Date of Award

5-2017

Document Type

Thesis - Closed Access

Degree Name

MS Human Genetics

Department

Human Genetics Graduate Program

Abstract

Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes that accounts for 2-5% of all diabetes diagnoses. It often presents after 25 years of age and is inherited in an autosomal dominant pattern. Thirteen genes are known to cause MODY, but three genes: HNF1A , HNF4A , and GCK account for 70% of all MODY cases. Some forms of MODY are most effectively treated with sulfonylureas, but because MODY is commonly misdiagnosed as type 1 or type 2 diabetes, or undiagnosed, we are missing the opportunity correct diagnosis and appropriate medical treatment. The advent of next-generation sequencing has allowed for better gene discovery in MODY and a stronger ability to understand complex disease. Our study aimed to use a genotype to phenotype approach to understand the clinical features that help distinguish MODY from the other forms of diabetes. Participants from the Geisinger MyCode cohort with variants in the HNF1A , HNF4A , and GCK genes were selected and charts were reviewed to collect demographic and phenotypic information. Next, variants in the GCK gene were curated following the ACMG guidelines. Of the ninety-seven participants, forty-nine were carriers of a pathogenic variant and nineteen of these individuals had diabetes; fourteen of the carriers had evidence of diabetic complications. Forty-eight of the ninety-seven participants were non-carriers; twenty-three of these individuals had diabetes and twenty-one of them had diabetic complications. Of the twenty variants identified in the GCK gene in this population, five were expected to be pathogenic, one was likely pathogenic, ten were variants of uncertain significance, and four were novel, private variants of the Geisinger population. We were unable to create an algorithm for distinguishing MODY from other forms of diabetes; furthermore, we were unable to add knowledge about the pathogenicity of variants that did not already exist in the literature. Our study highlights the need for considering genomic context when investigating how the genome impacts complex disease.

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