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dc.contributor.authorKleinberger, Jeffrey
dc.date.accessioned2017-08-29T18:44:20Z
dc.date.available2018-01-10T19:37:38Z
dc.date.issued2017
dc.identifier.urihttp://hdl.handle.net/10713/7072
dc.descriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2017en_US
dc.description.abstractMonogenic diabetes is hyperglycemia caused by a variant in a single gene, and it accounts for approximately 1-2% of all diabetes cases. A genetic diagnosis of monogenic diabetes is important because the most common gene etiologies can be effectively managed with treatment regimens other than first line treatments for either type 1 (T1D) or type 2 diabetes (T2D). However, monogenic diabetes can have a similar clinical presentation to either T1D or T2D, leading to clinical misdiagnosis of monogenic diabetes. The goal of this dissertation was to evaluate approaches for identifying patients with monogenic diabetes and a method for functionally testing monogenic diabetes variants to potentially improve diagnosis and treatment of these patients. Monogenic diabetes genetic testing was performed on 488 samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. A total of 4.5% (22/488) of individuals were determined to have pathogenic or likely pathogenic variants. Comparison of clinical characteristics of patients with and without monogenic diabetes discovered statistically, but not clinically, significant lower BMI Z-score, higher fasting glucose, and lower fasting insulin in patients with monogenic diabetes. Treatment outcomes from the TODAY trial showed that most patients with HNF4A monogenic diabetes variants failed treatment therapies rapidly, while none of the patients with GCK monogenic diabetes variants failed treatment. In the Personalized Diabetes Medicine Program (PDMP), an implementation study for screening, diagnosis, and return of results for monogenic diabetes, 1,734 participants were screened for monogenic diabetes at four diverse study sites. Of the 138 eligible participants that underwent monogenic diabetes genetic testing, 14 had pathogenic or likely pathogenic monogenic diabetes variants. PDMP patients with monogenic diabetes had a diverse range of ages, races/ethnicities, and previous treatment regimens. Finally, a zebrafish model of hnf1a-knockdown and rescue with HNF1A monogenic diabetes variants was evaluated to determine that the model could not accurately identify established damaging HNF1A genetic variants. The results from these studies have demonstrated the variable presentations of patients with monogenic diabetes as well as the challenges and potential of assessing the function of HNF1A variants using an in vivo model.en_US
dc.language.isoen_USen_US
dc.subjectMODYen_US
dc.subjectmonogenic diabetesen_US
dc.subjectscreeningen_US
dc.subject.meshClinical Trialen_US
dc.subject.meshDiabetes Mellitus, Type 2en_US
dc.subject.meshZebrafishen_US
dc.titleDiscovery and Analysis of Patients with Monogenic Diabetes in Multiple Cohorts to Guide Future Diagnosisen_US
dc.typedissertationen_US
dc.contributor.advisorPollin, Toni
dc.description.urinameFull Texten_US
dc.contributor.orcid0000-0003-0521-9848
refterms.dateFOA2019-02-19T18:14:49Z


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