Monogenic diabetes is a category of diabetes mellitus caused by a single gene mutation or chromosomal abnormality, usually sub-classified as either neonatal diabetes or maturity-onset diabetes of the young (MODY). Although monogenic diabetes affects up to 3.5% of all patients with diabetes diagnosed before age 30, misdiagnosis and/or improper treatment occurs frequently. The University of Chicago Monogenic Diabetes Registry, established in 2008, offers insight into the diagnosis, treatment, and natural history of individuals known or suspected to have monogenic diabetes. Those interested in participating in the Registry begin by completing a secure web-based registration form found on our website (http://monogenicdiabetes.uchicago.edu/registry/). Participants are then screened for eligibility and consented either by phone, video call, or in person. Relevant medical and family history is collected at baseline and then annually via surveys through our secure Research Electronic Data Capture (REDCap) database. The University of Chicago Monogenic Diabetes Registry has enrolled over 3800 participants from over 2000 families. Participants represent all 50 states and more than 20 different countries. To date, over 1100 participants have a known genetic cause of diabetes. While many Registry participants reported being referred through their diabetes care provider (54%), a large portion also learned about the Registry through web searching (24%), friends/family (18%), or other sources (13%). Around two-thirds of those with a known genetic cause had research-based genetic testing completed rather than clinical testing due to insurance coverage difficulties. Of those who were found to have monogenic diabetes, significant delays in diagnosis were identified, which highlights the need for increased access to clinical genetic testing covered by insurance companies specifically within the United States. Among genes that cause a MODY phenotype, GCK mutations were the most common (59%) followed by HNF1A mutations (28%), while mutations in KCNJ11 were the most common among genes that cause neonatal diabetes (35%) followed by INS (16%). Over the last decade, improvements in data collection for the University of Chicago Monogenic Diabetes Registry have resulted in increased knowledge of the natural history of monogenic diabetes, as well as a better understanding of the most effective treatments. The University of Chicago Monogenic Diabetes Registry serves as a valuable resource that will continue to provide evidence to support improved clinical care and patient outcomes in monogenic diabetes.
The University of Chicago National Monogenic Diabetes Registry houses a novel dataset of people presenting with possible or known monogenic diabetes and has over a decade of data points, despite the rarity of the disease relative to T1DM and especially T2DM. Currently, determination of genetic testing, including which specific panel or genes is most appropriate to sequence, is a manual process introducing variability and subjectivity. Aim: To test and compare performance of several models against the manual process and each other in identifying maturity-onset diabetes of the young (MODY) from available clinical information. Methods: Statistical models for prediction of monogenic diabetes were applied to clinical data for cases suspected of having MODY. The models tested in the study with this dataset ranged from the traditional methods of regression to more modern approaches of neural nets, classification trees, clustering, and other machine learning algorithms for classification of MODY against type 1 and type 2 and a possible subset of monogenic diabetes subtypes. Results: Using a sample size of N=330, with 70 testing positive for either GCK, HNF1A, or HNF4A, exploratory data models were able to achieve 75-80% validation accuracy (random validation data set at 10-20% of N) while internal human classification accuracy was roughly 42% over the same samples. The traditional logistic regression and neural net had equivalent performance. Conclusions: The 3750 participants within the Registry and more than a decade of follow-up presents a unique opportunity to assess which clinical features are most predictive in identifying those with monogenic diabetes. The results of this work will direct future testing efforts within the Registry to assist in efficient diagnosis of these uncommon yet clinically important forms of diabetes. Disclosure R. P. Mulligan: None. L. R. Letourneau-freiberg: None. T. L. Bowden: None. P. Tian: None. B. Kandasamy: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. S. W. Greeley: None. R. N. Naylor: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK020595)
Mitochondrial diabetes (MD) results from pathogenic variants in mitochondrial (MT) genes. MT disease is associated with neuromuscular disease. MD may occur either alone or with other conditions. The most common MD genetic variant is MT-TL1 m.3243 A>G, associated with Maternally Inherited Diabetes and Deafness and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes. The incidence, variability and optimum treatment are uncertain. We describe clinical characteristics of participants in the Univ. of Chicago Monogenic Diabetes Registry with MD variants. Participants enrolled in the Univ. of Chicago Monogenic Diabetes Registry (IRB 6858,15617B). Clinical and genetic information was collected. As of February 2023, 18 participants from 13 families had a known MT variant. Clinical characteristics are in Table 1. Clinicians should consider MD when the patient is negative for T1D antibodies, is non-obese, has high frequency bilateral hearing loss, and has a strong maternal family history of diabetes. However, the features are variable and can include multiple organs and tissues. Genetic testing panels should include MT variants because MD can be misdiagnosed and the prevalence is uncertain. Clinical phenotypes are heterogenous among family members. Cascade testing and screening for related conditions is encouraged. Our data shows that MD is misdiagnosed as T1 or T2DM (16/16). Disclosure T. L. Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B. Kandasamy: None. L. R. Letourneau-freiberg: None. K. Rodriguez: None. M. Mccullough: None. S. W. Greeley: None. L. H. Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation. Funding National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
Introduction: Transient neonatal diabetes mellitus (TNDM) is a heterogeneous subtype of neonatal diabetes that usually presents within the first days or weeks of life, spontaneously remits in infancy, but can recur in childhood or adolescence as a permanent form of diabetes. Approximately 70% of TNDM cases are due to overexpression of genes at chromosome 6q24 caused by one of three potential mechanisms: uniparental disomy (UPD6), paternal duplication, or hypomethylation of the maternal allele. Our aim was to further elucidate clinical characteristics of a relatively large group of individuals with this rare condition. Methods: Participants with a confirmed or suspected diagnosis of 6q24 TNDM were identified through the University of Chicago Monogenic Diabetes Registry. Research based genetic testing was provided. Clinical information was extracted from survey responses and medical records. Results: There were thirty-three participants with 6q24-TNDM (58% male). Eight (24%) had hypomethylation of the maternal allele, seven (21%) had paternal duplication, seventeen (52%) had UPD6, and one had UPD6 vs. hypomethylation of the maternal allele. The mean age of initial diabetes presentation was 4.6 days (n=33). Remission occurred at a mean age of 4.5 months (n=28). Nine participants reported having relapse of diabetes, with a mean age of relapse of 17.4 years (range 12 - 31 years). There were six participants who reported umbilical hernia (22%, n=27), fifteen participants reported macroglossia (54%, n=27), and ten (36%, n=28) indicated speech therapy was required. No significant differences in clinical characteristics were identified across the three mechanisms (UPD6, paternal duplication, hypomethylation). Conclusions: Clinical characteristics were not different across mechanism groups, suggesting that genetic testing is required to definitively determine a mechanism and diagnosis of 6q24 TNDM. Early assessment for speech therapy should be considered for this patient population. Disclosure M.Mccullough: None. L.R.Letourneau-freiberg: None. T.L.Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B.Kandasamy: None. D.Del gaudio: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation. S.W.Greeley: None. Funding National Institutes of Health (R01DK104942, P30DK020595)
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