referral for genetic testing for monogenic diabetes at an Australian tertiary hospital. 2. To estimate the proportion of individuals with confirmed monogenic diabetes out of those who are referred for genetic testing. 3. To investigate the clinical, biochemical and genetic characteristics of patients with confirmed monogenic diabetes in an Australian population. Methods: We conducted a retrospective audit of patients referred to the genetics service at Austin Health for testing for monogenic diabetes from August 2018 to January 2021, inclusive. We collected pre-existing clinical, biochemical and genetic data from electronic medical records from patients with both confirmed and suspected monogenic diabetes. Results: Of approximately 2576 referrals to the diabetes clinic at Austin Health between December 2018 and January 2021, 46 individuals (1.8%, 95% CI 1.3–2.3%) were referred for genetic testing. Of the individuals referred for testing, 16 (35%, 95% CI 23-49%) declined testing and 3 (6.5%, 95% CI 2.2–18%) did not proceed with genetic testing due to their clinician identifying this as low-yield. Of the 27 individuals who were tested, ten individuals had a positive genetic test result (37%, 95% CI 22-58%) and 1 (2.1%, 95% CI 0.38–11%) had a variant of uncertain significance. GCK variants were the most common variant detected. Conclusion: Approximately 0.39% (95% CI 0.21–0.71) of people seen in the diabetes clinics at a tertiary centre were diagnosed with monogenic diabetes over a period of 26 months.

Diabetes mellitus is a common long-term childhood condition, which paediatricians, allied healthcare professionals and paediatric trainees will encounter frequently. General or acute paediatric trainees will be involved in treatment initiation, requesting appropriate investigations and continued management. The vast majority of children with diabetes have type 1 diabetes mellitus (T1DM) and the minority have type 2 diabetes mellitus (T2DM) or monogenic causes (also known as maturity-onset diabetes of the young). Individuals with T1DM tend to present more acutely and may be unwell with diabetic ketoacidosis. Those with T2DM and MODY usually present less acutely. However, there is considerable overlap in the clinical features, which may lead to diagnostic uncertainty. It is essential to clarify the subtype of diabetes mellitus as this allows tailored management including education, lifestyle modifications, medication and appropriate family counselling. In this review, we consider three adolescents presenting with symptoms and signs of diabetes, highlight the key features of different types of MODY and consider their differential diagnoses. [ABSTRACT FROM AUTHOR]

Aims: Maturity‐onset diabetes of the young (MODY) is one of the rare monogenic forms of diabetes. To date, about 12 genes in the scientific literature are closely related to the occurrence of the disease phenotype. However, there is still a high prevalence of undiagnosed cases of so-called MODY-X whose genetic background is still unknown. Methods: We performed tNGS for 523 patients with suspected MODY. Next 357 selected patients, in whom no damaging variants were found in 12 major genes causing MODY, were screened for the presence of pathogenic variants in four candidate genes (MNX1, RFX6, NKX2.2, and NKX6.1). All data were generated in one tNGS sequencing reaction and confirmed by Sanger sequencing. Results: In total, we selected five potentially damaging variants, in eight patients, in RFX6, NKX2.2, and NKX6.1 genes. Four of them have never been described in literature before. The frequency of occurrence of two of them in the RFX6 gene significantly differed in relation to the healthy population. The analysis of segregation in the family did not reveal that they were the only cause of the disease phenotype. Conclusions: The very-rare variants indicated in this study show that this type of research on large population groups may help in the future for better understanding and more accurate diagnostics of extremely rare forms of MODY. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY. [ABSTRACT FROM AUTHOR]