Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

Johnson, Stéphanie; Ellis, Jonathan; Leo, Paul; Anderson, Lisa K.; Ganti, Uma; Harris, Jessica; Curran, Jacqueline; McInerney-Leo, Aideen; Paramalingam, Nirubasini; Song, Xiaoxia; Conwell, Louise S.; Harris, Mark; Jones, Timothy W.; Brown, Matthew A.; Davis, Elizabeth A.; Duncan, Emma L.

doi:10.1111/pedi.12766

Cited by 38 publications

(33 citation statements)

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“…Mean age at diagnosis and mean HbA 1c were based on WACDD data. The underlying prevalence of MODY was taken from our previous study of this cohort (7). For this current study, it was assumed that all pathogenic/likely pathogenic MODY variants result in the clinical phenotype of MODY.…”

Section: Model Structure Cohort and Assumptionsmentioning

confidence: 99%

“…However, diabetes autoantibodies may occur in MODY (6), and the increasing prevalence of pediatric obesity means BMI alone is less useful for distinguishing between T2DM and MODY. Thus, screening for MODY on clinical grounds alone may underestimate its true prevalence, as is evident from differences between prevalence rates of MODY in databases where testing was prompted by clinical criteria (6) compared with comprehensive population screening (7).…”

mentioning

confidence: 99%

“…MPS is rapidly translating into clinical practice (8). We recently screened an entire pediatric population with diabetes using targeted MPS, demonstrating a prevalence of pathogenic/likely pathogenic MODY variants of 2.10% (7). Considering only cases identified initially as T1DM or obvious monogenic cases, the prevalence was 2.14%.…”

mentioning

confidence: 99%

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Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life

et al. 2018

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Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features). RESEARCH DESIGN AND METHODS A Markov decision model was developed to estimate incremental costs and qualityadjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA 1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework. RESULTS Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%. CONCLUSIONS Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus.

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Section: Model Structure Cohort and Assumptionsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life

et al. 2018

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“…Diabetes in children is predominantly type 1 diabetes, but type 2 diabetes and MODY also occur (1,2). MODY accounts for 1-4% of pediatric diabetes (1,(3)(4)(5)(6)(7), but misdiagnosis results in many young people being treated unnecessarily with insulin (1,4), with many years' delay from initial diabetes diagnosis to correct genetic diagnosis (8).…”

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confidence: 99%

Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study

et al. 2019

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Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population. RESEARCH DESIGN AND METHODS Swedish patients (n 5 3,933) aged 1-18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing. RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P 5 2 3 10 244), HbA 1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P 5 1 3 10 220), plasma glucose (11.7 vs. 26.7 mmol/L; P 5 3 3 10 219), parental diabetes (63% vs. 12%; P 5 1 3 10 215), and diabetic ketoacidosis (0% vs. 15%; P 5 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA 1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA 1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment. CONCLUSIONS At diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA 1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

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“…To date, 13 MODY genes have been confirmed, all involved in pancreatic β-cell insulin secretion and all with autosomal dominant transmission 1 . 2-2.5% of pediatric diabetes cases carry pathogenic/likely pathogenic variants in MODY genes 2,3 ; however, MODY is often undiagnosed, either because the diagnosis is not considered 4 or because genetic screening is limited. There are also cases with compelling clinical histories in whom, despite comprehensive screening of known MODY genes, a genetic diagnosis cannot be made 3 , suggesting as-yet-unidentified genetic cause(s).…”

Section: Introductionmentioning

confidence: 99%

A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

Graff

Johnson

Leo

et al. 2020

Preprint

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Word count2820 3 ABSTRACT Background Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired glucose-stimulated insulin secretion (GSIS). Mechanisms include β-cell KATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. MethodsA four-generation family with autosomal dominant non-obese, non-ketotic antibody-negative diabetes, without mutations in known MODY genes, underwent exome sequencing. Whole-cell and single-channel K + currents, Ca 2+ handling, and GSIS were determined in cells expressing either mutated or wild-type (WT) protein. ResultsWe identified a novel non-synonymous genetic mutation in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and -cell-restricted K + channel transcript and encodes the two-pore-domain K + channel TALK-1. Whole-cell K + currents in transfected HEK293 cells demonstrated drastic (312-fold increase) gain-of-function with TALK-1 Leu144Pro vs. WT, due to greater single channel activity. Glucose-stimulated cytosolic Ca 2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) and less endoplasmic reticulum calcium storage (cyclopiazonic acid-induced release AUC:Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted GSIS compared to TALK-1 WT in both mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets.

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Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

Cited by 38 publications

References 39 publications

Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life

Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life

Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study

A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

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