Genetic Phenomena Commons^™

Exome Sequencing In Asian Populations Identifies Low-Frequency And Rare Coding Variation Influencing Parkinson’S Disease Risk, Elaine Gy Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y Ng, Louis Cs Tan, Wee Ling Chng, Tiak Ju Tan, Esther Kl Peh, Ying Swan Ho, Xiao Yin Chen, Erin Yt Lim, Chu Hua Chang, Jonavan J Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Yy Chan, Juei-Jueng Lin, Beom S Jeon, Kyuyoung Song, Clement C Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B Makarious, Cornelis Blauwendraat, Mike A Nalls, Laurie A Robak, Roy N Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo

Faculty, Staff and Students Publications

Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest …

The Golgi Complex Governs Natural Killer Cell Lytic Granule Positioning To Promote Directionality In Cytotoxicity, Luis A Pedroza, Frederique Van Den Haak, Alexander Frumovitz, Evelyn Hernandez, Everardo Hegewisch-Solloa, Tabitha K Orange, Keri B Sheehan, Susan Prockop, Aaron Bodansky, Ivan K Chinn, James R Lupski, Jennifer E Posey, Emily M Mace, Yu Li, Jordan S Orange

Faculty, Staff and Students Publications

Cytotoxic immune cells mediate precise attacks against diseased cells to maintain organismal health. Their operational unit of killing and host defense is lytic granules (LGs), which are specialized lysosomal-related organelles. Precision in cytotoxicity is achieved by converging the many LGs to the microtubule-organizing center (MTOC) and polarizing these to the diseased cell for secretion. We identify unappreciated intimate relationships between the Golgi, MTOC, and LGs after cytotoxic cell activation, as well as the trans-Golgin protein GCC2 on the LG surface. GCC2 serves to tether LGs to the Golgi following convergence, and both GCC2 and the Golgi are required for the …

Tfap2e Is Implicated In Central Nervous System, Orofacial And Maxillofacial Anomalies, Jeshurun C Kalanithy, Enrico Mingardo, Jil D Stegmann, Ramgopal Dhakar, Tikam Chand Dakal, Jill A Rosenfeld, Wen-Hann Tan, Stephanie A Coury, Audrey C Woerner, Jessica Sebastian, Paul A Levy, Leah R Fleming, Lea Waffenschmidt, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Bimaljeet K Babra, Andrea Christ, Britta Eiberger, Selina Hölzel, Clara Vidic, Felix Häberlein, Nina Ishorst, Juan E Rodriguez-Gatica, Behnaz Pezeshkpoor, Patrick A Kupczyk, Olivier M Vanakker, Sara Loddo, Antonio Novelli, Maria L Dentici, Albert Becker, Holger Thiele, Jennifer E Posey, James R Lupski, Alina C Hilger, Heiko M Reutter, Waltraut M Merz, Gabriel C Dworschak, Benjamin Odermatt

Faculty, Staff and Students Publications

Background: Previous studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (TFAP2E) in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.

Methods: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted TFAP2E gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression …

Update On Pediatric Surveillance Recommendations For Pten Hamartoma Tumor Syndrome, Dicer1-Related Tumor Predisposition, And Tuberous Sclerosis Complex, Kris Ann P Schultz, Suzanne P Macfarland, Melissa R Perrino, Sarah G Mitchell, Junne Kamihara, Alexander T Nelson, Paige H R Mallinger, Jack J Brzezinski, Kara N Maxwell, Emma R Woodward, Bailey Gallinger, Sun Young Kim, Mary-Louise C Greer, Kami Wolfe Schneider, Sarah R Scollon, Anirban Das, Jonathan D Wasserman, Charis Eng, David Malkin, William D Foulkes, Orli Michaeli, Andrew J Bauer, Douglas R Stewart

Faculty, Staff and Students Publications

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.

Genetic Profile Of Premature Coronary Artery Disease Associated With Dyslipidemia: A Preliminary Study In Tertiary Hospitals, Eman Ramadan

Pharmacy

Background Familial Hypercholesteolemia (FH) represents significant risk for premature Coronary Artery Disease (CAD) development. Testing for causative mutations is the gold standard diagnostic test for FH. This study aimed to estimate the prevalence of genetically-confirmed Familial Hypercholesterolemia in premature Coronary Artery Disease patients in an Egyptian cohort. Methods: An Observational Analytical Cross-sectional study was conducted at Kobri Alqoba military hospital in Egypt in 2022, including 47 participants. All participants underwent Next generation sequencing for 7 genes linked with FH development in 47 patients with Premature CAD. Results: 9 Variants of Uncertain Significance (VUS) were found in LDLR, APOB, and APOE …

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 …

Paternal Upd (15) With Disease-Causing Mutation And Small Supernumerary Ring Chromosome 15: A Case Report, David Lee Curtis, Nasim Bekheirnia, Lorraine Potocki, Ludmila Matyakhina, Mir Reza Bekheirnia

Faculty, Staff and Students Publications

Uniparental disomy (UPD) constitutes an unconventional mode of inheritance that disrupts the typical biparental genetic contribution and may result in phenotypic abnormalities. This report centers on a patient diagnosed with Bartter syndrome Type 1, attributed to a homozygous pathogenic variant in SLC12A1 unmasked by mosaic paternal UPD of chromosome 15. We hypothesize that this pattern (or constellation) emerged from a trisomy rescue event, resulting in two distinct cell lines. Concurrently, the unmasking of a pathogenic paternal SLC12A1 variant by trisomy rescue resulted in the manifestation of Bartter syndrome Type 1. The maternally derived ring chromosome 15 and its impact on …

Autosomal Dominant Hk1-Related Neurodevelopmental Disorder With Visual Defects And Brain Anomalies (Nedviba): An Emerging Mitochondrial Disorder, Bobby G Ng, Erik A Eklund, Jill A Rosenfeld, Abdallah F Elias, Aya Abu-El-Haija, Celine Bris, Magalie Barth, Jong-Hee Chae, Murim Choi, Holly A Dubbs, Carl Fratter, Nicola Foulds, Candace Gamble, Ralitza H Gavrilova, Jaclyn Haven, Trevor L Hoffman, Jill V Hunter, Austin Larson, Timothy Edward Lotze, Pilar Magoulas, Emily C Magness, Debra M Bootin, Eric D Marsh, Victoria Nesbitt, Matthew T Pastore, Joanna Poulton, Shamima Rahman, Fernando Scaglia, Chaya Murali, Jennifer Posey, Joshua Rotenberg, Betsy Schmalz, Deepali N Shinde, Zöe Powis, Rivka Sukenik-Halevy, Kristen V Truxal, Tami Uster, Matheus Vernet Machado Bressan Wilke, Erik Klee, Hyewon Woo, Donald Younkin, Jianhua Zhao, Jorge Granadillo, Seema Lalani, David Chitayat, Wendy K Chung, Hudson H Freeze, Volkan Okur

Faculty, Staff and Students Publications

Purpose: Hexokinase 1 (HK1) encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presently, there are clinical data available for 27 individuals with the monoallelic neurodevelopmental disorder with visual defects and brain anomalies. Delineation of the entire phenotypic spectrum and genotype-phenotype relations will aid in management and counseling decisions.

Methods: We present molecular and clinical data on 22 additional individuals with heterozygous, mostly de novo, variants in HK1. We …

Monoallelic Expression Can Govern Penetrance Of Inborn Errors Of Immunity, O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema Van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters …

Genetic Landscape Of Hypertrophic Cardiomyopathy In Hong Kong Chinese Population, Derek P H Lee, Ye Cao, Lilei Zhang

Faculty, Staff and Students Publications

Introduction: Asian populations are underrepresented in the hypertrophic cardiomyopathy (HCM) genomic databases, which are currently largely dominated by Caucasian population. We aim to characterize the genetic landscape of HCM in patients from Hong Kong Chinese population.

Methods: From March 2023 to March 2024, fifty-three unrelated patients with an unequivocal clinical diagnosis of HCM were enrolled at a single tertiary center in Hong Kong and underwent genetic testing using a standardized 19-gene panel.

Results: In this cohort study, we identified 13 patients (24.5%) with a predominant pathogenic or likely pathogenic (P/LP) variant and 12 patients (22.6%) with a predominant variant of …

Correction: Genetic Landscape Of Hypertrophic Cardiomyopathy In Hong Kong Chinese Population, Derek P H Lee, Ye Cao, Lilei Zhang

Faculty, Staff and Students Publications

[This corrects the article DOI: 10.3389/fgene.2025.1583838.].

Whole Exome Sequencing As A Screening Tool In Dogs: A Pilot Study, Fréderique Boeykens, Evelien Bogaerts, Liesbeth Vossaert, Luc Peelman, Filip Van Nieuwerburgh, Jimmy H Saunders, Bart J G Broeckx

Faculty, Staff and Students Publications

Background: Whole-exome sequencing (WES) is used to selectively sequence all exons of protein-coding genes. WES is considered as a cost-effective and direct approach for identifying phenotype-associated variants in protein-coding regions and is as such situated between the traditional Sanger sequencing and whole genome sequencing (WGS). While WES is already widely used as a clinical tool in human and medical genetics, its use in veterinary medicine is currently restricted to research purposes. In this article, we aimed to provide baseline performance characteristics of a WES design to assess its suitability with future applications in veterinary clinical genetics in mind.

Methods: To …

Mixed-Methods Evaluation And Behavior Change Interventions To Improve Hand Hygiene Resources And Practices Among Healthcare Workers In Polyclinics And Health Centers In Belize, 2023, Anh N Ly, Kelsey Mcdavid, Christina Craig, Rosalva Blanco, Vickie Romero, Melissa Diaz-Musa, Francis Morey, Russell Manzanero, Gerhaldine Morazan, Makenzie Towery, Anna Impellitteri, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Background: Hand hygiene (HH) is an effective public health measure to prevent the spread of infections in healthcare settings. A previous study in Belize showed gaps in HH practices in hospitals and large polyclinics; however, there are limited national data assessing access to and use of HH resources in smaller outpatient primary care facilities, especially in rural areas.

Methods: In February 2023, facility assessments were conducted at 26 health centers and polyclinics in Belize to assess the availability of HH resources. Of these, 12 pilot healthcare facilities (HCF) were selected for additional evaluation, which included observation of HH practices, hand …

Experiences From Dual Genome Next-Generation Sequencing Panel Testing For Mitochondrial Disorders: A Comprehensive Molecular Diagnosis, Elizabeth Gorman, Hongzheng Dai, Yanming Feng, William James Craigen, David C Y Chen, Fan Xia, Linyan Meng, Pengfei Liu, Robert Rigobello, Arpita Neogi, Christine M Eng, Yue Wang

Faculty, Staff and Students Publications

Introduction: The molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.

Methods: Dual genome panel testing by NGS was performed on a cohort of 1,509 unrelated affected individuals with suspected mitochondrial disorders. This test included …

Variants In Washc3, A Component Of The Wash Complex, Cause Short Stature, Variable Neurodevelopmental Abnormalities, And Distinctive Facial Dysmorphism, Youn Hee Jee, Julian C Lui, Dana Marafi, Zhi-Jie Xia, Ruchika Bhatia, Elaine Zhou, Isabella Herman, Adrian Temnycky, Philip Whalen, Gene Elliot, Ellen W Leschek, Robin Wijngaard, Ronald Van Beek, Annemarie De Vreugd, Maaike C De Vries, Clara D M Van Karnebeek, Machteld M Oud, Thomas C Markello, Kevin M Barnes, Hadil Alrohaif, Hudson H Freeze, William A Gahl, May Christine V Malicdan, Jennifer E Posey, James R Lupski, Jeffrey Baron

Faculty, Staff and Students Publications

Purpose: Genetic defects that impair growth plate chondrogenesis cause a phenotype that varies from skeletal dysplasia to mild short stature with or without other syndromic features. In many individuals with impaired skeletal growth, the genetic causes remain unknown.

Method: Exome sequence was performed in 3 unrelated families with short stature, distinctive facies, and neurodevelopmental abnormalities. The impact of identified variants was studied in vitro.

Results: Exome sequencing identified variants in WASHC3, a component of the WASH complex. In the first family, a de-novo-dominant missense variant (p.L69F) impaired WASHC3 participation in the WASH complex, altered PTH1R endosomal trafficking, diminished PTH1R …

Examining Parents’ Perceptions Of Their Children’S Autism And Completion Of Genetic Testing, Georgina J Sakyi, Sarah S Mire, Robin P Goin-Kochel, Chaya N Murali, Susan X Day

Faculty, Staff and Students Publications

Though genetic testing is recommended for children diagnosed with autism spectrum disorder (ASD), both internal (e.g. parents’ and providers’ valuation of genetic testing) and external (e.g. insurance coverage) barriers exist, and exploration of these factors is required to close the gap between provider recommendations and parent follow-through. In a sample of 290 parents, we explored (a) how parents’ ASD-related etiological beliefs and symptom attributions, as well as income, affected genetic testing completion; and (b) whether these factors influence parents’ hopes or concerns about genetic testing. Principal component analysis (PCA) was used to investigate the factor structure of the ASD attribution …

Refining The Interpretation Of Variants Of Uncertain Significance In Hereditary Cancer Screening Through Integrated Rna Sequencing, Youbao Sha, J Bryce Ortiz, Sara L Bristow, Kate Loranger, Linyan Meng, Xiaonan Zhao, Fan Xia, Sheetal Parmar, Adam C Elnaggar, Wenbo Xu

Faculty, Staff and Students Publications

Purpose: Although up to 25% of germline variants are predicted to affect splicing, most are classified as variants of uncertain significance (VUS) because of the limited understanding of their functional consequences. Here, we investigated the impact of RNA sequencing (RNA-seq) data on the ability to resolve splicing-related VUS.

Methods: Patients with VUS predicted to alter splicing identified through commercial hereditary cancer testing between October 2021 to July 2023 were included. RNA-seq was used to compare splicing patterns between patient blood samples and normal controls. VUS reclassification rates were calculated.

Results: In total, 411 VUS in 52 genes predicted to affect …

Refining The Interpretation Of Variants Of Uncertain Significance In Hereditary Cancer Screening Through Integrated Rna Sequencing, Youbao Sha, J Bryce Ortiz, Sara L Bristow, Kate Loranger, Linyan Meng, Xiaonan Zhao, Fan Xia, Sheetal Parmar, Adam C Elnaggar, Wenbo Xu

Faculty, Staff and Students Publications

Purpose: Although up to 25% of germline variants are predicted to affect splicing, most are classified as variants of uncertain significance (VUS) because of the limited understanding of their functional consequences. Here, we investigated the impact of RNA sequencing (RNA-seq) data on the ability to resolve splicing-related VUS.

Methods: Patients with VUS predicted to alter splicing identified through commercial hereditary cancer testing between October 2021 to July 2023 were included. RNA-seq was used to compare splicing patterns between patient blood samples and normal controls. VUS reclassification rates were calculated.

Results: In total, 411 VUS in 52 genes predicted to affect …

Heterologous Prime-Pull Mucosal Vaccination With An Adjuvanted Rbd Vaccine Elicits Robust Iga Production And Protects Against Sars-Cov-2, Allyson H Hirsch, Calder R Ellsworth, William A Lewis, Ryan Craig, Amy E Meyer, Jonatan Maldonado, Frania Ramirez Lopez, Syamala Rani Thimmiraju, James B Mclachlan, Xuebin Qin, Nicholas J Maness, Jeroen Pollet, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Lisa A Morici

Faculty, Staff and Students Publications

Despite the efficacy of approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in preventing severe disease and death, breakthrough infections continue to occur in vaccinated individuals, contributing to further viral mutation and spread. These limitations may be attributable to the poor induction of mucosal immunity by parenteral vaccination. Mucosal adjuvants, such as T-vant, can enhance vaccine-induced immune responses through the generation of antigen-specific antibodies and T cells in the respiratory tract. In this study, we evaluated the protective efficacy of adjuvanted SARS-CoV-2 receptor binding domain (RBD) subunit vaccines administered by homologous and heterologous routes. Immunized mice were challenged with …

Mmrt: Multimut Recursive Tree For Predicting Functional Effects Of High-Order Protein Variants From Low-Order Variants, Bryce Forrest, Houssemeddine Derbel, Zhongming Zhao, Qian Liu

Faculty, Staff and Student Publications

Protein sequences primarily determine their stability and functions. Mutations may occur at one, two, or three positions at the same time (low-order variants) or at multiple positions simultaneously (high-order variants), which affect protein functions. So far, low-order variants, such as single variants, double variants, and triple variants, have been well-studied through high-throughput experimental scanning techniques and computational prediction methods. However, research on high-order variants remains limited because of the difficulty of scanning an exponentially large number of potential variant combinations. Nonetheless, studying higher-order variants is crucial for understanding the pathogenesis of complex diseases, advancing protein engineering, and driving precision medicine. …

Orthogonal And Multiplexable Genetic Perturbations With An Engineered Prime Editor And A Diverse Rna Array, Qichen Yuan, Hongzhi Zeng, Tyler C Daniel, Qingzhuo Liu, Yongjie Yang, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M Abramson, Boyang Zhang, Yong Xu, Xue Gao

Faculty, Staff and Students Publications

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation. mvGPT can precisely edit human genome via PE coupled with a prime editing guide RNA and a nicking guide RNA, activate endogenous gene expression …

Optimizing Ewing Sarcoma And Osteosarcoma Biopsy Acquisition: A Children's Oncology Group Bone Tumor Committee Consensus Statement, Matthew S Dietz, Alyaa Al-Ibraheemi, Jessica L Davis, C Matthew Hawkins, Brian T Craig, Roshni Dasgupta, David S Geller, David S Shulman, Sarah Cohen-Gogo, Ajay Gupta, Susan L Whiteway, Emily K Slotkin, Christine M Heske, Safia K Ahmed, Daniel J Indelicato, Catherine M Albert, Nicole Montgomery, Jesse K Sandberg, Holcombe E Grier, Mark Krailo, Michael S Isakoff, Elyssa Rubin, Elizabeth R Lawlor, Steven G Dubois, Leo Mascarenhas, Patrick J Grohar, Odion Binitie, Damon Reed, Katherine Janeway, Ryan D Roberts, Kelly M Bailey

Faculty, Staff and Students Publications

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and …

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 …

Osteogenesis Imperfecta: Skeletal And Non-Skeletal Challenges In Adulthood, Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C S Nagamani, Cathleen Raggio, Stuart H Ralston, Oliver Semler, Laura Tosi, Eric Orwoll

Faculty, Staff and Students Publications

Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which …

Persistent Growth-Promoting Effects Of Vosoritide In Children With Achondroplasia Are Accompanied By Improvements In Physical And Social Aspects Of Health-Related Quality Of Life, Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Klaus Mohnike, Carlos E Prada, Takuo Kubota, Paul Arundel, Antonio Leiva-Gea, Richard Rowell, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia.

Methods: Participants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766).

Results: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the Quality of Life of Short Stature Youth physical score (5.99 [19.41], caregiver reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 [22.64], respectively). Changes were greatest in participants with …

Families’ Experiences Accessing Care After Genomic Sequencing In The Pediatric Cancer Context: “It’S Just Been A Big Juggle”, Blake Vuocolo, Amanda M Gutierrez, Jill O Robinson, Alva M Recinos, Lauren R Desrosiers, Mary A Majumder, Juan Carlos Bernini, Jonathan Gill, Timothy Griffin, Gail E Tomlinson, Kelly Vallance, Amy L Mcguire, D Williams Parsons, Sharon E Plon, Sarah Scollon

Faculty, Staff and Students Publications

Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing …

Cocaine-Induced Dna-Dependent Protein Kinase Relieves Rnap Ii Pausing By Promoting Trim28 Phosphorylation And Rnap Ii Hyperphosphorylation To Enhance Hiv Transcription, Adhikarimayum Lakhikumar Sharma, Priya Tyagi, Meenata Khumallambam, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages …

Autoimmunity And The Epigenome, Jeffrey S. Miller Jr

The Cardinal Edge

No abstract provided.

Genomic Insights For Personalised Care In Lung Cancer And Smoking Cessation: Motivating At-Risk Individuals Toward Evidence-Based Health Practices, Tony Chen, Giang Pham, Louis Fox, Nina Adler, Xiaoyu Wang, Jingning Zhang, Jinyoung Byun, Younghun Han, Gretchen R B Saunders, Dajiang Liu, Michael J Bray, Alex T Ramsey, James Mckay, Laura J Bierut, Christopher I Amos, Rayjean J Hung, Xihong Lin, Haoyu Zhang, Li-Shiun Chen

Faculty, Staff and Students Publications

BACKGROUND: Lung cancer and tobacco use pose significant global health challenges, necessitating a comprehensive translational roadmap for improved prevention strategies such as cancer screening and tobacco treatment, which are currently under-utilised. Polygenic risk scores (PRSs) may further motivate health behaviour change in primary care for lung cancer in diverse populations. In this work, we introduce the GREAT care paradigm, which integrates PRSs within comprehensive patient risk profiles to motivate positive health behaviour changes.

METHODS: We developed PRSs using large-scale multi-ancestry genome-wide association studies and standardised PRS distributions across all ancestries. We validated our PRSs in 561,776 individuals of diverse ancestry …

Homozygous Variants In Wdr83os Lead To A Neurodevelopmental Disorder With Hypercholanemia, Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte Von Der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan

Faculty, Staff and Students Publications

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of …