Medicine and Health Sciences Commons^™

Resolving The Longitudinal Triglyceride Phenotype Of Heterozygous Lpl And Apo A-V Deficiency, Shehan D. Perera

Electronic Thesis and Dissertation Repository

Hypertriglyceridemia (HTG) is a risk factor for cardiovascular disease. However, only the triglyceride (TG) phenotype produced by biallelic loss-of-function (LOF) variants in the canonical TG metabolism genes is well understood. The TG phenotype produced by monoallelic LOF variants is poorly understood. We aimed to evaluate the TG phenotype associated with monoallelic LOF variants in the canonical TG metabolism genes.

Next-generation sequencing panel was employed to identify patients heterozygous for LOF variants in two of the canonical TG metabolism genes LPL and APOA5, followed by chart review to determine baseline and longitudinal TG phenotype in these patients.

My findings suggest …

The Molecular Landscape Of Early-Stage Breast Cancer With Lymph Node Metastasis, Farhad Ghasemi

Electronic Thesis and Dissertation Repository

Axillary lymph nodes (ALNs) are the primary site of metastasis in breast cancer, and their involvement has implications in disease staging, prognostication, and treatment decisions. A non-invasive modality of assessing the risk of ALN metastasis can improve care in patients with early-stage breast cancer by omitting the morbidity and costs associated with axillary surgery.

This thesis explores the molecular landscape of early-stage breast cancers with ALN metastasis and shows the potential of tumour molecular signatures in predicting ALN involvement. After a systematic review of the literature, we use data from The Cancer Genome Atlas (TCGA) to develop molecular signatures correlated …

Identification Of Dna Methylation Episignatures For Classification And Phenotype/Genotype Correlation In Mendelian Neurodevelopmental Disorders, John Reilly

Electronic Thesis and Dissertation Repository

ABSTRACT: Diagnosis for neurodevelopmental disorders poses numerous challenges, related to the lack of specific findings and limited understanding of clinical impact of the majority of genetic variation. Epigenomics mechanisms involve chemical modifications in DNA that involve a range of cellular mechanisms. DNA methylation is an epigenetic mechanism involving addition and removal of methyl groups to cytosine residues. These methylation signals form episignatures; patterns of methylation that can be used as biomarkers capable of differentiating neurodevelopmental disorders. EpiSigns have enabled molecular diagnosis of a number of genetic conditions, classification of variants of unknown significance, and provided insights into the pathophysiology of …

The Genetics Of Pain: An Exploration Of Gene-By-Environment Interactions And Their Effects On Pain, Mohamad F. Fakhereddin

Electronic Thesis and Dissertation Repository

The findings presented in this dissertation are part of the bigger SYMBIOME project which aims to use the biopsychosocial model of pain to develop a prognostic clinical phenotype for people that experience musculoskeletal (MSK) trauma. Chapter 2 presents an exploratory analysis to assess the relationships between genetic polymorphisms and pain severity and interference. Early childhood trauma was also explored as a moderator between genetic polymorphisms and pain outcomes. For pain severity, major allele carriers (A/A and G/A) of FKBP5 rs9394314 reported significantly higher scores than minor allele carriers (G/G). Further, major allele carriers who had at least one adverse childhood …

Applications Of Genetic Testing For Endocrine And Metabolic Disorders, Amanda Berberich

Electronic Thesis and Dissertation Repository

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 …

The Genetic Landscape Of Neurodegenerative And Cerebrovascular Disease Phenotypes., Allison A. Dilliott

Electronic Thesis and Dissertation Repository

Neurodegenerative diseases are progressive, incurable conditions characterized by neuronal degeneration and protein aggregation, resulting in cognitive decline and/or motor dysfunction. Over half a million Canadians are affected with these diseases, and the number of cases is expected to rise as the aging population grows and average lifespans continue to increase. There are currently no curative treatments, and only few therapeutics are available to target disease symptoms or slow disease progression. Further, diagnosis can be challenging, relying on clinical features that are often highly heterogeneous between patients. Gaining a greater understanding of the full spectrum of genetic factors contributing to these …

Genetic Approaches For The Study Of Complex Human Diseases, Julieta Lazarte

Electronic Thesis and Dissertation Repository

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; …

Epigenetics A Decolonizing Science, Wade Paul

Electronic Thesis and Dissertation Repository

Epigenetics is the study of gene expression that does not entail alterations to the actual DNA. Decolonization is a theoretical and political movement that seeks to deconstruct colonial institutions and ideologies and reconstruct new and balanced approaches that accept and respect Indigenous worldviews. This project studies the decolonizing potential of epigenetics. Using genealogy as the method, the study establishes a long history of reductionist and deterministic thought that shaped the study of genetic science. Particular instances like thrift gene theory are explored to highlight how genetic explanations have been detrimental to the health and wellbeing of Indigenous people and illustrate …

Advanced Phenotyping Of Otosclerosis In An Ontario Population And Two Large Newfoundland Families, Matthew B. Lucas

Electronic Thesis and Dissertation Repository

Otosclerosis is a relatively common hearing loss disorder characterized by abnormal bone growth in the otic capsule leading to stapes fixation. In approximately half of cases, otosclerosis is inherited as an autosomal dominant trait. Typically, gene discovery efforts rely on surgical confirmation, audiometry and occasionally acoustic reflexes to identify affected cases of otosclerosis within families, requiring that the otosclerosis was at an advanced stage to be detected. This makes it difficult to identify individuals with early otosclerosis. The use of advanced phenotyping to identify cases of otosclerosis was tested in an Ontario otosclerotic population as well as in two large …

The Now Trial: A Pragmatic Randomized Controlled Trial Of Personalized, Genetic-Based Lifestyle Advice, Justine Rochelle Horne

Electronic Thesis and Dissertation Repository

Background: The impact of nutrigenomics and lifestyle genomics interventions on health outcomes and behaviours remains controversial and under-explored.

Objectives: To determine the short-term (3-month), moderate-term (6-month) and long-term (12-month) impact of providing personalized, genetic-based lifestyle information and advice on anthropometric measures, as well as dietary intake and adherence.

Methods: The nutrigenomics, overweight/obesity and weight management trial (NOW Trial) is a pragmatic randomized controlled trial that was incorporated into the Group Lifestyle Balance™ (GLB) program (N=140). Inclusion criteria: overweight or obesity (BMI ≥ 25 kg/m²), ≥ 18 years of age, English-speaking, having access to internet at least …

Language In Genetics Research Informed Consent: The Language Gap And Unrecognized Miscommunication, Justin Morgenstern

Electronic Thesis and Dissertation Repository

Informed choice is fundamentally a process of communication, reliant entirely on the tools of language. However, the meanings and understandings of words change with time, setting, and context, threatening the basis of consent. We conducted a qualitative content analysis of Canadian genetics research documents, exploring the impacts of language on informed consent. Numerous language usages were noted as potential barriers to informed consent, including language that was vague, variable, and unusually defined. Unique combinations of words were observed to generate novel concepts without clear meanings and definitions were absent or unclear. However, the ambiguity of the language was concealed by …