Medical Genetics Commons^™

Research For All: Building A Diverse Researcher Community For The All Of Us Research Program, Rubin Baskir, Minnkyong Lee, Sydney J Mcmaster, Jessica Lee, Faith Blackburne-Proctor, Romuladus Azuine, Nakia Mack, Sheri D Schully, Martin Mendoza, Janeth Sanchez, Yong Crosby, Erica Zumba, Michael Hahn, Naomi Aspaas, Ahmed Elmi, Shanté Alerté, Elizabeth Stewart, Danielle Wilfong, Meag Doherty, Margaret M Farrell, Grace B Hébert, Sula Hood, Cheryl M Thomas, Debra D Murray, Brendan Lee, Louisa A Stark, Megan A Lewis, Jen D Uhrig, Laura R Bartlett, Edgar Gil Rico, Adolph Falcón, Elizabeth Cohn, Mitchell R Lunn, Juno Obedin-Maliver, Linda Cottler, Milton Eder, Fornessa T Randal, Jason Karnes, Kitani Lemieux, Nelson Lemieux, Nelson Lemieux, Lilanta Bradley, Ronnie Tepp, Meredith Wilson, Monica Rodriguez, Chris Lunt, Karriem Watson

Faculty, Staff and Students Publications

OBJECTIVES: The NIH All of Us Research Program (All of Us) is engaging a diverse community of more than 10 000 registered researchers using a robust engagement ecosystem model. We describe strategies used to build an ecosystem that attracts and supports a diverse and inclusive researcher community to use the All of Us dataset and provide metrics on All of Us researcher usage growth.

MATERIALS AND METHODS: Researcher audiences and diversity categories were defined to guide a strategy. A researcher engagement strategy was codeveloped with program partners to support a researcher engagement ecosystem. An adapted ecological model guided the ecosystem …

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 …

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 …

Bayesian Covariate-Dependent Circadian Modeling Of Rest-Activity Rhythms, Beniamino Hadj-Amar, Vaishnav Krishnan, Marina Vannucci

Faculty, Staff and Students Publications

We propose a Bayesian covariate-dependent anti-logistic circadian model for analyzing activity data collected via wrist-worn wearable devices. The proposed approach integrates covariates into the modeling of the amplitude and phase parameters, facilitating cohort-level analysis with enhanced flexibility and interpretability. To promote model sparsity, we employ an l1-ball projection prior, enabling precise control over complexity while identifying significant predictors. We assess performances on simulated data and then apply the method to real-world actigraphy data from people with epilepsy. Our results demonstrate the model’s effectiveness in uncovering complex relationships among demographic, psychological, and medical factors influencing rest-activity rhythms, offering insights for …

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 …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Jesse D Bengtsson, Sameer S Bajikar, Christopher M Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J Trostle, Holly K Harris, Bernhard Suter, Sukru Aras, Melissa B Ramocki, Haowei Du, Michele G Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S Shinawi, Virginia E Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M Vianna-Morgante, Alberto S Cornier, Ahmed Abdelmoity, James P Hwang, Shalini N Jhangiani, Donna M Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G Glaze, Jawid M Fatih, Richard A Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J Sedlazeck, James R Lupski, Huda Y Zoghbi, Claudia M B Carvalho

Faculty, Staff and Students Publications

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

5-Fluorouracil Induced Oxidative Stress Is Variable Across Triple Negative Breast Cancer Cell Lines, Rachel L. Walker

Departmental Honors & Graduate Capstone Projects

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with treatment limited to chemotherapy. However, not all patient tumors respond to chemotherapy. The variable cytotoxic effects of chemotherapies may be due to how cancer cells regulate reactive oxygen species (ROS). In this study, we examined two mouse breast cancer cell lines: 4T1 and EO771, vary when treated with hydrogen peroxide (H2O2) and 5-Fluorouracil (5FU), known ROS-inducing substances. In 4T1 cells H2O2 increased oxidized DNA but caused minimal cell death. While in EO771 cells that same amount of H2O2 caused complete apoptosis. Cell number, ROS, and cell death showed …

Using Multiplexed Functional Data To Reduce Variant Classification Inequities In Underrepresented Populations, Moez Dawood, Shawn Fayer, Sriram Pendyala, Mason Post, Divya Kalra, Karynne Patterson, Eric Venner, Lara A Muffley, Douglas M Fowler, Alan F Rubin, Jennifer E Posey, Sharon E Plon, James R Lupski, Richard A Gibbs, Lea M Starita, Carla Daniela Robles-Espinoza, Willow Coyote-Maestas, Irene Gallego Romero

Faculty, Staff and Students Publications

BACKGROUND: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).

METHODS: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN.

RESULTS: Using two orthogonal statistical approaches, we …

Onset And Progression Of Disease In Nonhuman Primates With Pde6c Cone Disorder, Monica Ardon, Lily Nguyen, Rui Chen, Jeffrey Rogers, Tim Stout, Sara Thomasy, Ala Moshiri

Faculty, Staff and Students Publications

PURPOSE: The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time.

METHODS: We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 …

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 …

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 …

Rfc2 May Contribute To The Pathogenicity Of Williams Syndrome Revealed In A Zebrafish Model, Ji-Won Park, Tae-Ik Choi, Tae-Yoon Kim, Yu-Ri Lee, Dilan Wellalage Don, Jaya K George-Abraham, Laurie A Robak, Cristina C Trandafir, Pengfei Liu, Jill A Rosenfeld, Tae Hyeong Kim, Florence Petit, Yoo-Mi Kim, Chong Kun Cheon, Yoonsung Lee, Cheol-Hee Kim

Faculty, Staff and Students Publications

Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb-1.5 Mb microdeletions that include RFC2, as well as one patient with a 167-kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate …

A Proteome-Wide Association Study Identifies Putative Causal Proteins For Breast Cancer Risk, Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Jill E Henry, Bing Zhang, Xingyi Guo, Michele L Cote, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long

Faculty, Staff and Students Publications

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk.

METHODS: We profiled the proteome in fresh frozen breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank (KTB). Protein expression levels were log2-transformed then normalized via quantile and inverse-rank transformations. GWAS data were also generated for …

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

Faculty, Staff and Students Publications

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …

Development And Evaluation Of A Training Curriculum To Engage Researchers On Accessing And Analyzing The All Of Us Data, Julie R Coleman, Jasmine N Baker, Shamika Ketkar, Ashley M Butler, Laterrica Williams, Latanya Hammonds-Odie, Elizabeth G Atkinson, Debra D Murray, Brendan Lee, Kim C Worley

Faculty, Staff and Students Publications

OBJECTIVE: The All of Us Evenings with Genetics (EwG) Research Program at Baylor College of Medicine (BCM), funded to engage research scholars to work with the All of Us data, developed a training curriculum for the Researcher Workbench, the platform to access and analyze All of Us data. All of Us EwG developed the curriculum so that it could teach scholars regardless of their skills and background in programming languages and cloud computing. All of Us EwG delivered this curriculum at the first annual All of Us EwG Faculty Summit in May 2022. The curriculum was evaluated both during and …

Steering Research On Mrna Splicing In Cancer Towards Clinical Translation, Olga Anczukow, Frédéric H-T Allain, Brittany L Angarola, Douglas L Black, Angela N Brooks, Chonghui Cheng, Ana Conesa, Edie I Crosse, Eduardo Eyras, Ernesto Guccione, Sydney X Lu, Karla M Neugebauer, Priyanka Sehgal, Xiao Song, Zuzana Tothova, Juan Valcárcel, Kevin M Weeks, Gene W Yeo, Andrei Thomas-Tikhonenko

Faculty, Staff and Students Publications

Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. …

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 …

A Tetramer Of Bcl11a Is Required For Stable Protein Production And Fetal Hemoglobin Silencing, Ge Zheng, Maolu Yin, Stuti Mehta, I-Te Chu, Stacy Wang, Alia Alshaye, Kirstin Drainville, Altantsetseg Buyanbat, Frédérique Bienfait, Karin Tenglin, Qian Zhu, Stuart H Orkin

Faculty, Staff and Students Publications

Down-regulation of BCL11A protein reverses the fetal (HbF, α2γ2) to adult (HbA, α2β2) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Due to reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop novel small molecule approaches, we interrogated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc-finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for γ-globin gene repression, as an engineered monomer fails to engage a critical corepressor …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

Genotype-Specific Effects Of Elamipretide In Patients With Primary Mitochondrial Myopathy: A Post Hoc Analysis Of The Mmpower-3 Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russekk Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, Anthony Abbruscato, David A Brown, Alana Sullivan, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Students Publications

BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those …

High-Coverage Nanopore Sequencing Of Samples From The 1000 Genomes Project To Build A Comprehensive Catalog Of Human Genetic Variation, Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda P G Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachary B Anderson, Sophie H R Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, André Corvelo, Catherine Reeves, Adrienne Helland, Rajeeva Lochan Musunuri, Mahler Revsine, Karynne E Patterson, Cate R Paschal, Christina Zakarian, Sara Goodwin, Tanner D Jensen, Esther Robb, 1000 Genomes Ont Sequencing Consortium, University Of Washington Center For Rare Disease Research (Uw-Crdr), Genomics Research To Elucidate The Genetics Of Rare Diseases (Gregor) Consortium, William Richard Mccombie, Fritz J Sedlazeck, Justin M Zook, Stephen B Montgomery, Erik Garrison, Mikhail Kolmogorov, Michael C Schatz, Richard N Mclaughlin, Harriet Dashnow, Michael C Zody, Matt Loose, Miten Jain, Evan E Eichler, Danny E Miller

Faculty, Staff and Students Publications

Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control data sets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project (1KGP) Oxford Nanopore Technologies Sequencing Consortium aims to generate LRS data from at least 800 of the 1KGP samples. Our goal is to use LRS to identify a broader spectrum of variation …

Leveraging The T2t Assembly To Resolve Rare And Pathogenic Inversions In Reference Genome Gaps, Kristine Bilgrav Saether, Jesper Eisfeldt, Jesse D Bengtsson, Ming Yin Lun, Christopher M Grochowski, Medhat Mahmoud, Hsiao-Tuan Chao, Jill A Rosenfeld, Pengfei Liu, Marlene Ek, Jakob Schuy, Adam Ameur, Hongzheng Dai, Undiagnosed Diseases Network, James Paul Hwang, Fritz J Sedlazeck, Weimin Bi, Ronit Marom, Josephine Wincent, Ann Nordgren, Claudia M B Carvalho, Anna Lindstrand

Faculty, Staff and Students Publications

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the …

Tumor-Associated Antigen Prediction Using A Single-Sample Gene Expression State Inference Algorithm, Xinpei Yi, Hongwei Zhao, Shunjie Hu, Liangqing Dong, Yongchao Dou, Jing Li, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

We developed a Bayesian-based algorithm to infer gene expression states in individual samples and incorporated it into a workflow to identify tumor-associated antigens (TAAs) across 33 cancer types using RNA sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA). Our analysis identified 212 candidate TAAs, with 78 validated in independent RNA-seq datasets spanning seven cancer types. Eighteen of these TAAs were further corroborated by proteomics data, including 10 linked to liver cancer. We predicted that 38 peptides derived from these 10 TAAs would bind strongly to HLA-A02, the most common HLA allele. Experimental validation confirmed …

Sample Multiplexing For Retinal Single-Cell Rna Sequencing, Justin Ma, Ting-Kuan Chu, Maria Polo-Prieto, Yong H Park, Yumei Li, Rui Chen, Graeme Mardon, Benjamin J Frankfort, Nicholas M Tran

Faculty, Staff and Students Publications

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal …

Long-Read Sequencing Of An Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, And Reveals Methylation Landscapes, Kieran O'Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe Maclennan, Vanessa Porter, Andrew Galbraith, Cameron J Grisdale, Luka Culibrk, John H Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Eleanor Lewis, Luis F Paulin, Fritz J Sedlazeck, Jessica M T Nelson, Eric Chuah, Karen L Mungall, Richard A Moore, Robin Coope, Andrew J Mungall, Melissa K Mcconechy, Laura M Williamson, Kasmintan A Schrader, Stephen Yip, Marco A Marra, Janessa Laskin, Steven J M Jones

Faculty, Staff and Students Publications

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

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 …

Tfeb Controls Syncytiotrophoblast Formation And Hormone Production In Placenta, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Chiara Soldati, Margherita Mutarelli, Sandro Montefusco, Giuseppina Grieco, Lucia Vittoria Sepe, Barbara Rossi, Edoardo Nusco, Giada Rossignoli, Giorgia Panebianco, Fabrizio Merciai, Emanuela Salviati, Eduardo Maria Sommella, Pietro Campiglia, Graziano Martello, Davide Cacchiarelli, Diego Luis Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of …