Dataset Information

Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

ABSTRACT:

Objective

Monogenic diabetes (MD) is rare and can often be confused with type 1 diabetes (T1D) in a pediatric cohort. We sought to determine clinical criteria that could optimally identify candidates for genetic testing of two common forms of MD that alter therapy: glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1α).

Research design and methods

We performed a retrospective chart review of 939 patients with a presumed diagnosis of T1D, 6 months-20 yr of age, and identified four clinical criteria that were unusual for T1D and could warrant further evaluation for MD: (i) negative pancreatic autoantibodies, (ii) evidence of prolonged endogenous insulin production, or (iii) strong family history of diabetes in multiple generations. One hundred and twenty-one patients were identified as having one or more of these high-risk clinical criteria and were offered screening for mutations in GCK and HNF1α; 58 consented for genetic testing.

Results

Of 58 patients with presumed T1D who underwent genetic testing, four were found to have GCK and one had HNF1α. No patients with only one high-risk feature were found to have MD. Of 10 patients who had two or more high risk criteria, five had MD (50%).

Conclusion

A high frequency of MD from mutations in GCK/HNF1α may be identified among pediatric diabetic patients originally considered to have T1D by performing genetic testing on those patients with multiple clinical risk factors for MD.

SUBMITTER: Gandica RG

PROVIDER: S-EPMC4767163 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

Gandica Rachelle G RG Chung Wendy K WK Deng Liyong L Goland Robin R Gallagher Mary Pat MP

Pediatric diabetes 20140801 3

<h4>Objective</h4>Monogenic diabetes (MD) is rare and can often be confused with type 1 diabetes (T1D) in a pediatric cohort. We sought to determine clinical criteria that could optimally identify candidates for genetic testing of two common forms of MD that alter therapy: glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1α).<h4>Research design and methods</h4>We performed a retrospective chart review of 939 patients with a presumed diagnosis of T1D, 6 months-20 yr of age, and identif ...[more]

PMID: 25082184

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Project description:Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic β cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.

Project description:To date, more than 30 genes have been linked to monogenic diabetes. Candidate gene and genome-wide association studies have identified > 50 susceptibility loci for common type 1 diabetes (T1D) and approximately 100 susceptibility loci for type 2 diabetes (T2D). About 1-5% of all cases of diabetes result from single-gene mutations and are called monogenic diabetes. Here, we review the pathophysiological basis of the role of monogenic diabetes genes that have also been found to be associated with common T1D and/or T2D. Variants of approximately one-third of monogenic diabetes genes are associated with T2D, but not T1D. Two of the T2D-associated monogenic diabetes genes-potassium inward-rectifying channel, subfamily J, member 11 (KCNJ11), which controls glucose-stimulated insulin secretion in the β-cell; and peroxisome proliferator-activated receptor γ (PPARG), which impacts multiple tissue targets in relation to inflammation and insulin sensitivity-have been developed as major antidiabetic drug targets. Another monogenic diabetes gene, the preproinsulin gene (INS), is unique in that INS mutations can cause hyperinsulinemia, hyperproinsulinemia, neonatal diabetes mellitus, one type of maturity-onset diabetes of the young (MODY10), and autoantibody-negative T1D. Dominant heterozygous INS mutations are the second most common cause of permanent neonatal diabetes. Moreover, INS gene variants are strongly associated with common T1D (type 1a), but inconsistently with T2D. Variants of the monogenic diabetes gene Gli-similar 3 (GLIS3) are associated with both T1D and T2D. GLIS3 is a key transcription factor in insulin production and β-cell differentiation during embryonic development, which perturbation forms the basis of monogenic diabetes as well as its association with T1D. GLIS3 is also required for compensatory β-cell proliferation in adults; impairment of this function predisposes to T2D. Thus, monogenic forms of diabetes are invaluable "human models" that have contributed to our understanding of the pathophysiological basis of common T1D and T2D.

Project description:Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual's phenotype suggested monogenic diabetes. Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes.

Dataset Information

Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

Objective

Research design and methods

Results

Conclusion

Publications

Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

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