Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

Wolcott-Rallison\'s syndrome (WRS) is a rare nonautoimmune autosomal recessive disorder characterized by neonatal diabetes mellitus, epiphyseal dysplasia, and growth retardation. This is the most common cause of diabetes mellitus in patients with consanguineous parents. WRS is distinguished from other types of neonatal or early-onset diabetes by clinical characteristics and genetic testing. Here, we report four cases of WRS from South India. All four children reported here were born to consanguineous parents and were diagnosed with neonatal diabetes and skeletal dysplasia. Case 1 is a 13-year-old girl with neonatal diabetes and skeletal dysplasia. Case 2 is a 6-month-old male infant who also has primary hypothyroidism. Case 3 was a girl who lived until the age of 4 years before succumbing to liver failure. Case 4 is an 8-month-old female infant born to a third-degree married couple who presented with neonatal diabetes and diabetic ketoacidosis. Genetic testing revealed that she had WRS, which helps us in the anticipation and early treatment of complications.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes that presents with uncontrolled hyperglycemia during the first 6 months of life. NDM is a rare disease in which gene variants mainly cause β-cell loss or dysfunction (6q24 duplication, KCNJ11, and ABCC8). Although NDM is primarily treated through insulin therapy, it is highly challenging to manage blood glucose levels using insulin therapy during infancy. In contrast, KCNJ11 and ABCC8 mutant patients received oral sulfonylureas (SU) instead of insulin injections; however, the dose and frequency differ among individuals. Continuous glucose monitoring (CGM) is useful in patients with type 1 diabetes; but reports on patients with NDM are lacking. Herein, we report two cases of NDM with the KCNJ11 variant. We used CGM not only during insulin injection therapy but also after switching to oral SU therapy. The CGM data can also be used to determine the dose and frequency of SU. Furthermore, long-term CGM may be useful for adjusting SU dose and frequency, and maintaining good glycemic control not only during insulin injection but also during oral SU therapy.

Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare non-immunological monogenic disorder characterized by hyperglycemic conditions primarily occurring within the first 6 months of life. The majority of cases are attributed to pathogenic variants in genes affecting beta-cell survival, insulin regulation, and secretion. This study aims to investigate the genetic landscape of NDM in Iran.
METHODS: We recruited a total of 135 patients who were initially diagnosed with diabetes at <12 months of age in Iran and referred to pediatric endocrinology clinics across the country. These patients underwent genetic diagnostic tests conducted by the Exeter Molecular Genetics Laboratory in the UK. The pathogenic variants identified were sorted and described based on type, pathogenicity (according to ACMG/AMP criteria), novelty, and the affected protein domain.
RESULTS: Genetic defects were identified in 93 probands, presenting various pathogenic abnormalities associated with NDM and its associated syndromes. 76% of the patients were born as a result of consanguineous marriage, and a familial history of diabetes was found in 43% of the cases. A total of 58 distinct variants in 14 different genes were discovered, including 20 variants reported for the first time. Causative variants were most frequently identified in EIF2AK3, KCNJ11, and ABCC8, respectively. Notably, EIF2AK3 and ABCC8 exhibited the highest number of novel variants.
CONCLUSIONS: These findings provide valuable insights into the genetic landscape of NDM in the Iranian population and contribute to the knowledge of novel pathogenic variants within known causative genes.

Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.

Neonatal Diabetes Mellitus (NDM) is a disorder characterized by persistent, severe hyperglycemia presenting during the first 6 months of life. These disorders are rare and the incidence is approximately 1 in 90,000 live births. To describe the clinical presentation, molecular genetics and outcome of patients with NDM from a single paediatric endocrine center from a low middle income country. A retrospective study was conducted on patients diagnosed with NDM. Medical records were reviewed for demographic data and data on clinical, biochemical and genetic analysis. 96% of patients who underwent mutation analysis had pathogenic genetic mutations on Sanger sequencing. Permanent NDM (PNDM) was diagnosed in 19 patients with 3 of them having a syndromic diagnosis. The commonest mutation was found in KCNJ11 gene. Majority of the PNDM (63%) presented with severe diabetic ketoacidosis. All patients with Transient NDM (TNDM) remitted by 6 months of age. 47% of the cases with PNDM made a switch to sulfonylurea therapy with good glycemic control (glycosylated Haemoglobin A1C 6-7.5). Data from the Sri Lankan cohort is comparable with other populations. The majority of cases are due to KCNJ11 mutations resulting in PNDM.

UNASSIGNED: Neonatal diabetes is a monogenic type of diabetes mellitus. It arises at the first 6 months of age and can be classified as permanent or transient. There are limited cases of neonates with DKA who have heterozygous mutations in INS and PKHD1 genes, especially in Saudi Arabia. We present a case of neonatal diabetes with diabetic ketoacidosis (DKA) born to consanguineous parents in Saudi Arabia. This study aims to highlight the importance of the genetic mutations associated with neonatal diabetes and identify the clinical manifestation features of neonatal diabetes.
UNASSIGNED: A six-month-old boy born to consanguineous parents with a family history of neonatal diabetes was diagnosed with DKA. The case was presented to the emergency department (ED) with vomiting and increased urination for 3 days. The child showed signs of severe dehydration and severe metabolic acidosis with a high anion gap and elevated hemoglobin A1C level (16.3%) was reported. According to the genetic test, the patient had an INS and PKHD1gene mutation. The treatment was initiated according to the DKA protocol, and then he received subcutaneous insulin.
UNASSIGNED: Neonatal diabetes is a condition caused by several gene mutations. In this case, heterozygous mutations in INS and PKHD1 genes were reported. The type of gene mutation could predict neonatal diabetes type, whether permanent or transient, and its response to treatment.
UNASSIGNED: Genetic testing for neonates soon after birth is suggested for the early detection and classification of neonatal diabetes, especially among children with a family history of neonatal diabetes.

BACKGROUND: Neonatal diabetes mellitus (NDM) is characterized by severe hyperglycemia, usually diagnosed in the first few months of an individual\'s life. It is a genetic disease and one of the main forms of monogenic diabetes. Changes in different genes have already been associated with NDM, including changes in the gene PDX1.
METHODS: In this review, we intend to summarize all neonatal diabetes cases caused by PDX1 mutations reported in the literature. For this purpose, we searched keywords in the literature from PubMed and articles cited by the HGMD database. The search retrieved 84 articles, of which 41 had their full text accessed. After applying the study exclusion criteria, nine articles were included.
RESULTS: Of those articles, we detected thirteen cases of NDM associated with changes in PDX1; the majority in homozygous or compound heterozygous patients. Until now, variants in the PDX1 gene have been a rare cause of NDM; however, few studies have included the screening of this gene in the investigation of neonatal diabetes.
CONCLUSIONS: In this review, we reinforce the importance of the PDX1 gene inclusion in genetic NGS panels for molecular diagnosis of NDM, and systematic morphological and functional exams of the pancreas when NDM is present.

Early-onset diabetes is poorly diagnosed partly due to its heterogeneity and variable presentations. Although several genes have been associated with the disease, these genes are not well studied in Africa. We sought to identify the major neonatal, early childhood, juvenile, or early-onset diabetes genes in Africa; and evaluate the available molecular methods used for investigating these gene variants. A literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. The retrieved records were screened and analyzed to identify genetic variants associated with early-onset diabetes. Although 319 records were retrieved, 32 were considered for the current review. Most of these records (22/32) were from North Africa. The disease condition was genetically heterogenous with most cases possessing unique gene variants. We identified 22 genes associated with early-onset diabetes, 9 of which had variants (n = 19) classified as pathogenic or likely pathogenic (PLP). Among the PLP variants, IER3IP1: p.(Leu78Pro) was the variant with the highest number of cases. There was limited data from West Africa, hence the contribution of genetic variability to early-onset diabetes in Africa could not be comprehensively evaluated. It is worth mentioning that most studies were focused on natural products as antidiabetics and only a few studies reported on the genetics of the disease. ABCC8 and KCNJ11 were implicated as major contributors to early-onset diabetes gene networks. Gene ontology analysis of the network associated ion channels, impaired glucose tolerance, and decreased insulin secretions to the disease. Our review highlights 9 genes from which PLP variants have been identified and can be considered for the development of an African diagnostic panel. There is a gap in early-onset diabetes genetic research from sub-Saharan Africa which is much needed to develop a comprehensive, efficient, and cost-effective genetic panel that will be useful in clinical practice on the continent and among the African diasporas.