Clinical application of best practice guidelines for the genetic diagnosis of MODY2 and MODY3

Incani, Michela; Cambuli, Vm; Cavalot, Franco; Congiu, Tiziana; Paderi, M; Sentinelli, Federica; Romeo, Stefano; Poy, P; Soro, Maria Renata; Pilia, Sabrina; Loche, Sandro; Cossu, Efisio; Trovati, Mariella; Mariotti, Stefano; Baroni, Marco Giorgio

doi:10.1111/j.1464-5491.2010.03095.x

Cited by 7 publications

(5 citation statements)

References 8 publications

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“…Maturity Onset Diabetes of the Young (MODY), a monogenic diabetes inherited in an autosomal dominant mode, accounts for 1–2% of all diabetes forms in Europe [1], [2]. It is a clinically heterogeneous group of diseases caused by at least eight gene defects in the pancreatic β-cell that impair insulin secretion [3].…”

Section: Introductionmentioning

confidence: 99%

Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

et al. 2012

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Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2.

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Section: Introductionmentioning

confidence: 99%

Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

et al. 2012

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“…Consequently, a rationale search for different forms of diabetes is justified only when type 1 diabetes has been excluded. Although this strategy is not included in the EMGQN guidelines [5] , many researchers and clinicians apply it [13] , [14] , [17] , [18] . Regarding insulin treatment, most MODY2 patients have a modest impairment of glucose metabolism and usually do not need pharmacological intervention [17] .…”

Section: Discussionmentioning

confidence: 99%

“…This criterion was included because MODY2 is an autosomal dominant inherited disease, with rare de novo mutations described [17] . Familiarity is not mandatory in the EMGQN guidelines [5] , however recent studies found that it is the most powerful factor in distinguishing between MODY and sporadic forms of diabetes [10] , [13] , [14] . Furthermore, because MODY2 is usually discovered during infancy or in early adulthood, a diagnosis before 25 years of age is a criterion for the test in the 7-iF.…”

Section: Discussionmentioning

confidence: 99%

“…The guidelines included most of the relevant clinical parameters that define MODY, whereas others, such as the assay of the autoantibodies responsible for classical type 1 diabetes, were not taken into account [11] , [12] . In this context, the guidelines have a poor detection rate and diagnostic power that can be improved, particularly in pediatrics, by adding other clinical criteria [13] , [14] .…”

Section: Introductionmentioning

confidence: 99%

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Identification of Candidate Children for Maturity-Onset Diabetes of the Young Type 2 (MODY2) Gene Testing: A Seven-Item Clinical Flowchart (7-iF)

et al. 2013

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MODY2 is the most prevalent monogenic form of diabetes in Italy with an estimated prevalence of about 0.5–1.5%. MODY2 is potentially indistinguishable from other forms of diabetes, however, its identification impacts on patients' quality of life and healthcare resources. Unfortunately, DNA direct sequencing as diagnostic test is not readily accessible and expensive. In addition current guidelines, aiming to establish when the test should be performed, proved a poor detection rate. Aim of this study is to propose a reliable and easy-to-use tool to identify candidate patients for MODY2 genetic testing. We designed and validated a diagnostic flowchart in the attempt to improve the detection rate and to increase the number of properly requested tests. The flowchart, called 7-iF, consists of 7 binary “yes or no” questions and its unequivocal output is an indication for whether testing or not. We tested the 7-iF to estimate its clinical utility in comparison to the clinical suspicion alone. The 7-iF, in a prospective 2-year study (921 diabetic children) showed a precision of about the 76%. Using retrospective data, the 7-iF showed a precision in identifying MODY2 patients of about 80% compared to the 40% of the clinical suspicion. On the other hand, despite a relatively high number of missing MODY2 patients, the 7-iF would not suggest the test for 90% of the non-MODY2 patients, demonstrating that a wide application of this method might 1) help less experienced clinicians in suspecting MODY2 patients and 2) reducing the number of unnecessary tests. With the 7-iF, a clinician can feel confident of identifying a potential case of MODY2 and suggest the molecular test without fear of wasting time and money. A Qaly-type analysis estimated an increase in the patients' quality of life and savings for the health care system of about 9 million euros per year.

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“…The prevalence of antibodies to pancreatic islets in the monogenic diabetes remains unknown and the incidence estimation is difficult as the occurrence of autoantibodies in the patient is one of the well-known exclusion criteria for further genetic diagnostics [1][2][3]. This approach can lead to an underestimation and unreliably respond to the matter of the humoral response markers in diabetes of non-autoimmune etiology.…”

Section: Introductionmentioning

confidence: 99%

Humoral response markers in GCK MODY

Skała‐Zamorowska

Deja

Borowiec

et al. 2016

Pediatr Endocrino Diabetes Metab

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Clinical application of best practice guidelines for the genetic diagnosis of MODY2 and MODY3

Cited by 7 publications

References 8 publications

Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

Identification of Candidate Children for Maturity-Onset Diabetes of the Young Type 2 (MODY2) Gene Testing: A Seven-Item Clinical Flowchart (7-iF)

Humoral response markers in GCK MODY

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