Medical Genetics Commons^™

Parkinson’S Disease Phenotype Stratification Using Multiple Correspondence Analysis, Kelly Astudillo

Dissertations, Theses, and Capstone Projects

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with over 12 million people projected to be affected by 2040 (Dorsey et al., 2018). Deep phenotyping and stratification can provide useful information regarding PD pathogenesis and can aid in the  development of disease modifying therapies that aim to delay the progression or prevent the onset of neurodegeneration (Blandini et al., 2019; Smith & Schapira, 2022). Utilizing multivariate methods such as multiple correspondence analysis (MCA) permits for the simultaneous analysis of distinct data modalities. To the best of our knowledge, MCA has not been previously used to explore phenotype patterns …

Using Genetically Diverse Mice To Examine The Effects Of Environmental Enrichment Of The Transcriptome, Michael Richard Leonardo

Theses, Dissertations and Capstones

Environmental impoverishment is a model of early life stress with direct consequences across a wide range of neurological and physiological conditions. Neuron morphology and density as well as anxiety disorders and addiction have shown to have significant relationships with environmental impoverishment models. Conversely, environmental enrichment confers therapeutic benefits that are protective across these conditions. There is an observed spectrum of resistance or vulnerability to the effects of housing conditions across populations, indicating genetics as an influential factor. Understanding this interaction is critical for deepening our knowledge of how genes and environment interact in ways that confer resistance or vulnerability, and …

Transcriptomic And Epigenomic Profiling Of Immune Cells Responses To Simian Immunodeficiency Virus Infection In The Brain, Xiaoke Xu

Theses & Dissertations

Human immunodeficiency virus type 1 (HIV-1) is an enveloped retrovirus that significantly impairs the human immune system. A common complication of HIV-1 infection is HIV-associated neurocognitive disorder (HAND), which, prior to the introduction of antiretroviral therapy (ART), led to considerable morbidity and mortality due to untreated neuropsychiatric manifestations. Although ART has substantially reduced the incidence of HIV-associated dementia (HAD), approximately 50% of people living with HIV (PLWH) continue to experience milder forms of HAND. The CNS is seeded by HIV during the acute phase of infection. Once in the brain, HIV targets and activates resident immune cells, primarily microglia and …

Healthcare Utilization Patterns, Associated Factors, And Readmission Rates Among Children With Sickle Cell Disease., Daniya Mohammed Sabrah

Electronic Theses and Dissertations

Sickle Cell Disease (SCD) is common in Saudi Arabia, with a prevalence rate of 2.3%. It is an expensive disease to manage due to the extensive utilization of healthcare resources, including hospital readmissions, extended hospital stays, and frequent emergency department visits, which cost approximately $395 million annually in U.S. dollars. The primary objective of this study was to conduct a systematic literature review of healthcare utilization and cost of patients with SCD, following the PICO framework and PRISMA guidelines. The second aim utilized count models, including the negative binomial and Poisson, to identify factors associated with emergency, inpatient, and outpatient …

A Comparative Analysis Of Nf-Κb1 Gene Regulatory Sequence Methylation In Normotensive And Hypertensive Kenyans, Aaryan Barlas Piracha

Honors Theses

Accounting for the majority of deaths worldwide, non-communicable diseases (NCDs) present the greatest health challenge of the twenty-first century. Specifically, cardiovascular diseases (CVDs) exceed all other NCDs in annual deaths and especially affect low- and middle-income countries (LMICs). Hypertension, being the primary risk factor for CVD, affects over 75% of adults in LMICs due to inadequate health care and preventative measures. Additionally, epigenetic modifications of DNA are important mechanisms that regulate gene expression; DNA methylation, in particular, affects cytosine residues in cytosine-phosphate-guanine (CpG) islands on regulatory sequences. Previous research in our laboratory analyzed percent methylation at 8 different CpG islands …

Immune Landscape Of Early Liver Metastatic Lesions In A Novel Immunocompetent Murine Colorectal Cancer Metastasis Model, Alaa Mohamed

Dissertations and Theses (Open Access)

Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

Denial Of Inpatient Genetic Testing: A Study On Outpatient Yield And Outcomes, Cindy Y. Canales

Dissertations and Theses (Open Access)

This study investigates the difference in diagnostic yield between patients approved for inpatient genetic testing compared to those denied inpatient testing and the effect of an earlier diagnosis on outcomes and medical/clinical care. In the literature, research has explored the impact of a diagnostic delay for patients with genetics conditions, assessed the utility of genetic testing in the inpatient setting, and described the impact to care of an earlier diagnosis. However, gaps remain on research exploring the diagnostic yields of inpatient versus outpatient settings and the potential impact to care an inpatient genetic testing request denial may pose. This is …

A Stakeholder-Informed Conceptual Framework For Evaluating Genomics In Precision Oncology, Julie A. Wiedower

All Dissertations

This dissertation explores the value of genomic testing in precision oncology with an emphasis on how US payers conceptualize and prioritize elements of value. This research aims to address gaps in understanding payer perspectives and proposes a stakeholder-informed framework for evaluating genomic testing in oncology. To achieve this aim, the presented research investigates payer perspectives, value-based cancer care priorities, and the conceptual understanding of the value of a genetic diagnosis to establish a framework for value with the payer audience in mind. Chapter 1 outlines relevant background information relating to the genomic revolution and challenges in translating genomic testing technologies …

The Genomic Landscape And Prognostic Impact Of Kras, Stk11, And Smarca4 Mutations And Co-Mutations On Survival Outcomes In Non-Small Cell Lung Cancer, Peter Manolakos

All Dissertations

Non-small lung cancer (NSCLC) accounts for 85% of lung cancer cases, and Kirsten rat sarcoma viral oncogene homolog (KRAS), Serine/Threonine Kinase 11 (STK11), and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations and co-mutations have been increasingly recognized for their potential prognostic significance. However, clear knowledge gaps remain regarding which treatments should be selected for patients who present clinically with KRAS/STK11 or KRAS/SMARCA4 co-mutations, as outlined in Chapter 1. Despite significant clinical development advancements in immunotherapy and targeted therapy, a deeper understanding of the influence of these genomic …

Identification Of Novel Genetic Biomarkers Linked To The Prodromal Stage Of Parkinson’S Disease (Pd) Patients, Marwa Tawfik Badawy

Theses and Dissertations

Background and Objective: The early diagnosis of neurodegenerative diseases, such as Parkinson's disease (PD), is particularly challenging because symptoms appear only after significant neuronal damage has already occurred. This study is utilizing variant call format (VCF) analysis to identify genetic variants and novel genes that could serve as early prognostic markers for prodromal PD. Materials and Methods: Data were sourced from the Parkinson's Progression Markers Initiative (PPMI), focusing on prodromal patients with gVCF data from the 2021 cohort. The study included 304 participants, comprising 100 healthy controls, 146 individuals with prodromal genetic indicators, 21 individuals with prodromal hyposmia, and 37 …

Mir-125a-3p And Its Targets: Promising Biomarkers For Ovarian, Liver, And Breast Cancers, Offering A Beacon Of Hope For More Effective Diagnosis And Treatment Strategies, Eman Kamaleldien Anwer

Theses and Dissertations

Cancer is a worldwide health problem with various genetic and epigenetic alterations, resulting in disease heterogeneity. Effective diagnostic, therapeutic, and monitoring markers have been determined recently; however, new diagnostic, prognostic, and therapeutic markers are needed. MicroRNAs (miRNA), short non-coding RNAs, have a highlighted role in cancer progression, migration, and programmed cell death. Our study aims to investigate the significance of miR-125a-3p and its downstream targets in breast (BRCA), hepatocellular (HCC), and ovarian (OVCA) malignancies and their possibility as diagnostic biomarkers and targets for therapeutic agents. Bioinformatics and online tools were used to determine the miRNA-predicted downstream targets, analyze GEO datasets, …

In Vivo Evaluation Of Novel Nanoparticles And Repurposed Pharmaceuticals To Combat Antimicrobial Resistance, Sarah E. Evans

Theses, Dissertations and Capstones

In a 2019 report by the Centers for Disease Control and Prevention (CDC), infections resistant to antibiotic treatment amount to about three million infections and 48,000 deaths. Antimicrobial resistance is an escalating global threat as existing antibiotics lose efficacy over time. The project described is focused on partnering with pharmaceutical researchers and producers to test new nanoparticle-based or repurposed compounds. The central hypothesis of this thesis is that pharmaceutical formulations such as nanoparticles may provide a cost-effective means of combating the emerging antimicrobial resistance. The nanoparticle compounds allowed for a wide range of customization for the pharmaceutical design, since the …

Characterizing A Rad23 Dependent Ultraviolet Radiation Resistance In Tetrahymena Thermophila, Emma June Liimatta

Graduate Theses/Dissertations

In 2020, 10 million deaths were attributed to cancer, with multidrug resistance being responsible for over 90% of deaths in cancer patients receiving treatment. This study utilized the model organism Tetrahymena thermophila to study how cells become resistant to Ultraviolet Radiation (UV) radiation, a process similar to multidrug resistance, specifically focusing on the nucleotide excision repair and ubiquitin shuttle protein Rad23. The National Cancer Institute documented 30-60% of cancers tested had a mutation in RAD23. Knockdown of RAD23 in Tetrahymena thermophila demonstrated a UV resistance phenotype with decreased nucleotide excision repair and differential expression of proteins active within caspase-independent …

Enhancing Clinical Trial Matching In Molecular Diagnostics: Using Natural Language Processing And Clustering Approaches In Hematological Malignancies, Gillian Fanning

Theses and Dissertations

Clinical trial matching is a critical component of personalized medicine, particularly in the management of hematologic malignancies. At Virginia Commonwealth University (VCU) Health, the Molecular Diagnostics (MDX) Lab produces somatic variant reports and recommends clinical trials based on the presence of clinically significant mutations. However, the current manual trial recommendation process is time-intensive and lacks scalability.

This study introduces a computational framework to streamline and standardize clinical trial matching using natural language processing (NLP) and unsupervised clustering. Trial brief descriptions were analyzed to extract frequent terms, and trials were grouped based on term similarity using joint dimensionality reduction and clustering. …

Rare Variant Analysis Of Electronic Health Record-Defined Major Depressive Disorder In The All Of Us Research Program, Stephen Emil Vieno

Theses and Dissertations

The underlying pathogenesis of MDD remains poorly understood, with multiple competing hypotheses regarding its exact etiology. As a heterogeneous disorder with relatively low heritability, large-scale genome-wide association studies of MDD have relied on increasingly large sample sizes to identify common genetic variants associated with the disorder. However, the rare variant genetic architecture of MDD is still largely unknown. The aim of the present analysis was to use the AoU—a United States-based biobank that integrates healthcare records from over 50 healthcare systems and possesses whole genome sequencing data for participants—to perform a gene set–based analysis of MDD. This analysis presented several …

Determining Essential Regulatory Factors In Extravillous-Trophoblast Differentiation And Splice Variants Associated With The Development Of Preeclampsia, Brandt Hugh Beck

Electronic Theses & Dissertations (2024 - present)

Preeclampsia is a common condition affecting mothers across the world. Rates for preeclampsia have been rising in the past years due to factors such as obesity and diabetes. Since this condition has been more prevalent, a better understanding of the factors surrounding the preeclamptic state are needed. Core cell types and biological functions of placenta development are known but the cause behind the preeclamptic environment is not well understood. This research aims to investigate the potential causes behind preeclampsia by first reviewing Extravillous-Trophoblast differentiation factors in the context of differential gene expression and alternative splicing then evaluate towards preeclamptic tissue. …

5-Fluorouracil Induced Oxidative Stress Is Variable Across Triple Negative Breast Cancer Cell Lines, Rachel L. Walker

Departmental Honors & Graduate Capstone Projects

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with treatment limited to chemotherapy. However, not all patient tumors respond to chemotherapy. The variable cytotoxic effects of chemotherapies may be due to how cancer cells regulate reactive oxygen species (ROS). In this study, we examined two mouse breast cancer cell lines: 4T1 and EO771, vary when treated with hydrogen peroxide (H2O2) and 5-Fluorouracil (5FU), known ROS-inducing substances. In 4T1 cells H2O2 increased oxidized DNA but caused minimal cell death. While in EO771 cells that same amount of H2O2 caused complete apoptosis. Cell number, ROS, and cell death showed …

The Role Of Epigenetic Aberrations In The Cold Tumor Phenotype And Inflammatory Signaling In High-Risk Neuroblastoma, Pamela Morgan Watson

Alternative Theses and Dissertations (AETDs)

Neuroblastoma (NB) is a highly aggressive, heterogeneous disease that arises from the sympathetic nervous system (SNS) and originates from neural crest cells (NCCs) (1). NB is the most common extracranial cancer in pediatric accounts for 15% of pediatric cancer deaths (2). This high mortality rate is the result of the metastatic, immune evasive, and treatment resistant characteristics of the disease (3). It has been proposed that NB arises from blocks in differentiation during development, resulting in a mixture of two distinct cell types within the tumor: mesenchymal and adrenergic (Figure 1.1) (4,5). The adrenergic cell type is more differentiated, and …

Stargardt’S: Trends In Treatment Modalities, Dallas Myers

Theses and Graduate Projects

Background: This review is aimed at furthering understanding of Stargardt’s, including disease pathophysiology, treatment methods, and the future of vision restoration.

Purpose: Stargardt’s (STGD) was initially discovered in 1909, but it was not fully understood until 1997. It is the most common form of inherited macular degeneration. There are few resources for patients and providers regarding treatment options and lifestyle recommendations.

Methods: A comprehensive literature review was conducted using NIH, UpToDate, and Google Scholar. Specific terms are further detailed in the review. Inclusion criteria were studies focused on STGD patients. Exclusion criteria for were those that only …

The Characterization Of Cacna1a-Related Hemiplegic Migraine, Donna P. Schaare

All Dissertations

CACNA1A-related Hemiplegic Migraine (HM) is a rare neurodevelopmental disorder characterized by paroxysmal episodes of hemiparesis/hemiplegia with or without headache. The presentation of CACNA1A-related HM can range from mild HM events in neurotypical individuals to life-threatening prolonged periods of hemiplegia with cerebral edema in individuals with baseline neurodevelopmental features. CACNA1A-related HM has been studied extensively in its familial form, Familial Hemiplegic Migraine type 1 (FHM1), but the often more severe disorder attributed to de novo variants, Sporadic Hemiplegic Migraine type 1 (SHM1), has had limited description. Genetic resources and the 3^rd edition of the International Classification of …

Exploring The Functional Significance Of A Yap1 Missense Variant Of Uncertain Significance In Caenorhabditis Elegans, Nathan Jones

Theses

Polycystic ovary syndrome (PCOS) is a complex disorder with various implications, such as polycystic ovaries, visceral obesity, and increased risk of cancer. YAP1 was recently identified as a gene of interest in the development of PCOS. Researchers have established that single nucleotide variants in YAP1 are likely to play a role in PCOS development. This project aims to provide insight into the potential impact of a YAP1 variant of uncertain significance (VUS). Studies in C. elegans have established yap-1 as a nematode ortholog for human YAP1. A YAP1 VUS was identified through ClinVar, YAP1 c.1015A>G (p.Asn339Asp). Evolutionary conservation …

Examining Patient Preferences And Perceptions Of Provider Communication Strategies For Variant Reclassification In Hereditary Cancer Genetic Testing, Mitchell Mcelfresh, Katie Hutto, Gwen Reiser, Bronson Riley, Charlie King

Capstones: Genetic Counseling

Genetic testing plays a role in oncology care by providing insight into patient’s cancer risk and guiding medical management. Variants in genes are classified by their potential to cause disease according to the five-tier system recommended by the American College of Medical Genetics (ACMG). Reclassification of variants is fluid and can lead to both changes in medical management and challenging discussions. Previous research has described methods genetic counselors use for recontacting patients about reclassification, but not whether these methods align with patient preferences. This study employed a mixed methods survey for patients in Nebraska (recruited via flyer and mail) and …

Nutrigenetic And Dietary Factors Impacting The Relationship Between Linoleic Acid And Apolipoprotein B, Gregory Nacarelli

All Dissertations

This dissertation investigates the relationship between the omega-6 fatty acid, linoleic acid (LA), and the cardiovascular disease (CVD) risk marker apolipoprotein B (apoB). ApoB is considered to be the most important causal marker of CVD. However, the impact of LA on CVD risk has been subject to debate within the scientific literature, with various studies showing LA can decrease or increase apoB concentrations. To foster more clarity regarding this relationship, we first investigated all dietary, macronutrient, micronutrient, and nutrigenetic factors that impact concentrations of apolipoproteins via a narrative analysis approach. We found that more Westernized diets containing more processed foods, …

Mutational Landscape Of Noncoding Ultraconserved Elements In Human Cancers: Functional Relevance And Clinical Utility, Recep Bayraktar

Dissertations and Theses (Open Access)

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNA regions (ncUCEs), and their functional and clinical relevance in cancers remain poorly characterized. In this thesis, we perform a systematic analysis of whole-genome sequencing (WGS) data from the International Cancer Genome Consortium (ICGC) and in-house targeted sequencing of 13,736 UCEs and demonstrate that ncUCE somatic alterations are pervasive. Using a genome-wide multiplexed CRISPR knockout screen in colorectal cancer (CRC) cell lines, we show that the loss of several mutated ncUCEs impacts cancer cell proliferation. In-depth functional studies in vitro and in vivo further reveal that UCE_11311 is …

Sleep Disturbances In Adults With Tsc: Influences Of Treatment And Clinical Features, Kirstin Risgaard

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a rare genetic condition caused by pathogenic variants in the TSC1 or TSC2 genes. TSC is characterized by a multisystem, neurocutaneous phenotype including skin lesions, hamartomas, and epilepsy. Additionally, TSC can present with an array of behavioral, psychiatric, academic, psychosocial, intellectual, or neuropsychological difficulties comprehensively known as TAND, or TSC-associated neuropsychiatric disorders. Sleep disorders are a common feature of TAND; however, they are not well characterized in the adult TSC population. Likewise, little is known about how clinical features of the condition and commonly prescribed medications impact sleep. Therefore, this study aimed to determine the …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Genetic Analysis Of Hereditary Gingival Fibromatosis Associated Sos1 Missense Variants Of Uncertain Significance In Caenorhabditis Elegans, Himani Patel

Theses

Hereditary gingival fibromatosis (HGF) is a disease that can present as benign overgrowth of gingival tissue in the mouth. The overgrowth can enclose the entire mouth and teeth in severe cases or present itself in a concentrated area. Researchers have identified that mutations in the SOS1 gene can be responsible for HGF. This disease can impair basic functions related to the mouth. Eating, smiling, speaking can all be affected. Additionally, excess inflammation can cause periodontal disease because of the difficulty in maintaining proper oral health. Periodontal disease can lead to severe bone loss which can lead to complete loss of …

The Role Of Liver-Specific Transcription Factor Hnf4 In Reprogramming Of Fibroblasts, Mary Odubote

Masters Theses

The mammalian liver, a vital organ with complex functions, relies on a network of transcription factors to regulate gene expression. Fusion of hepatoma cells with fibroblasts often leads to gene extinction, silencing approximately 400 liver-enriched genes, including critical transcription factors such as HNF4. Previous studies revealed that ectopic expression of HNF4 in fibroblasts failed to prevent the extinction of SERPINA1, a liver-specific gene, upon subsequent fusion with hepatoma cells. Here, we sought to investigate the extent to which ectopic expression of HNF4 can reprogram fibroblast cells and prevent gene extinction in hybrid cells.

Using whole-genome expression analysis, we compared RAT1 …

The Influence Of Drd2 Polymorphism Exon 8 C/T (Rs6276) On Manifestations Of Delirium Tremens & Alcohol Withdrawal Seizures, Naomi Schneider

Honors Theses and Capstones

This study explores the correlation between the DRD2 Polymorphism exon 8 C/T (rs6276) and manifestations of delirium tremens (DT). DT is a condition that is clinically diagnosed utilizing two characteristic symptom manifestations: the presence of delirium and severe alcohol withdrawal. It is not entirely understood why DT can occur in some patients, but evidence has suggested that genetic predisposition can play a role. Utilizing the National Institutes of Health (NIH) All of Us Research database and performing a secondary analysis of existing genomic data, this candidate gene association study aims to determine the genotype frequencies within three cohorts: a healthy …