Genetics and Genomics Commons^™

A Zika Virus Protein Expression Screen In Drosophila To Investigate Targeted Host Pathways During Development, Nichole Link, J Michael Harnish, Brooke Hull, Shelley Gibson, Miranda Dietze, Uchechukwu E Mgbike, Silvia Medina-Balcazar, Priya S Shah, Shinya Yamamoto

Faculty, Staff and Students Publications

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. Although adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of disease caused by this virus, which includes microcephaly. In this study, we generated a toolkit to ectopically express ZIKV proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We used this toolkit to identify phenotypes and potential host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins caused …

Deep Learning Prediction Boosts Phosphoproteomics-Based Discoveries Through Improved Phosphopeptide Identification, Xinpei Yi, Bo Wen, Shuyi Ji, Alexander B Saltzman, Eric J Jaehnig, Jonathan T Lei, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

Shotgun phosphoproteomics enables high-throughput analysis of phosphopeptides in biological samples. One of the primary challenges associated with this technology is the relatively low rate of phosphopeptide identification during data analysis. This limitation hampers the full realization of the potential offered by shotgun phosphoproteomics. Here we present DeepRescore2, a computational workflow that leverages deep learning-based retention time and fragment ion intensity predictions to improve phosphopeptide identification and phosphosite localization. Using a state-of-the-art computational workflow as a benchmark, DeepRescore2 increases the number of correctly identified peptide-spectrum matches by 17% in a synthetic dataset and identifies 19% to 46% more phosphopeptides in biological …

Association Between Regulatory T Cells And Ischemic Heart Disease: A Mendelian Randomization Study, Yucheng Hou, Ke Si, Jingyue Yang, Tan Liu, Basel Abdelazeem, Nonthikorn Theerasuwipakorn, Jingwei Zhao, Zhenya Shen

Faculty, Staff and Student Publications

BACKGROUND: An imbalance of innate and acquired immune responses is significantly involved in the pathophysiology of coronary atherosclerosis and the occurrence of ischemic heart disease (IHD). Regulatory T cells (Tregs) play an essential regulatory role in atherosclerotic plaque formation and maintenance; therefore, dysfunction of Tregs triggers the formation of atherosclerotic plaques and accelerates their progression. However, due to the inherent limitations of observational research, clinical evidence is limited concerning the relationship between the variation in peripheral Tregs and the risk of IHD, and the cause-and-effect relationship between these factors is unclear. Mendelian randomization (MR) uses genetic variation as a proxy …

Expression Of Atoh1, Gfi1, And Pou4f3 In The Mature Cochlea Reprograms Nonsensory Cells Into Hair Cells, Melissa M Mcgovern, Ishwar V Hosamani, Yichi Niu, Ken Y Nguyen, Chenghang Zong, Andrew K Groves

Faculty, Staff and Students Publications

Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate; consequently, loss of hair cells leads to permanent hearing loss. Although nonmammalian vertebrates can regenerate hair cells from neighboring supporting cells, many humans with severe hearing loss lack both hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of nonsensory cells. To determine whether the mature cochlea can produce hair cells in vivo, we reprogrammed nonsensory cells adjacent to the organ of Corti with three hair cell transcription factors: Gfi1, Atoh1, and Pou4f3. We generated numerous hair cell–like …

Frozen Tissue Coring And Layered Histological Analysis Improves Cell Type-Specific Proteogenomic Characterization Of Pancreatic Adenocarcinoma, Sara R Savage, Yuefan Wang, Lijun Chen, Scott Jewell, Chelsea Newton, Yongchao Dou, Qing Kay Li, Oliver F Bathe, Ana I Robles, Gilbert S Omenn, Mathangi Thiagarajan, Hui Zhang, Galen Hostetter, Bing Zhang

Faculty, Staff and Students Publications

BACKGROUND: Omics characterization of pancreatic adenocarcinoma tissue is complicated by the highly heterogeneous and mixed populations of cells. We evaluate the feasibility and potential benefit of using a coring method to enrich specific regions from bulk tissue and then perform proteogenomic analyses.

METHODS: We used the Biopsy Trifecta Extraction (BioTExt) technique to isolate cores of epithelial-enriched and stroma-enriched tissue from pancreatic tumor and adjacent tissue blocks. Histology was assessed at multiple depths throughout each core. DNA sequencing, RNA sequencing, and proteomics were performed on the cored and bulk tissue samples. Supervised and unsupervised analyses were performed based on integrated molecular …

Single-Cell Multiomics Decodes Regulatory Programs For Mouse Secondary Palate Development, Fangfang Yan, Akiko Suzuki, Chihiro Iwaya, Guangsheng Pei, Xian Chen, Hiroki Yoshioka, Meifang Yu, Lukas M Simon, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Perturbations in gene regulation during palatogenesis can lead to cleft palate, which is among the most common congenital birth defects. Here, we perform single-cell multiome sequencing and profile chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. We construct five trajectories representing continuous differentiation of cranial neural crest-derived multipotent cells into distinct lineages. By linking open chromatin signals to gene expression changes, we characterize the underlying lineage-determining transcription factors. In silico perturbation analysis identifies transcription factors SHOX2 and MEOX2 as important regulators …

Systematic Review Of Mortality And Survival Rates For Apds, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical …

Integrative Genomic Analyses Reveal Putative Cell Type-Specific Targets Of The Drosophila Ets Transcription Factor Pointed, Komal Kumar Bollepogu Raja, Kelvin Yeung, Yoon-Kyung Shim, Graeme Mardon

Faculty, Staff and Students Publications

The Ets domain transcription factors direct diverse biological processes throughout all metazoans and are implicated in development as well as in tumor initiation, progression and metastasis. The Drosophila Ets transcription factor Pointed (Pnt) is the downstream effector of the Epidermal growth factor receptor (Egfr) pathway and is required for cell cycle progression, specification, and differentiation of most cell types in the larval eye disc. Despite its critical role in development, very few targets of Pnt have been reported previously. Here, we employed an integrated approach by combining genome-wide single cell and bulk data to identify putative cell type-specific Pnt targets. …

Fusionnw, A Potential Clinical Impact Assessment Of Kinases In Pan-Cancer Fusion Gene Network, Chengyuan Yang, Himansu Kumar, Pora Kim

Faculty, Staff and Student Publications

Kinase fusion genes are the most active fusion gene group in human cancer fusion genes. To help choose the clinically significant kinase so that the cancer patients that have fusion genes can be better diagnosed, we need a metric to infer the assessment of kinases in pan-cancer fusion genes rather than relying on the sample frequency expressed fusion genes. Most of all, multiple studies assessed human kinases as the drug targets using multiple types of genomic and clinical information, but none used the kinase fusion genes in their study. The assessment studies of kinase without kinase fusion gene events can …

Sigma Leverages Protein Structural Information To Predict The Pathogenicity Of Missense Variants, Hengqiang Zhao, Huakang Du, Sen Zhao, Zefu Chen, Yaqi Li, Kexin Xu, Bowen Liu, Xi Cheng, Wen Wen, Guozhuang Li, Guilin Chen, Zhengye Zhao, Guixing Qiu, Deciphering Disorders Involving Scoliosis & Comorbidities (Disco) Study, Pengfei Liu, Terry Jianguo Zhang, Zhihong Wu, Nan Wu

Faculty, Staff and Students Publications

Leveraging protein structural information to evaluate pathogenicity has been hindered by the scarcity of experimentally determined 3D protein. With the aid of AlphaFold2 predictions, we developed the structure-informed genetic missense mutation assessor (SIGMA) to predict missense variant pathogenicity. In comparison with existing predictors across labeled variant datasets and experimental datasets, SIGMA demonstrates superior performance in predicting missense variant pathogenicity (AUC = 0.933). We found that the relative solvent accessibility of the mutated residue contributed greatly to the predictive ability of SIGMA. We further explored combining SIGMA with other top-tier predictors to create SIGMA+, proving highly effective for variant pathogenicity prediction …

Enabling The Clinical Application Of Artificial Intelligence In Genomics: A Perspective Of The Amia Genomics And Translational Bioinformatics Workgroup, Nephi A Walton, Radha Nagarajan, Chen Wang, Murat Sincan, Robert R Freimuth, David B Everman, Derek C Walton, Scott P Mcgrath, Dominick J Lemas, Panayiotis V Benos, Alexander V Alekseyenko, Qianqian Song, Ece Gamsiz Uzun, Casey Overby Taylor, Alper Uzun, Thomas Nate Person, Nadav Rappoport, Zhongming Zhao, Marc S Williams

Faculty, Staff and Student Publications

OBJECTIVE: Given the importance AI in genomics and its potential impact on human health, the American Medical Informatics Association-Genomics and Translational Biomedical Informatics (GenTBI) Workgroup developed this assessment of factors that can further enable the clinical application of AI in this space.

PROCESS: A list of relevant factors was developed through GenTBI workgroup discussions in multiple in-person and online meetings, along with review of pertinent publications. This list was then summarized and reviewed to achieve consensus among the group members.

CONCLUSIONS: Substantial informatics research and development are needed to fully realize the clinical potential of such technologies. The development of …

Novel Pan-Err Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism And Mitochondrial Function, Weiyi Xu, Cyrielle Billon, Hui Li, Andrea Wilderman, Lei Qi, Andrea Graves, Jernie Rae Dela Cruz Rideb, Yuanbiao Zhao, Matthew Hayes, Keyang Yu, Mckenna Losby, Carissa S Hampton, Christiana M Adeyemi, Seok Jae Hong, Eleni Nasiotis, Chen Fu, Tae Gyu Oh, Weiwei Fan, Michael Downes, Ryan D Welch, Ronald M Evans, Aleksandar Milosavljevic, John K Walker, Brian C Jensen, Liming Pei, Thomas Burris, Lilei Zhang

Faculty, Staff and Students Publications

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.

METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We …

Armc5 Controls The Degradation Of Most Pol Ii Subunits, And Armc5 Mutation Increases Neural Tube Defect Risks In Mice And Humans, Hongyu Luo, Linjiang Lao, Kit Sing Au, Hope Northrup, Xiao He, Diane Forget, Marie-Soleil Gauthier, Benoit Coulombe, Isabelle Bourdeau, Wei Shi, Lucia Gagliardi, Maria Candida Barisson Villares Fragoso, Junzheng Peng, Jiangping Wu

Faculty, Staff and Student Publications

BACKGROUND: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).

RESULTS: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi

Faculty, Staff and Students Publications

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function …

Exploiting The Carboxylate-Binding Pocket Of Β-Lactamase Enzymes Using A Focused Dna-Encoded Chemical Library, Suhyeorn Park, Jiayi Fan, Srinivas Chamakuri, Murugesan Palaniappan, Kiran Sharma, Xuan Qin, Jian Wang, Zhi Tan, Allison Judge, Liya Hu, Banumathi Sankaran, Feng Li, B V Venkataram Prasad, Martin M Matzuk, Timothy Palzkill

Faculty, Staff and Students Publications

β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the β-lactamase enzyme-substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 10

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Genome-Wide Study Investigating Effector Genes And Polygenic Prediction For Kidney Function In Persons With Ancestry From Africa And The Americas, Odessica Hughes, Amy R Bentley, Charles E Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M Lin, Thomas Gilliland, Mariah C Meyer, Jiawen Du, Laura M Raffield, Holly Kramer, Robert W Morton, Mateus H Gouveia, Elizabeth G Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C Jones, Charles Kooperberg, Jose E Krieger, Ethan M Lange, Matthew B Lanktree, James P Lash, Paulo A Lotufo, Ruth J F Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J Raffel, Stephen S Rich, Erik J Rodriquez, Eduardo Tarazona-Santos, Kent D Taylor, Jason G Umans, Jia Wen, Bessie A Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A Cole, April P Carson, Leslie A Lange, Yun Li, Eliseo J Perez-Stable, Ron Do, Fadi J Charchar, Maciej Tomaszewski, Josyf C Mychaleckyj, Charles Rotimi, Andrew P Morris, Nora Franceschini

Faculty, Staff and Students Publications

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10−8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

Variants In The Wdr44 Wd40-Repeat Domain Cause A Spectrum Of Ciliopathy By Impairing Ciliogenesis Initiation, Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A Rosenfeld, Seema R Lalani, Tiana M Scott, Daryl Scott, Mahshid S Azamian, Raymond Louie, Hannah W Moore, Neena L Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J Larsen, Suzanne Specht, Kylie J Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, Christopher J Westlake

Faculty, Staff and Students Publications

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of …

Contextualizing The Revised Patient Perception Of Patient-Centeredness (Pppc-R) Scale In Primary Healthcare Settings: A Validity And Reliability Evaluation Study, Yiyuan Cai, Pengfei Guo, Jiong Tu, Mengyao Hu, Lingrui Liu, Bridget L Ryan, Jing Liao, Rubee Dev, Yiran Li, Tianyu Huang, Ruilin Wang, Li Kuang, Ruonan Huang, Xinfang Li, Edmundo Roberto Melipillán, Shuaixiang Zhao, Wenjun He, Xiaohui Wang, Nan Zhang, Dong Roman Xu

Faculty, Staff and Student Publications

BACKGROUND: An English version of the Patient Perception of Patient-Centeredness (PPPC) scale was recently revised, and it is necessary to test this instrument in different primary care populations.

AIM: This study aimed to assess the validity and reliability of a Chinese version of the PPPC scale.

DESIGN: A mixed method was used in this study. The Delphi method was used to collect qualitative and quantitative data to address the content validity of the PPPC scale by calculating the Content Validity Index, Content Validity Ratio, the adjusted Kappa, and the Item Impact Score. Confirmatory factor analysis (CFA) and exploratory factor analysis …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

Factors Associated With Blood Mercury Concentrations And Their Interactions With Three Glutathione S-Transferase Genes (Gstt1, Gstm1, And Gstp1): An Exposure Assessment Study Of Typically Developing Jamaican Children, Sheikh Farzana Zaman, Maureen Samms-Vaughan, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L Grove, Sydonnie Shakespeare Pellington, Katherine A Loveland, Mohammad H Rahbar

Faculty, Staff and Student Publications

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms.

METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

The Use Of Cardiac Magnetic Resonance In Hypertrophic Cardiomyopathy Over The Past 10 Years [2013-2023]: A Citespace-Based Bibliometric Analysis, Mengyao Hu, Yu Shen, Yipei Song, Shuhao Li, Pei Yang, Ao Kan, Qiming Fang, Yun Peng, Haibo Ren, Yajing Zhang, Lianggeng Gong

Faculty, Staff and Student Publications

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder characterized by the hypertrophy of a segment of the myocardium. Cardiac magnetic resonance (CMR) has been widely used in the assessment of HCM. However, no bibliometric assessment has been conducted on the progress of research in this field. This study thus aimed to examine the current state of research into the application of CMR in HCM and the hotspots and trends that have emerged in this field over the past decade.

METHODS: A systematic search was conducted on the Web of Science regarding CMR in the assessment of HCM. The …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Harnessing Microrna-Enriched Extracellular Vesicles For Liquid Biopsy, Song Yi Ko, Wonjae Lee, Honami Naora

Faculty, Staff and Student Publications

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given …

Unraveling The Prognostic Significance Of Frgs Gene Family In Gastric Cancer And The Potential Implication Of Rgs4 In Regulating Tumor-Infiltrating Fibroblast, Yalan Yang, Siyuan Xing, Xi Luo, Lulu Guan, Yao Lu, Yiting Wang, Feng Wang

Faculty, Staff and Student Publications

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an …

Failure To Mate Enhances Investment In Behaviors That May Promote Mating Reward And Impairs The Ability To Cope With Stressors Via A Subpopulation Of Neuropeptide F Receptor Neurons, Julia Ryvkin, Liora Omesi, Yong-Kyu Kim, Mali Levi, Hadar Pozeilov, Lital Barak-Buchris, Bella Agranovich, Ifat Abramovich, Eyal Gottlieb, Avi Jacob, Dick R Nässel, Ulrike Heberlein, Galit Shohat-Ophir

Faculty, Staff and Student Publications

Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward …

Cffdna Screening For Niemann-Pick Disease, Type C1: A Case Series, Sydney A Lau, Romy I Fawaz, Robert Rigobello, Shahad Bawazeer, Nouf M Alajaji, Eissa Faqeih, Yanchun Li, Yanming Feng, Fan Xia, Christine M Eng, Malak Abedalthagafi

Faculty, Staff and Students Publications

Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or …

Case Report: An Association Of Left Ventricular Outflow Tract Obstruction With 5p Deletions, Kira Mascho, Svetlana A Yatsenko, Cecilia W Lo, Xinxiu Xu, Jennifer Johnson, Lindsey R Helvaty, Stephanie Burns Wechsler, Chaya N Murali, Seema R Lalani, Vidu Garg, Jennelle C Hodge, Kim L Mcbride, Stephanie M Ware, Jiuann-Huey Ivy Lin

Faculty, Staff and Students Publications

INTRODUCTION: 5p deletion syndrome, also called Cri-du-chat syndrome 5p is a rare genetic syndrome with reports up to 36% of patients are associated with congenital heart defects. We investigated the association between left outflow tract obstruction and Cri-du-chat syndrome.

METHODS: A retrospective review of the abnormal microarray cases with congenital heart defects in Children's Hospital of Pittsburgh and the Cytogenomics of Cardiovascular Malformations Consortium.

RESULTS: A retrospective review at nine pediatric centers identified 4 patients with 5p deletions and left outflow tract obstruction (LVOTO). Three of these patients had additional copy number variants. We present data suggesting an association of …

Human Plcg2 Haploinsufficiency Results In A Novel Natural Killer Cell Immunodeficiency, Joshua B Alinger, Emily M Mace, Justin R Porter, Annelise Y Mah-Som, Allyssa L Daugherty, Stephanie Li, Allison A Throm, Jeanette T Pingel, Nermina Saucier, Albert Yao, Ivan K Chinn, James R Lupski, Mohammad Ehlayel, Michael Keller, Greg R Bowman, Megan A Cooper, Jordan S Orange, Anthony R French

Faculty, Staff and Students Publications

Background:

Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in NK cells, lymphocytes which recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK cell and B cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date.

Objective:

We aimed to identify the genetic cause of NK cell immunodeficiency in two families, and herein describe the functional consequences of two novel loss-of-function …