Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy




Hegele, Robert A.


The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; and iii) familial partial lipodystrophy. From my research efforts, we implicated rare loss-of-function variants in cardiomyopathy genes to “lone” atrial fibrillation, providing evidence that atrial cardiomyopathy is a genetic sub-phenotype of atrial fibrillation. Additionally, we determined that “lone” atrial fibrillation has a significant accumulation of common variants that together elevate susceptibility to the disease. Also, considering the application of genetics in Medicine, I directly evaluated the increasing responsibility that clinicians have to adjudicate causality of various genetic factors. For instance, having successfully identified a novel apparently pathogenic genetic variant in a family with hypercholesterolemia, I sought to determine its pathogenicity by performing cascade screening and co-segregation analysis in the extended family. My analysis demonstrated that the novel variant was independent of the disease phenotype, preventing a potential misdiagnosis and emphasized the importance of gathering additional confirmatory data in the clinical setting. Further, by studying a well-genotyped and phenotype familial partial lipodystrophy cohort, I uncovered that the prevalence of severe hypertriglyceridemia and its most severe complication, namely acute pancreatitis was more common in affected individuals who had concurrently developed diabetes. In spite of these contributions, significant work remains to explain the full genetic contributions to complex diseases. The benefits of understanding the complete genetic architecture of a disease are potentially immense, allowing advances in pre-symptomatic detection to the development of novel targeted therapies. For the patients this could translate into such benefits as earlier detection, screening for the family, personalized therapies, and a confirmed diagnosis.

Summary for Lay Audience

Despite great advances in our understanding of the role of genetics in complex diseases, most patients with a complex disease have no identified genetic cause. This lack of understanding poses significant limitations on the application of genetic testing in the clinical setting. About 99.9% of the genetic code is practically unchanged among humans, however the remainder 0.01% that is variable is a key contributing factor for differences we observe between people, especially related to disease. The field of human genetics has evolved to our current understanding that for most diseases there is a broad spectrum of rare to common mutations that can determine susceptibility to or expression of a disease. To better understand the contribution of different types of genetic variants – or “mutations” - I used several genetic technologies to identify both rare genetic variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; and iii) familial partial lipodystrophy. The work conducted over the course of my graduate studies determined that rare mutations in cardiomyopathy genes contribute to atrial fibrillation without affecting the ventricles. Additionally, for a significant portion of “lone” atrial fibrillation patients the accumulation of many inherited common variants from across the genome increases their risk for atrial fibrillation. As a future clinician-scientist, I am also interested in the application of genetics in Medicine and how it can improve patient care. During my research, I used pedigree extension to assess the potential causality of a novel apparently pathogenic mutation in a family with hypercholesterolemia, and then demonstrated how feasible and helpful it is for a clinician to perform such additional work to help determine causality by incorporating such data. Lastly, I analyzed a genetically homogeneous group of familial partial lipodystrophy patients and identified a risk factor for a severe complication, namely acute pancreatitis. From my collective research efforts, we now have a better understanding of the different genetic variants or mutations that can cause or increase risk for “lone” atrial fibrillation. Further, careful use of genetics in the clinic has the potential for benefits in medical care from the perspective of both the provider and patient.