Medical Genetics Commons^™

The Development Of A Crispr-Based Calibrated Functional Assay For Classifying Pathogenicity Of Msh2 And Msh6 Variants In Lynch Syndrome, Olivia N. Amodeo

Honors Scholar Theses

Lynch syndrome is a hereditary disease caused by the inheritance of a mismatch repair gene variant. Individuals with this condition are predisposed to cancer development, most commonly colorectal cancer. Current guidelines for variant classification are based on numerous evidence categories, including functional evidence. However, many novel clinical variants are not well characterized, and evidence is difficult to obtain if functional assays are not calibrated.

To address this, our lab created a calibrated functional assay that calculates an odds of pathogenicity score for MSH2 and MSH6 gene variants that can be used as evidence for classifying variants of uncertain significance. This …

Single-Nuclei Transcriptomic Profiling Of Human Myocardium In Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency, Hanna J Tadros, Diwakar Turaga, Yi Zhao, Chang-Ru Tsai, Lalita Wadhwa, Debra L Kearney, Iki Adachi, Xiao Li, James F Martin

Faculty, Staff and Students Publications

No abstract provided.

The "Hallett Sign" Of Functional Jerky Movement Disorder, Jon Stone, Anthony E Lang, Joseph Jankovic, Michele Tinazzi, Barbara A Dworetzky, Alan Carson, Marina A J Tijssen

Faculty, Staff and Students Publications

No abstract provided.

Validation Of The German Version Of The Movement Disorder Society Non-Motor Scale (Mds-Nms), Jonas Bendig, Anika Frank, Adrianna Lipska-Dieck, Kristof Wunderlich, David Geißler-Lösch, Isabel Wurster, Roswitha Kemmner, Kathrin Brockmann, Sheng Luo, Christopher G Goetz, Glenn T Stebbins, Pablo Martinez-Martin, Tiago A Mestre, Alvaro Sanchez-Ferro, Monica M Kurtis, Michelle H S Tosin, Roberta Balestrino, Chi-Ying R Lin, Carmen Gasca-Salas, Heinz Reichmann, Bjoern H Falkenburger

Faculty, Staff and Students Publications

No abstract provided.

Potential Impact Of Parasites In The Transmission Of Chronic Wasting Disease, Paulina Soto, Rodrigo Morales

Faculty, Staff and Student Publications

No abstract provided.

Optimized Ultrasound Imaging Of Phase-Change Nanodroplets, Charles R Dyall, Dmitry Nevozhay, Andy Liu, Trevor M Mitcham, George J Lu, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

Phase-change nanodroplets (PCNDs) continue to generate significant research interest due to their potential to extravasate into tissue, to be targeted for molecular imaging and drug delivery, and to undergo an induced phase-change to "activated" microbubbles (MBs) for ultrasound (US) imaging. To accurately quantify molecular markers, however, one assumes a consistent proportion of PCNDs in a region of interest (ROI) are stably activated and imaged. Herein we present a framework for developing a diagnostic sequence that is optimized for PCND activation uniformity, contrast, and acquisition time. To develop this framework, activation was examined at three scales of increasing complexity: single, adjacent, …

Corrigendum To 'Risk Factors For Bronchiolitis Obliterans Syndrome After Initial Detection Of Pulmonary Impairment After Hematopoietic Cell Transplantation' [Transplantation And Cellular Therapy 29/3 (2023) 204-204], Mansour Alkhunaizi, Badar Patel, Luis Bueno, Neel Bhan, Tahreem Ahmed, Muhammad H Arain, Rima Saliba, Gabriela Rondon, Burton F Dickey, Lara Bashoura, David E Ost, Liang Li, Shikun Wang, Elizabeth Shpall, Richard E Champlin, Rohtesh Mehta, Uday R Popat, Chitra Hosing, Amin M Alousi, Ajay Sheshadri

Faculty, Staff and Student Publications

No abstract provided.

Growth Hormone Pathway As A Prognostic And Therapeutic Biomarker In Patients With Unresectable Hepatocellular Carcinoma Treated With Radiation Therapy, Joe R Eid, Safa Kaseb, Lianchun Xiao, Ryan Sun, Mahesh Kumar Kannan, Manal Hassan, Asif Rashid, Hop S Tran Cao, Hesham M Amin, Eugene J Koay

Faculty, Staff and Student Publications

Purpose: Radiation therapy (RT) has emerged as an effective local therapy option for patients with unresectable hepatocellular carcinoma (HCC) and is associated with improved overall survival (OS). However, some patients still have poor outcomes after RT, and biomarkers are needed to stratify prognostic groups. High circulating growth hormone (GH) levels promote HCC proliferation and survival and are associated with aggressive disease. In this study, we evaluated whether pretreatment GH levels are associated with OS and progression-free survival (PFS) in patients who underwent RT for unresectable HCC.

Methods and materials: Patients undergoing RT for HCC during 2017-2023 were identified from a …

Inherited Tbx4 Frameshifting Variants Predicted To Escape Nonsense Mediated Decay In Two Families With Variable Phenotypes, Including Lethal Lung Developmental Disorders, Shruti A Pande, Hiuling Chan Joiner, Przemyslaw Szafranski, Tomasz Gambin, Michelle Wright, Qian Wang, Maiah Walters, Jan M Friedman, Jessica Saunders, Nicholas Avdimiretz, Cornelius F Boerkoel, Nahir Cortes-Santiago, Gail Deutsch, Pawel Stankiewicz

Faculty, Staff and Students Publications

Background: Pathogenic variants involving the transcription factor TBX4 gene have been associated with various skeletal and pulmonary abnormalities, including lethal lung developmental disorders (LLDD).

Methods: Whole-genome sequencing (WGS) with AI-powered platform for variant detection and interpretation followed by Sanger sequencing targeted variant segregation analysis were used. Reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) studies were performed to assess gene and protein expression levels, respectively.

Results: We describe two unrelated families with intrafamilial variability in the TBX4 phenotypic expressivity, including LLDDs. WGS analyses revealed two frameshift variants, c.1019del; p.(Arg340GlnfsTer40) in the penultimate exon and c.1167dup; p.(Arg390GlnfsTer30) in the last exon …

Yap Induces A Prorenewal Metabolic State In Cardiomyocytes, Lin Liu, Jeffrey D Steimle, Chang-Ru Tsai, Fansen Meng, Yuka Morikawa, Yi Zhao, Sandra Carmichael, Xiao Li, James F Martin

Faculty, Staff and Students Publications

BACKGROUND: Cardiomyocytes, as highly specialized and differentiated somatic cells, possess a limited capacity for renewal. Neonatal rodents possess the ability to regenerate cardiomyocytes after injury; however, this regenerative capacity declines rapidly with cardiomyocyte maturation, suggesting an inhibitory network between cellular maturation and cardiomyocyte proliferation. Maturing cardiomyocytes undergo a metabolic shift from predominantly glycolysis in the neonatal state to increased fatty acid oxidation in the mature state, which poses a barrier to cardiomyocyte proliferation and cardiac regenerative repair. YAP, a transcriptional cofactor regulated by the Hippo signaling pathway, promotes cardiac regenerative repair. We investigated the role of YAP in mediating metabolic …

Prodromal Lewy Body Disorder Features In Rem Sleep Behavior Disorder With Biomarker-Defined Synucleinopathy, Daniel Weintraub, Michele K York, Roseanne Dobkin, Anuprita R Nair, Ryan Kurth, David-Erick Lafontant, Chelsea Caspell-Garcia, Roy N Alcalay, Ethan G Brown, Lana M Chahine, Christopher Coffey, Tatiana Foroud, Douglas Galasko, Karl Kieburtz, Kenneth Marek, Kalpana Merchant, Brit Mollenhauer, Kathleen L Poston, Andrew Siderowf, Cristina Simonet, Tanya Simuni, Caroline M Tanner, Thomas F Tropea, Aleksandar Videnovic, Parkinson's Progression Markers Initiative

Faculty, Staff and Students Publications

Objective: Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders and exhibits biological heterogeneity that may influence clinical expression and progression. We examined clinical features in individuals with iRBD and biomarker-defined synucleinopathy.

Methods: Parkinson's Progression Markers Initiative (PPMI) is a longitudinal, multi-center observational study. Participants included polysomnogram (PSG)-confirmed iRBD individuals who were cerebrospinal fluid (CSF) α-synuclein seed amplification assay positive with no clinical diagnosis of Parkinson's disease or dementia with Lewy bodies, along with robust healthy controls (HCs). Clinical and biological features of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold …

A Performance And Quality Improvement Intervention Integrating Molecular Testing To Support Personalized Cancer Care In Lung And Thyroid Cancers, Suzanne Murray, Monica Augustyniak, John Vu, Elbert Y. Kuo, Manolo G. Pasia Jr., Sheri L. Rivera, Kelly M. Rodriguez, Vivek Subbiah, Patrice Lazure, Ecaterina E. Dumbrava

Advances in Cancer Education and Quality Improvement

Introduction: Molecular testing has been underutilized in the diagnosis and treatment of cancer patients, despite its potential to significantly impact clinical decision-making and resulting health outcomes.

Objectives: This project aimed to evaluate the process and impact of a performance/quality improvement (PI/QI) intervention to optimize the integration of molecular testing for patients with non-small cell lung cancer (NSCLC) or thyroid cancer (TC).

Methods: Physicians, advanced practice providers, and nurses were engaged in the PI/QI at 2 cancer centers (Site A and Site B) for up to 18 months following a pre-intervention needs assessment. Gaps identified at baseline informed …

Trends In The National Resident Matching Program: Shifting Applicant Priorities In The Setting Of Application Limits And Pass/Fail Step 1 Grading, Joshua Morrow, Siena Blackwell, Zibi Gugala, Atul Maheshwari, Peter Boedeker

Faculty, Staff and Students Publications

Purpose: This study evaluated differences in expected and observed proportions of activities, average Step 2 scores, and abstracts, publications, and presentations since the adoption of a 10-experience maximum for residency applications and pass/fail Step 1 grading.

Method: The authors queried National Resident Matching Program data for MD senior applicants from 2016 to 2024 across 22 specialties. Data included average Step 2 scores; research, work, and volunteer experiences; and number of research products for matched and unmatched students by specialty. Repeated-measures multilevel models were used to estimate the difference in observed outcome in 2024 and expected outcome based on trends from …

Global Impact Of Germline Structural Variation On The Cancer Proteome, Fengju Chen, Yiqun Zhang, Luis F Paulin, Darshan S Chandrashekar, Sooryanarayana Varambally, Fritz J Sedlazeck, Chad J Creighton

Faculty, Staff and Students Publications

Proteome and transcriptome data combined can help assess the relevance of non-coding germline variants. Here, we combine germline Structural Variants (SVs) with mass spectrometry-based proteomics on tumors from 1637 cancer patients spanning various tumor tissues of origin to determine the extent SV breakpoint patterns involve differential protein expression of nearby genes. Rare and singleton SVs disrupting protein expression of known cancer susceptibility genes collectively involve 6% of patients. About 24% of the hundreds of genes with SV-associated non-coding cis-regulatory alterations at the mRNA level are similarly associated at the protein level. Both rare and common SVs may associate with differential …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

Evaluating The Utility Of Rnaseq In Prenatal Diagnostics: Expression Profiles Of Cultured Chorionic Villus And Amniotic Fluid Samples, Maria C Vladoiu, Sen Zhao, Roni Zemet, Christian M Parobek, Jefferson Cruz Sinson, Stacy Tankersley, Ignatia B Van Den Veyver, Pengfei Liu

Duncan NRI Faculty and Staff Publications

Objective: While RNAseq has enhanced variant interpretation in postnatal cases, its potential in the prenatal setting remains underexplored. This study investigates the utility of RNAseq in prenatal diagnostics by analyzing the expression profiles of cultured chorionic villus samples (cCVS) and amniotic fluid (cAF) samples.

Methods: We performed RNAseq on 25 prenatal samples (10 cCVS and 15 cAF) and compared their expression profiles with those of postnatal tissues-blood and skin fibroblasts.

Results: To evaluate the clinical relevance of gene expression in these samples, we curated a list of genes associated with fetal-onset genetic disorders (n = 375). Using this curated list …

Clingen Api Platform For Classification Of Human Genetic Variants, Neethu Shah, Tierra Farris, Arturo Alejandro Zuniga, Andrew R Jackson, Jessie Arce, Kevin Riehle, Christine G Preston, Mark E Mandell, Bryan Wulf, Gloria Cheung, Keyang Yu, Deborah I Ritter, Dubravka Jevtic, Miroslav Milinkov, Novak Martinovic, Nevena Vucinic, Aleksandar Mihajlovic, Alan F Rubin, Melissa S Cline, Marina Distefano, Malachi Griffith, Obi L Griffith, Matt W Wright, Teri E Klein, Sharon E Plon, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

In this commentary, we describe how the Clinical Genome Resource's (ClinGen's) application programming interface-based microservices accelerate growth and dissemination of knowledge about human genetic variation. By exposing findable, accessible, interoperable, reusable, and AI-ready variant data, ClinGen lays a foundation for next-generation software applications, AI systems, and variant classification workflows.

Correction: The Formation Of Tau Pore-Like Structures Is Prevalent And Cell Specific: Possible Implications For The Disease Phenotypes, Cristian A Lasagna-Reeves, Urmi Sengupta, Diana Castillo-Carranza, Julia E Gerson, Marcos Guerrero-Munoz, Juan C Troncoso, George R Jackson, Rakez Kayed

Faculty, Staff and Students Publications

This corrects the article "The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes" in volume 2, 56.

Relative Impact Of Multidomain Lifestyle Interventions On Deficit Accumulation Frailty Over 24 Months In The U.S. Pointer Trial, Mark A Espeland, Kayloni Olson, Christy C Tangney, Darren R Gitelman, Maryjo Cleveland, Amber A Thro, Yitbarek N Demesie, Heather M Snyder, Rachel A Whitmer, Pankaja Desai, Rifat Alam, Lucia Crivelli, Thomas M Holland, Olivia Preissle, Rema Raman, Michele K York, Laura D Baker

Faculty, Staff and Students Publications

Background: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear.

Methods: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability …

Drd2 Rs6276 Polymorphism And Trait Impulsivity In Individuals With Mixed Behavioral And Substance Addictions, Gabriela Zdunek, Remigiusz Recław, Aleksandra Suchanecka, Krzysztof Chmielowiec, Dariusz Larysz, Patryk Ilków, Kinga Łosińska, Jolanta Chmielowiec, Łukasz Jaworski, Anna Grzywacz

Baltic Journal of Health and Physical Activity

Background/Objectives: Impulsivity is a key transdiagnostic trait linked to dysregulated reward processing in both behavioral and substance-related addictions, as recognized in DSM-5. Dopaminergic genes, including DRD2, may modulate individual differences in impulsivity, particularly under conditions of increased addiction vulnerability. This study examined whether the DRD2 Exon 8 rs6276 polymorphism predicts impulsivity levels in men with mixed addictive behaviors compared with healthy controls. Methods: A total of 328 males (128 with mixed behavioral and substance addictions and 200 controls) were assessed. Diagnoses were confirmed using the MINI interview, and impulsivity was measured with the Barratt Impulsiveness Scale (BIS-11). Genotyping of …