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AimsMaturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with autosomal dominant inheritance pattern. The diagnosis of MODY and its subtypes is based on genetic testing. Our aim was investigating MODY by means of next-generation sequencing in the Tunisian population.MethodsWe performed a targeted sequencing of 27 genes known to cause monogenic diabetes in 11 phenotypically suspected Tunisian patients. We retained genetic variants passing filters of frequency in public databases as well as their probable effects on protein structures and functions evaluated by bioinformatics prediction tools.ResultsFive heterozygous variants were found in four patients. They include two mutations in HNF1A and GCK that are the causative genes of the two most prevalent MODY subtypes described in the literature. Other possible mutations, including novel frameshift and splice-site variants were identified in ABCC8 gene.ConclusionsOur study is the first to investigate the clinical application of targeted next-generation sequencing for the diagnosis of MODY in Africa. The combination of this approach with a filtering/prioritization strategy made a step towards the identification of MODY mutations in the Tunisian population.

Background Myocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2 , has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients. Methods SNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n = 1060) and the Gargano Heart Study-cross sectional design (GHS, n = 779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram. Results Carriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ = OR 0.380, 95% CI 0.175–0.823, p  = 0.014), (GHS = 0.497, 0.267–0.923, p  = 0.027), (Pooled = 0.458, 0.283–0.739, p  = 0.001)] which remained significant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ = 0.307, 0.106–0.885, p  = 0.029), (GHS = 0.512, 0.270–0.970, p  = 0.040), (Pooled = 0.458, 0.266–0.787, p  = 0.005)]. Conclusions We found that rs9267551 polymorphism is significantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.

Clinical characteristics of the study cohort and of all monogenic diabetes patients Characteristics All probands (n = 151) Probands with monogenic diabetes (n = 68) Patients with mutations in non-SD genes (n = 62) Patients with mutations in SD genes (n = 6) P values Age at diagnosis of diabetes (y) 14 (10–29) 12.5 (8–17.3) 14 (11–32) 0.31 Age at genetic diagnosis (y) 20 (12–39) 17.5 (11–33.5) 26.5 (14–57) 0.23 Diabetes duration (y) 2 (0–10) 3 (0–10.3) 8.5 (2.3–23.8) 0.25 Female (n) 85 41 5 BMI (Kg/m2) 21.8 (18.9–26.2), (n = 140) 21.2 (18.9–23.8), (n = 58) 21.5 (19–28.1) 0.34 Reporting parents with diabetes (n) 116 56 5 0.49 HbA1c (%) 6.2 (5.8–7.1) (n = 118) 6.1 (5.8–6.4), (n = 45) 8.6 (6.4–9.2), (n = 5) 0.01 Therapy (n) Diet only 77 40 0 AD 26 11 1 Insulin (± AD) 48 11 5 0.002 Data are presented as median value (25th–75th percentile). (n) number of patients with available data; (y) = years; AD: anti-diabetes drugs other than insulin P values are for comparison between patients with mutations in non-SD and SD genes Subjects positive to MD genetic test MD was confirmed in 68 probands (pick-up rate = 45%). List of mutations Gene DNA change Protein change Variant type (P/LP) Sequencing methods n of probands GCK c.107G > A p.Arg36Gln Missense (P) CES 1 GCK c.110 T > C p.Met37Thr Missense (LP) Sanger 1 GCK c.113A > C p.Gln38Pro Missense (LP) Sanger 1 GCK c.127C > T p.Arg43Cys Missense (P) CES 1 GCK c.175C > T p.Pro59Ser Missense (P) 1 by Sanger 1 by CES 2 GCK c.214G > A p.Gly72Arg Missense (P) Sanger 2 GCK c.218A > G p.Asp73Gly Missense (LP) Sanger 1 GCK c.316C > T p.Gln106* Nonsense (P) Sanger 1 GCK c.1019 + 2 T > C p.? Aberrant splicing (LP) tNGS 1 GCK§ c.545 T > C p.Val182Ala Missense (LP) Sanger 1 GCK c.556C > G p.Arg186Gly Missense (LP) Sanger 1 GCK c.562G > A p.Ala188Thr Missense (P) tNGS 1 GCK c.571C > T p.Arg191Thr Missense (P) 1 by Sanger 1 by CES 2 GCK c.667G > A p.Gly223Ser Missense (P) 3 by Sanger 1 by tNGS 1 by CES 5 GCK c.675C > G p.Ile225Met Missense (P) Sanger 1 GCK c.676G > A p.Val226Met Missense (P) Sanger 1 GCK c.766G > T p.Glu256* Nonsense (P) tNGS 1 GCK c.775G > A p.Ala259Thr Missense (P) Sanger 2 GCK c.781G > C p.Gly261Arg Missense (P) CES 1 GCK c.796C > G p.Leu266Val Missense (LP) Sanger 1 GCK c.867 T > A p.Tyr289* Nonsense (P) Sanger 1 GCK c.907C > T p.Arg303Trp Missense (P) tNGS 1 GCK c.955G > T p.Glu319* Nonsense (LP) Sanger 1 GCK c.971 T > C p.Leu324Pro Missense (LP) Sanger 1 GCK c.976A > C p.Thr326Pro Missense (LP) CES 1 GCK c.1116G > C p.Glu372Asp Missense (LP) tNGS 1 GCK c.1195G > T p.Glu399* Nonsense (P) Sanger 1 GCK c.1278_1286del p.Ser426_Arg428del In frame deletion (LP) CES 1 GCK c.1358C > T p.Ser453Leu Missense (P) CES 1 HNF1A§ c.351G > T p.Lys117Asn Missense (LP) Sanger 1 HNF1A c.392G > A p.Arg131Gln Missense (P) CES 1 HNF1A c.476G > A p.Arg159Gln Missense (P) tNGS 1 HNF1A c.508C > T p.Gln170* Nonsense (P) tNGS 1 HNF1A c.608G > A p.Arg203His Missense (P) tNGS 1 HNF1A c.617G > A p.Try206* Nonsense (P) tNGS 1 HNF1A c.686G > A Arg229Gln Missense (P) CES 1 HNF1A c.814C > T p.Arg272Cys Missense (P) tNGS 1 HNF1A§ c.850delG p.Asp284fs Frameshift (LP) tNGS 1 HNF1A c.864delG p.Pro291fs Frameshift (LP) 1 by Sanger 1 by tNGS 2 HNF1A c.1137delT p.Val380fs Frameshift (P) tNGS 1 HNF1A c.1340C > T p.Pro447Leu Missense (P) tNGS 1 HNF1A§ c.1375delC p.Leu459fs Frameshift (LP) CES 1 HNF1A c.1859C > T p.Thr620Ile Missense (LP) CES 2 HNF4A c.341G > A p.Arg114Gln Missense (P) tNGS 1 HNF4A c.340C > T p.Arg114Trp Missense (P) tNGS 1 HNF4A§ c.347G > C p.Ser116Thr Missense (LP) CES 1 HNF4A§ c.424C > T p.Gln142* Nonsense (LP) tNGS 1 HNF4A c.733C > A p.Arg245Ser Missense (LP) tNGS 1 HNF4A§ c.825delA p.Pro275fs Frameshift (LP) CES 1 HNF4A c.932G > A p.Arg311His Missense (LP) tNGS 1 ABCC8 c.4372G > A p.Ala1458Thr Missense (LP) CES 1 KCNJ11 c.185C > T p.Thr62Met Missense (LP) CES 1 WFS1 c.605A > G p.Glu202Gly Missense (LP) tNGS 1 WFS1 c.1240_1243T; c.2104G > A p.Val415del; p.Gly702Ser Inframe Deletion (LP); Missense (LP) CES 1 WFS1 c.1673G > A p.Arg558His Missense (LP) tNGS 1 WFS1 c.2099G > A p.Trp700* Nonsense (LP) CES 1 PPARG c.1273C > T p.Arg425Cys Missense (LP) CES 1 INSR c.3472C > T p.Arg1158Trp Missense (LP) CES 1 The following genes were sequenced by tNGS or CES: Clinical features of patients with mutations in SD genes The clinical features of probands with SD gene mutations were compared with those of patients carrying mutations in non-SD genes (Table 1). Age at diagnosis tended to be older in patients carrying SD gene mutations.

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1–5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions (“actionable genes”). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in “actionable genes”, including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.

INTRODUCTION:Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before.METHODS:HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195).RESULTS:During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported.DISCUSSION:PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below the level that allows the normal digestion of nutrients. Pancreatic disease and surgery are the main causes of PEI. However, other conditions and upper gastrointestinal surgery can also affect the digestive function of the pancreas. PEI can cause symptoms of nutritional malabsorption and deficiencies, which affect the quality of life and increase morbidity and mortality. These guidelines were developed following the United European Gastroenterology framework for the development of high‐quality clinical guidelines. After a systematic literature review, the evidence was evaluated according to the Oxford Center for Evidence‐Based Medicine and the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted on using the Delphi method. The diagnosis of PEI should be based on a global assessment of symptoms, nutritional status, and a pancreatic secretion test. Pancreatic enzyme replacement therapy (PERT), together with dietary advice and support, are the cornerstones of PEI therapy. PERT is indicated in patients with PEI that is secondary to pancreatic disease, pancreatic surgery, or other metabolic or gastroenterological conditions. Specific recommendations concerning the management of PEI under various clinical conditions are provided based on evidence and expert opinions. This evidence‐based guideline summarizes the prevalence, clinical impact, and general diagnostic and therapeutic approaches for PEI, as well as the specifics of PEI in different clinical conditions. Finally, the unmet needs for future research are discussed.