Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy




Hegele, Robert A.


Knowledge of inherited diseases and the ability to rapidly, efficiently and comprehensively perform genetic testing are advancing steadily. However, the ideal approach to translate this ability into clinical applications for endocrine disorders has yet to be determined. This work focuses on aspects of clinically translating knowledge of select heritable endocrine and metabolic conditions.

For maturity onset diabetes of the young (MODY), a monogenic disorder with no current consensus guidelines governing testing procedures, this work addresses methods to improve detection by validating the use of next generation sequencing-based techniques to identify MODY cases and to detect copy number variations.

For very severe hypertriglyceridemia, a largely polygenic trait, this work explores clinical differences associated with the underlying genotype, assesses treatment of pancreatitis, the most severe acute complication of hypertriglyceridemia, and presents a population-based study of Ontario adults to identify the most important modifiable risk factors associated with expression of hypertriglyceridemia, and to identify any gaps in appropriate care for this population.

For heterozygous familial hypercholesterolemia, a condition for which universal genetic screening has been recommended, this work explores the personal impact of this diagnosis on the patient in terms of quality of life, lifestyle and self-care habits.

The ultimate goal of this project is to expand the available knowledge on how best to translate the laboratory ability and findings into the clinical realm for these select endocrine and metabolic conditions.

Summary for Lay Audience

Understanding of the role that genetics plays in human diseases and the technology available to investigate this influence is increasing. With this knowledge comes the opportunity to improve the care of clinic patients by incorporating this new information into their care and treatment plan. In this work, I explore several aspects related to the care of endocrine and metabolic conditions that have genetic components.

I aimed to improve the ability to detect and diagnose individuals suspected of having an inherited form of diabetes called maturity onset diabetes of the young (MODY). I did this by examining ways to improve the testing process for these conditions by using newer technology and software to avoid missing cases.

I also aimed to improve care and counselling for patients with very high levels of a blood lipid called triglycerides. To accomplish this, I examined three separate populations. I looked at a group of patients with a rare condition called familial chylomicronemia syndrome (FCS), caused by different DNA changes, to assess if there are differences in their physical symptoms or bloodwork. Secondly, I looked at adults with very elevated triglyceride levels in Ontario, Canada to evaluate factors that can contribute to these severe triglyceride elevations. Lastly, I looked at management of pancreatitis, a condition that can be caused by very high levels of triglycerides to assess what happens naturally to patients with this complication with no active interventions to lower triglycerides.

Finally, I aimed to assess the positive and negative impacts of genetic testing on the patient. To do this, individuals with elevated cholesterol who underwent genetic testing were asked to participate in a survey assessing their experience and perceptions.

Ultimately, the goal of this project is to improve the ability of doctors to use genetic information in the clinic to provide more personalized and optimized care.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.