scholarly journals Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes

2014 ◽  
Vol 16 (3) ◽  
pp. 227-233 ◽  
Author(s):  
Rachelle G. Gandica ◽  
Wendy K. Chung ◽  
Liyong Deng ◽  
Robin Goland ◽  
Mary Pat Gallagher
Keyword(s):  
Type 1 Diabetes ◽  
Monogenic Diabetes

Dextrose-Sulfonylurea Challenge as a Screening Test for Monogenic Diabetes in Patients Diagnosed with Type 1 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 310-LB
Author(s):  
AURELIA C.H. WOOD ◽  
MARIA S. REMEDI ◽  
COLIN NICHOLS ◽  
BESS A. MARSHALL
Keyword(s):  
Type 1 Diabetes ◽  
Screening Test ◽  
Monogenic Diabetes

scholarly journals Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

2021 ◽  
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stress Response ◽  
Stress Responses ◽  
Disease Process ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Expression ◽  
Increased Risk ◽  
Gene And Protein Expression

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized <i>in situ</i> using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

scholarly journals Monogenic causes in the Type 1 Diabetes Genetics Consortium cohort; low genetic risk for autoimmunity in case selection

2021 ◽  
Author(s):  
Luc Marchand ◽  
Meihang Li ◽  
Coralie Leblicq ◽  
Ibrar Rafique ◽  
Tugba Alarcon-Martinez ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Large Scale ◽  
Wolfram Syndrome ◽  
Monogenic Diabetes ◽  
Therapeutic Implications ◽  
Pathogenic Variants ◽  
Affected Parent ◽  
Diabetes Genetics

Abstract: Hypothesis About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. Methods As proof of principle, we examined by exome sequencing families with two or more children, recruited by the Type 1 Diabetes Genetics Consortium and selected for negativity for two autoantibodies and absence of risk HLA haplotypes. Results We examined 46 families that met the criteria. Of the 17 with an affected parent, seven (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including five with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. Conclusions Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that non-syndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.

scholarly journals Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Sven Pörksen ◽  
◽  
Lene Bjerke Laborie ◽  
Lotte Nielsen ◽  
Marie Louise Max Andersen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Monogenic Diabetes ◽  
Onset Type ◽  
New Onset

scholarly journals Application of NGS to improve the effectiveness of molecular genetic diagnostics of monogenic forms of diabetes in children

2020 ◽  
pp. 86-88
Author(s):  
О.С. Глотов ◽  
Е.А. Серебрякова ◽  
М.Е. Туркунова ◽  
Е.Б. Башнина ◽  
А.С. Глотов ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Genetic Variants ◽  
Wide Spectrum ◽  
Direct Sequencing ◽  
Monogenic Diabetes ◽  
Genetic Diagnostics ◽  
Number Of Patients

Исследованы образцы ДНК 60 пациентов с подозрением на наличие моногенного сахарного диабета (МСД-MODY) путем секвенирования NGS панели 13 генов MODY и 22 гена «неонатального» диабета и синдромальных форм диабета. МСД был подтвержден у 55% (n=33). Из 33 пациентов 27 (81,8%) имели мутации (варианты) в MODY генах. Наиболее часто встречались варианты в гене GCK-31,6% (n=19). Спектр вариантов в гене GCK включал 13 миссенс мутаций, 3 нонсенс, 4 со сдвигом рамки считывания и 1 в промоторной области. Были также выявлены варианты в других генах: HNF1A (n=3), WFS1(n=4), PAX4 (n=1), EIF2AK3 (n=1, гомозигота), GATA6 (n=1), KCNJ11(n=1), ABCC8 (n=1), SLC19A2 (n=2), BLK (n=2). Из 38 детектированных вариантов 15 оказались новыми. Высокая выявляемость может быть связана как с особенностями нашей группы, так и с использованным биоинформатическим подходом. Молекулярно-генетическая верификация диагноза при помощи NGS секвенирования позволяет повысить эффективность диагностики, прогнозировать течение заболевания и вносить коррективы в лечение СД. The present study included 60 unrelated Russian children with non-type 1 diabetes mellitus diagnosed before the age of 18 years. Genetic variants were analyzed using whole-exome sequencing (WES) in a panel of 35 genes causative of maturity onset diabetes of the young (MODY) and transient or permanent neonatal diabetes. Verification of the WES results was performed using PCR-direct sequencing. A total of 38 genetic variants were identified in 33 out of 60 patients (55%). The majority of patients (27/33, 81.8%) had variants in MODY-related genes: GCK (n=19), HNF1A (n=2), PAX4 (n=1), ABCC8 (n=1), KCNJ11 (n=1), GCK+HNF1A (n=1), GCK+BLK (n=1) and GCK+BLK+WFS1 (n=1). A total of 6 patients (6/33, 18.2%) had variants in MODY-unrelated genes: GATA6 (n=1), WFS1 (n=3), EIF2AK3 (n=1) and SLC19A2 (n=1). A total of 15 out of 38 variants were novel, including GCK, HNF1A, BLK, WFS1, EIF2AK3 and SLC19A2. To summarize, the present study demonstrates a high frequency and a wide spectrum of genetic variants causative of monogenic diabetes in Russian children with non-type 1 diabetes mellitus. The spectrum includes previously known and novel variants in MODY-related and unrelated genes, with multiple variants in a number of patients. The prevalence of GCK variants indicates that diagnostics of monogenic diabetes in Russian children may begin with testing for MODY2. However, the remaining variants are present at low frequencies in 9 different genes, altogether amounting to ~50% of the cases and highlighting the efficiency of using WES in non-GCK-MODY cases.

scholarly journals The epidemiology and genetic analysis of children with idiopathic type 1 diabetes in the state of Qatar

2021 ◽  
Author(s):  
Tasneem Abdel-Karim ◽  
Basma Haris ◽  
Houda Afyouni ◽  
Shayma Mohammed ◽  
Amel Khalifa ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Wolfram Syndrome ◽  
Insulin Requirement ◽  
Monogenic Diabetes ◽  
C Peptide ◽  
Peptide Level ◽  
Uncertain Significance ◽  
Age Of Diagnosis ◽  
History Of

Abstract Background To study the epidemiology, describe the clinical characteristics and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes. Methods Prospective study of type 1 diabetes patients attending Sidra Medicine from 2018-2020. Autoantibodies (GAD65, IAA, IA-2A and ZnT8) measured and genetic testing undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes compared to patients with autoimmune type 1 diabetes. Results 1157 patients had type 1 diabetes of which 63 were antibody negative. Upon genome sequencing, four had MODY, two had Wolfram syndrome, one had H syndrome and three had variants of uncertain significance in MODY genes. 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10-14 years and C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average BMI was in the normal range and 33% of the patients had history of DKA. Conclusions 4% of children have Idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the two groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is not known but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes

2009 ◽  
Vol 26 (10) ◽  
pp. 1070-1074 ◽  
Author(s):  
O. Rubio-Cabezas ◽  
E. L. Edghill ◽  
J. Argente ◽  
A. T. Hattersley
Keyword(s):  
Type 1 Diabetes ◽  
Children And Adolescents ◽  
Monogenic Diabetes

scholarly journals Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes

Diabetes Care ◽  
2018 ◽  
Vol 42 (2) ◽  
pp. e16-e17 ◽  
Author(s):  
Kashyap A. Patel ◽  
Michael N. Weedon ◽  
Beverley M. Shields ◽  
Ewan R. Pearson ◽  
Andrew T. Hattersley ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Testing ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Monogenic Diabetes ◽  
Zinc Transporter ◽  
Zinc Transporter 8

scholarly journals Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

2021 ◽  
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stress Response ◽  
Stress Responses ◽  
Disease Process ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Expression ◽  
Increased Risk ◽  
Gene And Protein Expression

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized <i>in situ</i> using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

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