Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Dolutegravir Induces Folr1 Expression During Brain Organoid Development, Carlo Donato Caiaffa, Gabriel Tukeman, Christian Zevallos Delgado, Yogeshwari S Ambekar, Taye T Mekonnen, Manmohan Singh, Victoria Rodriguez, Emily Ricco, Daniel Kraushaar, Salavat R Aglyamov, Giuliano Scarcelli, Kirill V Larin, Richard H Finnell, Robert M Cabrera

Faculty, Staff and Students Publications

During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have …

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Yosi Gilad, Ortal Shimon, Sang Jun Han, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in …

Identification Of Constrained Sequence Elements Across 239 Primate Genomes, Lukas F K Kuderna, Jacob C Ulirsch, Sabrina Rashid, Mohamed Ameen, Laksshman Sundaram, Glenn Hickey, Anthony J Cox, Hong Gao, Arvind Kumar, Francois Aguet, Matthew J Christmas, Hiram Clawson, Maximilian Haeussler, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Ioannis Karakikes, Kevin C Wang, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Adam Siepel, Anshul Kundaje, Benedict Paten, Kerstin Lindblad-Toh, Jeffrey Rogers, Tomas Marques Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of …

Scientific Impact Of The National Birth Defects Prevention Network Multistate Collaborative Publications, Jacqueline T Bascom, Sara B Stephens, Philip J Lupo, Mark A Canfield, Russell S Kirby, Eirini Nestoridi, Jason L Salemi, Cara T Mai, Wendy N Nembhard, Nina E Forestieri, Paul A Romitti, Amanda M St Louis, A J Agopian

Faculty, Staff and Students Publications

BACKGROUND: Given the lack of a national, population-based birth defects surveillance program in the United States, the National Birth Defects Prevention Network (NBDPN) has facilitated important studies on surveillance, research, and prevention of major birth defects. We sought to summarize NBDPN peer-reviewed publications and their impact.

METHODS: We obtained and reviewed a curated list of 49 NBDPN multistate collaborative publications during 2000-2022, as of December 31, 2022. Each publication was reviewed and classified by type (e.g., risk factor association analysis). Key characteristics of study populations and analytic approaches used, along with publication impact (e.g., number of citations), were tabulated.

RESULTS: …

A Comprehensive Analysis Of Neuroblastoma Incidence, Survival, And Racial And Ethnic Disparities From 2001 To 2019, Kevin Campbell, David A Siegel, Puja J Umaretiya, Shifan Dai, Andras Heczey, Philip J Lupo, Jeremy M Schraw, Trevor D Thompson, Michael E Scheurer, Jennifer H Foster

Faculty, Staff and Students Publications

BACKGROUND: We characterize the incidence and 5-year survival of children and adolescents with neuroblastoma stratified by demographic and clinical factors based on the comprehensive data from United States Cancer Statistics (USCS) and the National Program of Cancer Registries (NPCR).

METHODS: We analyzed the incidence of neuroblastoma from USCS (2003-2019) and survival data from NPCR (2001-2018) for patients less than 20 years old. Incidence trends were calculated by average annual percent change (AAPC) using joinpoint regression. Differences in relative survival were estimated comparing non-overlapping confidence intervals (CI).

RESULTS: We identified 11,543 primary neuroblastoma cases in USCS. Age-adjusted incidence was 8.3 per …

Neutrophil-Derived Activin-A Moderates Their Pro-Netotic Activity And Attenuates Collateral Tissue Damage Caused By Influenza A Virus Infection, Georgios Divolis, Evgenia Synolaki, Athanasia Doulou, Ariana Gavriil, Christina C Giannouli, Anastasia Apostolidou, Martyn L Foster, Martin M Matzuk, Panagiotis Skendros, Ioanna-Evdokia Galani, Paschalis Sideras

Faculty, Staff and Students Publications

BACKGROUND: Pre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood.

METHODS:To address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhba fl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, …

Developing A Pathway To Clinical Trials For Cacna1a-Related Epilepsies: A Patient Organization Perspective, Pangkong M Fox, Sunitha Malepati, Lisa Manaster, Elsa Rossignol, Jeffrey L Noebels

Faculty, Staff and Students Publications

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function …

Spatial Transcriptomics Resolve An Emphysema-Specific Lymphoid Follicle B Cell Signature In Chronic Obstructive Pulmonary Disease, Joselyn Rojas-Quintero, Scott A Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E Banovich, Ivan O Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J Mckenna, Francesca Polverino

Faculty, Staff and Students Publications

Rationale

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.

Objectives

To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema.

Methods

Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. …

Idppub: Illuminating The Dark Phosphoproteome Through Pubmed Mining, Sara R Savage, Yaoyun Zhang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Huy Anh Pham, Hua Xu, Bing Zhang

Faculty, Staff and Students Publications

Global phosphoproteomics experiments quantify tens of thousands of phosphorylation sites. However, data interpretation is hampered by our limited knowledge on functions, biological contexts, or precipitating enzymes of the phosphosites. This study establishes a repository of phosphosites with associated evidence in biomedical abstracts, using deep learning-based natural language processing techniques. Our model for illuminating the dark phosphoproteome through PubMed mining (IDPpub) was generated by fine-tuning BioBERT, a deep learning tool for biomedical text mining. Trained using sentences containing protein substrates and phosphorylation site positions from 3000 abstracts, the IDPpub model was then used to extract phosphorylation sites from all MEDLINE abstracts. …

Mitochondrial-Related Hub Genes In Dermatomyositis: Muscle And Skin Datasets-Based Identification And In Vivo Validation, Shuo Wang, Yiping Tang, Xixi Chen, Siyuan Song, Xi Chen, Qiao Zhou, Li Zeng

Faculty, Staff and Students Publications

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of dermatomyositis (DM), a rare autoimmune disease affecting the skin and muscles. However, the genetic basis underlying dysfunctional mitochondria and the development of DM remains incomplete.

Methods: The datasets of DM muscle and skin tissues were retrieved from the Gene Expression Omnibus database. The mitochondrial related genes (MRGs) were retrieved from MitoCarta. DM-related modules in muscle and skin tissues were identified with the analysis of weighted gene co-expression network (WGCNA), and then compared with the MRGs to obtain the overlapping mitochondrial related module genes (mito-MGs). Subsequently, differential expression genes (DEGs) obtained …

Prevalence Of Congenital Anomalies According To Maternal Race And Ethnicity, Texas, 1999–2018, Jeremy M Schraw, Elwin Jaime, Charles J Shumate, Mark A Canfield, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: Few studies of congenital anomalies provide prevalence estimates stratified by maternal race/ethnicity. We sought to determine whether the prevalence of a broad spectrum of anomalies varies among offspring of women from different race/ethnic groups.

METHODS: We obtained information on cases with anomalies from the population-based Texas Birth Defects Registry, and denominator data on livebirths among Texas residents during 1999-2018 from the Texas Center for Health Statistics. We estimated the prevalence ratio (PR) and 95% confidence interval (CI) of N = 145 anomalies among offspring of Hispanic and non-Hispanic Black relative to non-Hispanic White women using Poisson regression, adjusting for …

Effects And Plasma Proteomic Analysis Of Glp-1ra Versus Cpa/Ee, In Combination With Metformin, On Overweight Pcos Women: A Randomized Controlled Trial, Mingyu Liao, Xing Li, Hao Zhang, Ling Zhou, Liu Shi, Weixin Li, Rufei Shen, Guiliang Peng, Huan Zhao, Jiaqing Shao, Xiujie Wang, Zheng Sun, Hongting Zheng, Min Long

Faculty, Staff and Students Publications

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS.

METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-μg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. …

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 …

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 …

Comparative Exploration Of Mammalian Deafness Gene Homologues In The Drosophila Auditory Organ Shows Genetic Correlation Between Insect And Vertebrate Hearing, Daniel C Sutton, Jonathan C Andrews, Dylan M Dolezal, Ye Jin Park, Hongjie Li, Daniel F Eberl, Shinya Yamamoto, Andrew K Groves

Faculty, Staff and Students Publications

Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to …

Improved Sequence Mapping Using A Complete Reference Genome And Lift-Over, Nae-Chyun Chen, Luis F Paulin, Fritz J Sedlazeck, Sergey Koren, Adam M Phillippy, Ben Langmead

Faculty, Staff and Students Publications

Complete, telomere-to-telomere genome assemblies promise improved analyses and the discovery of new variants, but many essential genomic resources remain associated with older reference genomes. Thus, there is a need to translate genomic features and read alignments between references. Here we describe a new method called levioSAM2 that accounts for reference changes and performs fast and accurate lift-over between assemblies using a whole-genome map. In addition to enabling the use of multiple references, we demonstrate that aligning reads to a high-quality reference (e.g. T2T-CHM13) and lifting to an older reference (e.g. GRCh38) actually improves the accuracy of the resulting variant calls …

Case Report: P40phox Deficiency Underlying Pediatric-Onset Systemic Lupus Erythematosus, Alejandro Nieto-Patlán, Natalia S Fernández Dávila, Yuqing Wang, Michelle Zelnick, Eyal Muscal, Martha Curry, James R Lupski, Steven M Holland, Bo Yuan, Douglas B Kuhns, Tiphanie P Vogel, Ivan K Chinn

Faculty, Staff and Students Publications

Introduction

Systemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40^phox deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells.

Case presentation

We report the case of a now 18-year-old female with pSLE onset at 7 years of age. She presented with recurrent fever and malar rash. Aspects of her immune dysregulation over time have included typical pSLE …

Tracking Updates In Clinical Databases Increases Efficiency For Variant Reanalysis, Lele Li, Xia Tian, Vaughan Woodzell, Richard A Gibbs, Bo Yuan, Eric Venner

Faculty, Staff and Students Publications

PURPOSE: Variant interpretation, guided by American College of Medical Genetics and Genomics guidelines, can inform clinical decision-making. However, interpretations may change over time for a variety of reasons. Periodic reanalysis of previous variant interpretations is important to ensure that reported genetic findings remain accurate according to current knowledge.

METHODS: We performed automated filtering by comparing ClinVar variants available in August 2020 with those from August 2021 to screen for potential reanalysis candidates from 3 projects. These variants were subsequently interpreted based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology variant interpretation guideline or ClinGen revised gene-specific …

Prospective Associations Of Psychedelic Treatment For Co-Occurring Alcohol Misuse And Posttraumatic Stress Symptoms Among United States Special Operations Forces Veterans, Stacey B Armstrong, Yitong Xin, Nathan D Sepeda, Martín Polanco, Lynnette A Averill, Alan K Davis

Faculty, Staff and Students Publications

This study evaluated prospective associations of ibogaine and 5-MeO-DMT treatment for risky alcohol use and post-traumatic stress disorder (PTSD) symptoms among United States (US) Special Operations Forces Veterans (SOFV). Data were collected during standard clinical operations at pre-treatment and 1-month (1 m), 3-months (3 m), and 6-months (6 m) post-treatment in an ibogaine and 5-MeO-DMT treatment program in Mexico. Of the 86 SOFV that completed treatment, 45 met criteria for risky alcohol use at pre-treatment (mean age = 44; male = 100%; White = 91%). There was a significant reduction in alcohol use from pre-treatment (M = 7.2, SD = …

Research Participants' Perspectives On Precision Diagnostics For Alzheimer's Disease, Hadley Stevens Smith, Jill O Robinson, Ariel Levchenko, Stacey Pereira, Belen Pascual, Kathleen Bradbury, Victoria Arbones, Jamie Fong, Joshua M Shulman, Amy L Mcguire, Joseph Masdeu

Faculty, Staff and Students Publications

BACKGROUND: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies.

OBJECTIVE: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk.

METHODS: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses …

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 …

Succinic Semialdehyde Dehydrogenase Deficiency: A Metabolic And Genomic Approach To Diagnosis, Kevin E Glinton, Charul Gijavanekar, Abbhirami Rajagopal, Laura P Mackay, Kirt A Martin, Phillip L Pearl, K Michael Gibson, Theresa A Wilson, V Reid Sutton, Sarah H Elsea

Faculty, Staff and Students Publications

Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in

Blind To The Perils Of Pursuing Food: Behaviors Of Individuals With Smith-Magenis Syndrome, Citrine Elatrash, Jenna Shi, Theresa Wilson, Sarah H Elsea, Stephanie Sisley

Faculty, Staff and Students Publications

PURPOSE: Discrepancies exist between the need to lock food away and satiety scores in the Smith-Magenis syndrome (SMS) population. This study sought to uncover food-related behaviors within this unique group of individuals.

METHODS: Caregivers (

RESULTS: This study identified a global theme of "Blind to the perils while pursuing their goals," supported by 5 organizing themes: (1) Biology-impacting behaviors, (2) Need for personalized strategies, (3) Controlling food experiences, (4) Need for parents to orchestrate life, and (5) Surprising resourcefulness. Subthemes within these organizing themes highlighted that individuals with SMS have unique food-related behaviors and often fixate on certain types of …

De Novo Missense Variants In Zbtb47 Are Associated With Developmental Delays, Hypotonia, Seizures, Gait Abnormalities, And Variable Movement Abnormalities, Scott K Ward, Alexandrea Wadley, Chun-Hui Anne Tsai, Paul J Benke, Lisa Emrick, Kristen Fisher, Kimberly M Houck, Hongzheng Dai, Undiagnosed Diseases Network, Maria J Guillen Sacoto, William Craigen, Kimberly Glaser, David R Murdock, Luis Rohena, Karin E M Diderich, Hennie T Bruggenwirth, Brendan Lee, Carlos Bacino, Lindsay C Burrage, Jill A Rosenfeld

Faculty, Staff and Students Publications

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected …

The Challenges And Opportunities Of Offering And Integrating Training In Clinical Molecular Genetics And Clinical Cytogenetics: A Survey Of Lgg Fellowship Program Directors, Joshua L Deignan, Vimla Aggarwal, Allen E Bale, Daniel B Bellissimo, Jessica K Booker, Yang Cao, Kristy R Crooks, Kristen L Deak, Daniela Del Gaudio, Birgit Funke, Nicole L Hoppman, Vanessa Horner, Robert B Hufnagel, Colleen Jackson-Cook, Prasad Koduru, Marco L Leung, Shibo Li, Pengfei Liu, Minjie Luo, Rong Mao, Heather Mason-Suares, Fady M Mikhail, Stephen R Moore, Rizwan C Naeem, Laura M Pollard, Elena A Repnikova, Lina Shao, Brandon M Shaw, Shashirekha Shetty, Teresa A Smolarek, Elizabeth Spiteri, Jessica Van Ziffle, Gail H Vance, Cindy L Vnencak-Jones, Eli S Williams

Faculty, Staff and Students Publications

PURPOSE: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model.

METHODS: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time. The data …

International Society For Extracellular Vesicles Workshop Quantitatevs: Multiscale Analyses, From Bulk To Single Extracellular Vesicle, Manuela Basso, Alessandro Gori, Caterina Nardella, Mari Palviainen, Marija Holcar, Ioannis Sotiropoulos, Sylwia Bobis-Wozowicz, Vito G D'Agostino, Elena Casarotto, Yari Ciani, Shiro Suetsugu, Alice Gualerzi, Lorena Martin-Jaular, Daniela Boselli, Anna Kashkanova, Pietro Parisse, Lien Lippens, Martina Pagliuca, Martin Blessing, Roberto Frigerio, Thibaut Fourniols, Ana Meliciano, Anna Fietta, Paolo Vincenzo Fioretti, Karolina Soroczyńska, Silvia Picciolini, Amanda Salviano-Silva, Paolo Bergese, Davide Zocco, Marcella Chiari, Guido Jenster, Levi Waldron, Aleksandar Milosavljevic, John Nolan, Marco P Monopoli, Kenneth W Witwer, Benedetta Bussolati, Dolores Di Vizio, Juan Falcon Perez, Metka Lenassi, Marina Cretich, Francesca Demichelis

Faculty, Staff and Students Publications

The “QuantitatEVs: multiscale analyses, from bulk to single vesicle” workshop aimed to discuss quantitative strategies and harmonized wet and computational approaches toward the comprehensive analysis of extracellular vesicles (EVs) from bulk to single vesicle analyses with a special focus on emerging technologies. The workshop covered the key issues in the quantitative analysis of different EV‐associated molecular components and EV biophysical features, which are considered the core of EV‐associated biomarker discovery and validation for their clinical translation. The in‐person‐only workshop was held in Trento, Italy, from January 31st to February 2nd, 2023, and continued in Milan on February 3rd with “Next …

Parkinson's Disease And Other Alzheimer's Disease And Related Dementia Pathologies And The Progression Of Parkinsonism In Older Adults, Aron S Buchman, Lei Yu, Shahram Oveisgharan, Andrea R Zammit, Tianhao Wang, Joshua M Shulman, Veronique Vanderhorst, Sukrit Nag, David A Bennett

Faculty, Staff and Students Publications

BACKGROUND: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear.

OBJECTIVE: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies.

METHODS: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined …

Regulatory Elements In Sem1-Dlx5-Dlx6 (7q213) Locus Contribute To Genetic Control Of Coronal Nonsyndromic Craniosynostosis And Bone Density-Related Traits, Paola Nicoletti, Samreen Zafer, Lital Matok, Inbar Irron, Meidva Patrick, Rotem Haklai, John Erol Evangelista, Giacomo B Marino, Avi Ma'ayan, Anshuman Sewda, Greg Holmes, Sierra R Britton, Won Jun Lee, Meng Wu, Ying Ru, Eric Arnaud, Lorenzo Botto, Lawrence C Brody, Jo C Byren, Michele Caggana, Suzan L Carmichael, Deirdre Cilliers, Kristin Conway, Karen Crawford, Araceli Cuellar, Federico Di Rocco, Michael Engel, Jeffrey Fearon, Marcia L Feldkamp, Richard Finnell, Sarah Fisher, Christian Freudlsperger, Gemma Garcia-Fructuoso, Rhinda Hagge, Yann Heuzé, Raymond J Harshbarger, Charlotte Hobbs, Meredith Howley, Mary M Jenkins, David Johnson, Cristina M Justice, Alex Kane, Denise Kay, Arun Kumar Gosain, Peter Langlois, Laurence Legal-Mallet, Angela E Lin, James L Mills, Jenny E V Morton, Peter Noons, Andrew Olshan, John Persing, Julie M Phipps, Richard Redett, Jennita Reefhuis, Elias Rizk, Thomas D Samson, Gary M Shaw, Robert Sicko, Nataliya Smith, David Staffenberg, Joan Stoler, Elizabeth Sweeney, Peter J Taub, Andrew T Timberlake, Jolanta Topczewska, Steven A Wall, Alexander F Wilson, Louise C Wilson, Simeon A Boyadjiev, Andrew O M Wilkie, Joan T Richtsmeier, Ethylin Wang Jabs, Paul A Romitti, David Karasik, Ramon Y Birnbaum, Inga Peter

Faculty, Staff and Students Publications

PURPOSE: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown.

METHODS: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model.

RESULTS: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine …

Inference Of Phylogenetic Trees Directly From Raw Sequencing Reads Using Read2tree, David Dylus, Adrian Altenhoff, Sina Majidian, Fritz J Sedlazeck, Christophe Dessimoz

Faculty, Staff and Students Publications

Current methods for inference of phylogenetic trees require running complex pipelines at substantial computational and labor costs, with additional constraints in sequencing coverage, assembly and annotation quality, especially for large datasets. To overcome these challenges, we present Read2Tree, which directly processes raw sequencing reads into groups of corresponding genes and bypasses traditional steps in phylogeny inference, such as genome assembly, annotation and all-versus-all sequence comparisons, while retaining accuracy. In a benchmark encompassing a broad variety of datasets, Read2Tree is 10-100 times faster than assembly-based approaches and in most cases more accurate-the exception being when sequencing coverage is high and reference …

Folate Regulation Of Planar Cell Polarity Pathway And F-Actin Through Folate Receptor Alpha, Xiao Han, Xuanye Cao, Robert M Cabrera, Paula Andrea Pimienta Ramirez, Ying Linda Lin, Bogdan J Wlodarczyk, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, Folic acid (FA) and 5-methyltetrahydrofolate(5mTHF), at concentration of 5uM, 500nM, 50nM and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages and cell proliferation and F-actin was monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and …