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Background: Maturity‐onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort. Methods: MODY variants were assessed using massively parallel sequencing in the population‐based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6 million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n = 993). Results: DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody‐negative type 1 diabetes (T1DM), three diagnosed with antibody‐positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls. Conclusions: This is the first comprehensive study of MODY variants in an unselected population‐based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features. [ABSTRACT FROM AUTHOR]

Objective: 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 quality-adjusted 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 HbA1c 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. [ABSTRACT FROM AUTHOR]

Insulin gene (INS) mutations cause a rare form of maturity‐onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least 14 confirmed causative genes. Here, we describe a family with MODY due to a novel INS mutation, detected using massively parallel sequencing (MPS). The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes affecting both her two siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin, and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5%‐30%). Sanger sequencing of HNF4A, HNF1A, and HNF1B in the proband was negative. Targeted MPS using a custom‐designed amplicon panel sequenced on an Illumina MiSeq detected a heterozygous INS mutation c.277G>A (p.Glu93Lys). Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested disruption of a critical hydrogen bond between insulin and the insulin receptor; however, the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency. This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations. [ABSTRACT FROM AUTHOR]

The authors respond to the comment on a 2019 article by Johnson et al on the cost-effectiveness of routine screening via massive parallel sequencing for maturity-onset diabetes of the young (MODY). They state that specific variant screening costs less than comprehensive initial screening, and that testing of presymptomatic individuals may lead to genetic discrimination. Also noted are time-consuming issues for genetic counseling due to the lack of certainty and unknown penetrance of variants.