Medical Molecular Biology Commons^™

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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. …

Neuronal Ablation Of Ghsr Mitigates Diet-Induced Depression And Memory Impairment Via Ampk-Autophagy Signaling-Mediated Inflammation, Hongying Wang, Zheng Shen, Chia-Shan Wu, Pengfei Ji, Ji Yeon Noh, Cédric G Geoffroy, Sunja Kim, David Threadgill, Jianrong Li, Yu Zhou, Xiaoqiu Xiao, Hui Zheng, Yuxiang Sun

Faculty, Staff and Students Publications

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the …

Phenotypic And Functional Assessment Of Two Novel Kcnq2 Gain-Of-Function Variants Y141n And G239s And Effects Of Amitriptyline Treatment, Allan Bayat, Stefano Iavarone, Francesco Miceli, Anne V Jakobsen, Katrine M Johannesen, Marina Nikanorova, Rafal Ploski, Krystyna Szymanska, Robert Flamini, Edward C Cooper, Sarah Weckhuysen, Maurizio Taglialatela, Rikke S Møller

Faculty, Staff and Students Publications

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell …

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: …

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 …

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 …

Combined Bioinformatic And Splicing Analysis Of Likely Benign Intronic And Synonymous Variants Reveals Evidence For Pathogenicity, Owen R Hirschi, Stephanie A Felker, Surya P Rednam, Kelly L Vallance, D Williams Parsons, Angshumoy Roy, Gregory M Cooper, Sharon E Plon

Faculty, Staff and Students Publications

PURPOSE: Clinical variant analysis pipelines likely have poor sensitivity to the effects on splicing from variants beyond 10 to 20 bases of exon-intron boundaries. Here, we demonstrate the value of SpliceAI to inform curation of rare variants previously classified as benign/likely benign (B/LB) under current guidelines.

METHODS: Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored >10 by combined annotation-dependent depletion. Rare synonymous or intronic B/LB variants in 61 genes submitted to ClinVar were …

Twenty Years Of Epithelial-Mesenchymal Transition: A State Of The Field From Temtia X, Pierre Savagner, Thomas Brabletz, Chonghui Cheng, Christine Gilles, Tian Hong, Myriam Polette, Guojun Sheng, Marc P Stemmler, Erik W Thompson

Faculty, Staff and Students Publications

This report summarizes the 10th biennial meeting of The Epithelial Mesenchymal Transition International Association (TEMTIA), that took place in Paris on November 7-10, 2022. It provides a short but comprehensive introduction to the presentations and discussions that took place during the 3-day meeting. Similarly to previous TEMTIA meetings, TEMTIA X reviewed the most recent aspects of the epithelial-mesenchymal transition (EMT), a cellular process involved during distinct stages of development but also during wound healing and fibrosis to some degree. EMT has also been associated at various levels during tumor cell progression and metastasis. The meeting emphasized the intermediate stages of …

Pretreatment Characteristics Associated With Symptom Reduction During Group Cognitive Processing Therapy Versus Exposure Therapy For Ptsd: An Exploratory Study Of Veterans, Christopher Hunt, Brooks Casas, Pearl H Chiu, Lia J Smith, Laura Priorello, Kelly Lee, Matthew Estey, Mary R Newsome, M Wright Williams

Faculty, Staff and Students Publications

Exposure and cognitive-based therapies are both effective for PTSD, but knowledge of which intervention is best for which patient is lacking. This lack of knowledge is particularly noticeable for group treatments, as no study has examined whether responses to different group therapies are associated with different pretreatment characteristics. Here, we explored whether pretreatment levels of three types of psychological characteristics-PTSD symptom clusters, posttraumatic cognitions, and emotion regulation difficulties-were associated with symptom reduction during group-delivered cognitive versus exposure-based PTSD treatment. Participants were Veterans with PTSD drawn from two previous clinical trials: one of group CPT (GCPT;

Continuing Education And Professional Development: Unifying Opportunities For Genetic Counselors Globally, Kathleen D Valverde, Tiffiney R Hartman, Sara L Reichert, Robin L Bennett, Martha Dudek, Debra Duquette, Daniel Riconda, Nancy J Cox, Gail P Jarvik, Sarah H Elsea, Elizabeth M Mcnally, Kim C Worley, Daniel J Rader

Faculty, Staff and Students Publications

No abstract provided.