Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Abstract

Various forms of early-onset non-autoimmune diabetes are recognized as monogenic diseases, each subtype being caused by a single highly penetrant gene defect at the individual level. Monogenic diabetes (MD) is clinically and genetically heterogeneous, including maturity-onset diabetes of the young (MODY), infancy-onset and neonatal diabetes mellitus, which are characterized by functional defects of insulin-producing pancreatic -cells and hyperglycemia early in life. Depending on the genetic cause, MD differs in ages at diabetes onset, the severity of hyperglycemia, long-term diabetic complications and extra-pancreatic manifestations. In this review, we discuss the many challenges of molecular genetic diagnosis of MD in the face of a substantial genetic heterogeneity; as well as the clinical benefit and cost-effectiveness of an early genetic diagnosis as demonstrated by simulation models based on lifetime complications and treatment costs. We also discuss striking examples of proof-of-concept of genomic medicine, which enabled to remarkably improve patients' care and long-term evolution. Recent advances in genome editing and pluripotent stem-cell reprogramming technologies provide new opportunities for in vitro diabetes modelling and the discovery of novel drug targets and cell-based diabetes therapies. A review of these future directions makes the case for exciting translational research for further understanding early-onset diabetes pathophysiology. Keywords:Diabetes, Genetics, Genomic medicine, Insulin secretion, Monogenic diabetes, MODY, Mutation, Next-generation sequencing, pancreatic -cell.This article is protected by copyright. All rights reserved. Genetic subtypes and clinical spectrum of monogenic diabetesMonogenic diabetes (MD) is caused by a rare single-gene defect that strongly contributes to the disease phenotype without or not much environmental contribution (meaning that is each individual DNA mutation or genome structural abnormality has a high or almost complete penetrance).1 MD encompasses a broad spectrum of clinically and genetically highly heterogeneous forms of nonautoimmune diabetes, which are mainly characterized by functional defects of pancreatic -cells resulting in insulin deficiency and moderate to severe hyperglycemia early in life. 1,2 MD includes maturity-onset diabetes of the young (MODY), early-infancy onset and neonatal diabetes mellitus (NDM), and many rare forms of atypical diabetes. [1][2][3] Decades of genetic and clinical research to decipher etiological mechanisms underlying MODY, NDM and early-infancy diabetes led to identify major genes and molecular pathways relevant to -cell physiology, that allowed to better understand the sustained genetic and clinical heterogeneity among the different MD subtypes in young people. MODY subtypesMODY usually presents in lean young individuals before age 25-30 years, as a dominantly inherited familial form of diabetes, and it may account for at least ~1-2% of all cases with type 2 diabetes. 4,5Epidemiology of MODY. Although M...

Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options

“…There are now 14 genes that have been associated with a distinct subtype of MODY, each differing in function, clinical presentation (age at onset and pattern of hyperglycemia), extra-pancreatic manifestations, risk of complications, and response to treatment (Table 1) [32]. Although pathogenic mutations in any of the 14 genes may result in MODY, mutations in GCK , HNF1A , and HNF4A are the most common causes of MODY, representing 52, 10, and 32% of MODY cases in the UK, respectively [15, 33].…”

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

“…MODY has been classified into 14 subtypes according to the Online Mendelian Inheritance in Man (OMIM) database and characterized by autosomal dominant inheritance, young age at onset, and continued secretion of endogenous insulin (2). The precise diagnosis of MODY on the basis of genetics and phenotypic characteristics allows for more informed decisions to be made regarding treatment, resulting in improved prognosis (3,4). However, the current knowledge informing these decisions remains inadequate.…”

Exploring the feasibility of delivering standardized genomic care using ophthalmology as an example

“…Demonstrable impacts on diagnostic rates and treatment have already been shown across a broad range of specialties. [1][2][3][4] In order to achieve widespread implementation of genomic care, it will be necessary to alter care pathways to incorporate early genomic testing and then expand the delivery of genetic and genomic care beyond clinical genetics and into mainstream clinical specialties. [5][6][7] A recent review of genetic service models has suggested that multidisciplinary clinics and coordinated services are key to delivering proper care in rare genetic disorders.…”