Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes

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.

Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance

Summary We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants. Learning points Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents. Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history. Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Glycemic control in children and young adults with different types of diabetes mellitus in Ukraine

Introduction. Until recently, glycated hemoglobin (HbA1c) has not been studied in children with different types of diabetes mellitus (DM). With the development of molecular genetics, new types of diabetes have been diagnosed, including neonatal (ND) and maturity onset diabetes of the young (MODY), which usually require specific pathogenetic therapy, including sulfonylureas (SU), which improve glycemic control in patients with certain mutations. The aim of this study, which was conducted for the first time in Ukraine, was to analyze glycemic control in patients with different types of DM, including ND and MODY and changing their treatment after genetic testing. Materials and methods. We studied conducted the analysis of glycemic control in patients depending on the type of diabetes, namely: type 1 diabetes (n = 9282), type 2 diabetes (n = 23), ND (n = 16) with mutations KCNJ11, ABCC8 and MODY (n = 16) with mutations in HNF1A/HNF4A and ABCC8 genes. To confirm the nature of monogenic diabetes, targeting next-generation sequencing (tNGS) of all known neonatal and monogenic diabetes genes was performed. Results. According to the Register in 2018, in Ukraine the average age of children with type 1 DM was 11.5 ± 1.4 years, and the level of HbA1c was unsatisfactory (8.8 ± 2.01 %). The proportion of children who had ideal or optimal glycemic control (HbA1c

The invaluable role of consanguinity in providing insight into paediatric endocrine conditions: Lessons learned from congenital hyperinsulinism, monogenic diabetes, and short stature

Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review is to shed light on the lessons learned from consanguineous pedigrees with the help of three fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity – from congenital hyperinsulinism, a typically single cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth – the most complex developmental phenomenon.

Syndromic Monogenic Diabetes Genes Should be Tested in Patients With a Clinical Suspicion of MODY

At present, outside of infancy, genetic testing for monogenic diabetes is typically for mutations in MODY genes that predominantly result in isolated diabetes. Monogenic diabetes syndromes are usually only tested when this is supported by specific syndromic clinical features. It is not known how frequently patients with suspected MODY have a mutation in a monogenic syndromic diabetes gene and thus missed by present testing regimes. We performed<b> </b>genetic testing of 27 monogenic diabetes genes (including 18 associated with syndromic diabetes) for 1280 patients with a clinical suspicion of MODY from routine clinical care that were not suspected of having monogenic syndromic diabetes. We confirmed monogenic diabetes in 297 (23%) patients. Mutations in 7 different syndromic diabetes genes accounted for 19% (95%CI 15-24%) of all monogenic diabetes. The mitochondrial m.3243A>G and mutations in <i>HNF1B</i> were responsible for the majority of mutations in syndromic diabetes genes. They were also the 4^th and 5^th most common causes of monogenic diabetes overall. These patients lacked typical features and their diabetes phenotypes overlapped with non-syndromic monogenic diabetes patients. Syndromic monogenic diabetes genes (particularly m.3243A>G and <i>HNF1B</i>) should be routinely tested in patients with suspected MODY that do not have typical features of a genetic syndrome.