Current and Best Practices of Genetic Testing for Maturity Onset Diabetes of the Young: Views of Professional Experts

Zwaag, Angeli M. van der; Weinreich, S.; Bosma, A. R.; Rigter, Tessel; Losekoot, Monique; Henneman, Lidewij; Cornel, Martina C.

doi:10.1159/000367963

Cited by 17 publications

(22 citation statements)

References 30 publications

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“…Despite the availability of genetic testing, there are a significant number of patient-and physician-related factors that may be prohibitive to uptake, including the perceived lack of possibilities for treatment (if coexistent MODY and T2D develop over time, many would argue that it may not change management if hyperglycaemia is mild; however, we believe that it makes a difference to management and monitoring) and prevention, cost implications of a positive diagnosis to patients, and lack of awareness of MODY as a diagnosis. 40 These factors should all be discussed with the patient when considering genetic or genomic testing. The patient should be counselled regarding the treatment implications of a positive diagnosis, including the possibility that they may have not required the treatment they were prescribed many years prior.…”

Section: Resultsmentioning

confidence: 99%

A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase‐MODY

Bishay

Greenfield

2016

Medical Journal of Australia

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Maturity onset diabetes of the young (MODY), the most common monogenic form of diabetes, accounts for 1-2% of all diabetes diagnoses. Glucokinase (GCK)-MODY (also referred to as MODY2) constitutes 10-60% of all MODY cases and is inherited as an autosomal dominant heterozygous mutation, resulting in loss of function of the GCK gene. Patients with GCK-MODY generally have mild, fasting hyperglycaemia that is present from birth, are commonly leaner and diagnosed at a younger age than patients with type 2 diabetes, and rarely develop complications from diabetes. Hence, treatment is usually unnecessary and may be ceased. Therefore, genetic screening is recommended in all young patients (< 40 years) with an autosomal dominant family history of diabetes and who lack features of the metabolic syndrome and type 1 diabetes. Further, treatment discontinuation should be discussed with the patient as part of the informed consent process, as the realisation that prior treatment may have not been necessary - or that it could have been less burdensome - may have psychological implications for the patient. This is true for other forms of MODY, such as hepatocyte nuclear factor 1A mutations (MODY3) where hyperglycaemia is managed with low dose sulfonylurea rather than insulin. Patients with GCK-MODY, in line with trends in the general population, are becoming older and more overweight and obese, and are concomitantly developing features of insulin resistance and glucose intolerance. Therefore, controversy exists as to whether such "treatment-exempt" patients should be reassessed for treatment later in life. As testing becomes more accessible, clinicians and patients are likely to embrace genetic screening earlier in the course of diabetes, which may avert the consequences of delayed testing years after diagnosis and treatment initiation.

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Section: Resultsmentioning

confidence: 99%

A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase‐MODY

Bishay

Greenfield

2016

Medical Journal of Australia

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Section: Current Challenges In Molecular Genetic Diagnosis Of MDmentioning

confidence: 99%

“…The issues of the costs of genetic testing and healthcare benefits are recurrently debated so as to improve practical guidelines for both patient care and educational perspectives. 47 A simulation model for diabetes complications was used to evaluate the cost-effectiveness of a genetic testing policy for mutations in GCK/ MODY2, HNF1A/MODY3, and HNF4A/MODY1 in a hypothetical case cohort with a MODY prevalence of 2 %. 48 With a conservative interpretation of costeffectiveness and based on incremental cost-effectiveness ratio thresholds in the US, model sensitivity analysis showed that small increases in MODY prevalence in the case cohort (from 2 % to 6 %) made the genetic screening policy cost-effective.…”

Section: Current Challenges In Molecular Genetic Diagnosis Of MDmentioning

confidence: 99%

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Vaxillaire

Froguel

2016

Journal of Diabetes

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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...

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“…Even if patients had whole-genome sequence data already available in their medical records, this treatment effect is still too small to be clinically useful. For MODY, which often has a clear genetic cause, most cases appear to be undiagnosed, in part because of uncertainty from clinicians about the clinical benefits of genetic testing (132). Making treatment decisions based on genetic tests that lack clinical validity, clinical utility, or both can have unintended consequences, including withholding beneficial treatments, an unnecessary increase in costs, or the use of drugs with harmful effects.…”

Section: Framework For Evaluating a Genomic Testmentioning

confidence: 99%

The Application of Genomics in Diabetes: Barriers to Discovery and Implementation

Floyd

Psaty

2016

Diabetes Care

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The emerging availability of genomic and electronic health data in large populations is a powerful tool for research that has drawn interest in bringing precision medicine to diabetes. In this article, we discuss the potential application of genomics to the prediction, prevention, and treatment of diabetes, and we use examples from other areas of medicine to illustrate some of the challenges involved in conducting genomics research in human populations and implementing findings in practice. At this time, a major barrier to the application of genomics in diabetes care is the lack of actionable genomic findings. Whether genomic information should be used in clinical practice requires a framework for evaluating the validity and clinical utility of this approach, an improved integration of genomic data into electronic health records, and the clinical decision support and educational resources for clinicians to use these data. Efforts to identify optimal approaches in all of these domains are in progress and may help to bring diabetes into the era of genomic medicine.

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Current and Best Practices of Genetic Testing for Maturity Onset Diabetes of the Young: Views of Professional Experts

Cited by 17 publications

References 30 publications

A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase‐MODY

A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase‐MODY

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

The Application of Genomics in Diabetes: Barriers to Discovery and Implementation

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