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1. An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration

Author

Amina Kurtovic-Kozaric, Moriel Singer-Berk, Jordan Wood, Emily Evangelista, Leena Panwala, Amanda Hope, Stefanie M. Heinrich, Samantha Baxter, and Mark J. Kiel

Subjects
PLA2G6-associated neurodegeneration, INAD, Genetic prevalence, Medicine
Abstract

Abstract Background PLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated. Methods To provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium. Results In the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and/or conflicting variants are included, the overall genetic prevalence was estimated to be between 1 in 987,267 to 1 in 1,570,079 pregnancies, with the highest genetic prevalence in African/African-American (1 in 421,960 to 1 in 365,197) and East-Asian (1 in 683,978 to 1 in 190,771) populations. Conclusion Our estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.

Published
2024
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2. O11: An atlas of 1.2M structural variants across global populations in the Genome Aggregation Database (gnomAD)

Author

Harrison Brand, Xuefang Zhao, Jack Fu, Ryan Collins, Isaac Wong, Cal Liao, Lily Wang, Samantha Baxter, Matthew Solomonson, Philip Darnowsky, Sinéad Chapman, Christine Stevens, Caroline Cusick, Alba Sanchis-Juan, Mark Walker, Nehir Kurtas, Katherine Chao, Stacey Gabriel, Eric Banks, Anne O’Donnell-Luria, Daniel MacArthur, Heidi Rehm, Benjamin Neale, Mark Daly, Kaitlin Samocha, Konrad Karczewski, and Michael Talkowski

Subjects
Genetics, QH426-470, Medicine
Published
2024
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5. O43: Analysis of >800,000 diverse sequenced humans in gnomAD improves clinical interpretation and provides insight into gene function

Author

Heidi Rehm, Julia Goodrich, Katherine Chao, Kristen Laricchia, Michael Wilson, Jack Fu, Grace Tiao, Qin He, Daniel Marten, Timothy Poterba, Christopher Vittal, Siwei Chen, Wenhan Lu, Samantha Baxter, Sinéad Chapman, Caroline Cusick, Philip Darnowsky, Laura Gauthier, Leonhard Gruenschloss, Riley Grant, Stephen Jahl, Matthew Solomonson, Christine Stevens, Daniel MacArthur, Michael Talkowski, Benjamin Neale, Anne O'Donnell-Luria, Kaitlin Samocha, Konrad Karczewski, and Mark Daly

Subjects
Genetics, QH426-470, Medicine
Published
2024
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6. P575: The Rare Genomes Project: Improving access to genomic sequencing and identifying causes of rare disease

Author

Christina Austin-Tse, Stephanie DiTroia, Melanie O'Leary, Grace VanNoy, Brian Mangilog, Gulalai Shah, Eva Martinez, Jillian Serrano, Lynn Pais, Emily O'Heir, Ikeoluwa Osei-Owusu, Gabrielle Lemire, Vijay Ganesh, Sarah Stenton, Mutaz Amin, Kayla Socarras, Mugdha Singh, Stacey Hall, Katie Larsson, Moriel Singer-Berk, Daniel Marten, Michael Wilson, Hana Snow, Benjamin Blankenmeister, Jialan Ma, Ben Weisburd, Alba Sanchis-Juan, Harrison Brand, Emily Groopman, Alysia Lovgren, Clara Williamson, Marissa Hollyer, Eleina England, Eleanor Seaby, Katherine Chao, Julia Goodrich, Samantha Baxter, Daniel MacArthur, Michael Talkowski, Monica Wojcik, Anne O'Donnell-Luria, and Heidi Rehm

Subjects
Genetics, QH426-470, Medicine
Published
2024
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11. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Author

Julia K. Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, Ben Weisburd, Nick Watts, Lizz Caulkins, Peter Dornbos, Ryan Koesterer, Zachary Zappala, Haichen Zhang, Kristin A. Maloney, Andy Dahl, Carlos A. Aguilar-Salinas, Gil Atzmon, Francisco Barajas-Olmos, Nir Barzilai, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Federico Centeno-Cruz, John C. Chambers, Nathalie Chami, Edmund Chan, Juliana Chan, Ching-Yu Cheng, Yoon Shin Cho, Cecilia Contreras-Cubas, Emilio Córdova, Adolfo Correa, Ralph A. DeFronzo, Ravindranath Duggirala, Josée Dupuis, Ma Eugenia Garay-Sevilla, Humberto García-Ortiz, Christian Gieger, Benjamin Glaser, Clicerio González-Villalpando, Ma Elena Gonzalez, Niels Grarup, Leif Groop, Myron Gross, Christopher Haiman, Sohee Han, Craig L. Hanis, Torben Hansen, Nancy L. Heard-Costa, Brian E. Henderson, Juan Manuel Malacara Hernandez, Mi Yeong Hwang, Sergio Islas-Andrade, Marit E. Jørgensen, Hyun Min Kang, Bong-Jo Kim, Young Jin Kim, Heikki A. Koistinen, Jaspal Singh Kooner, Johanna Kuusisto, Soo-Heon Kwak, Markku Laakso, Leslie Lange, Jong-Young Lee, Juyoung Lee, Donna M. Lehman, Allan Linneberg, Jianjun Liu, Ruth J. F. Loos, Valeriya Lyssenko, Ronald C. W. Ma, Angélica Martínez-Hernández, James B. Meigs, Thomas Meitinger, Elvia Mendoza-Caamal, Karen L. Mohlke, Andrew D. Morris, Alanna C. Morrison, Maggie C. Y. Ng, Peter M. Nilsson, Christopher J. O’Donnell, Lorena Orozco, Colin N. A. Palmer, Kyong Soo Park, Wendy S. Post, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Claudia Schurmann, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Timothy D. Spector, Konstantin Strauch, Tim M. Strom, E. Shyong Tai, Claudia H. T. Tam, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Russell P. Tracy, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Rob M. van Dam, Ramachandran S. Vasan, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, AMP-T2D-GENES Consortia, Noël P. Burtt, Noah Zaitlen, Mark I. McCarthy, Michael Boehnke, Toni I. Pollin, Jason Flannick, Josep M. Mercader, Anne O’Donnell-Luria, Samantha Baxter, Jose C. Florez, Daniel G. MacArthur, and Miriam S. Udler

Subjects
Science
Abstract

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

Published
2021
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12. BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

Author

Melissa S Cline, Rachel G Liao, Michael T Parsons, Benedict Paten, Faisal Alquaddoomi, Antonis Antoniou, Samantha Baxter, Larry Brody, Robert Cook-Deegan, Amy Coffin, Fergus J Couch, Brian Craft, Robert Currie, Chloe C Dlott, Lena Dolman, Johan T den Dunnen, Stephanie O M Dyke, Susan M Domchek, Douglas Easton, Zachary Fischmann, William D Foulkes, Judy Garber, David Goldgar, Mary J Goldman, Peter Goodhand, Steven Harrison, David Haussler, Kazuto Kato, Bartha Knoppers, Charles Markello, Robert Nussbaum, Kenneth Offit, Sharon E Plon, Jem Rashbass, Heidi L Rehm, Mark Robson, Wendy S Rubinstein, Dominique Stoppa-Lyonnet, Sean Tavtigian, Adrian Thorogood, Can Zhang, Marc Zimmermann, BRCA Challenge Authors, John Burn, Stephen Chanock, Gunnar Rätsch, and Amanda B Spurdle

Subjects
Genetics, QH426-470
Abstract

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Published
2018
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14. Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data

Author

Moriel Singer-Berk, Sanna Gudmundsson, Samantha Baxter, Eleanor G. Seaby, Eleina England, Jordan C. Wood, Rachel G. Son, Nicholas A. Watts, Konrad J. Karczewski, Steven M. Harrison, Daniel G. MacArthur, Heidi L. Rehm, and Anne O’Donnell-Luria

Subjects
Article
Abstract

Predicted loss of function (pLoF) variants are highly deleterious and play an important role in disease biology, but many of these variants may not actually result in loss-of-function. Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines’s PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 autosomal recessive disease-genes from the Genome Aggregation Database (gnomAD, v2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in low per-base expression (pext) score regions, or the presence of cryptic splice rescues. Variants predicted to be potential artifacts or to evade LoF were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of LoF evading variants assessed, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines, and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.

Published
2023
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17. An osteopathic approach to carpal tunnel syndrome

Author

Samantha Baxter, Alexandra Millhuff, Gautam J. Desai, and Dennis J. Dowling

Subjects
Osteopathic manipulative therapy, medicine.medical_specialty, Activities of daily living, business.industry, Osteopathic medicine in the United States, medicine.disease, Quality of life (healthcare), Treatment plan, Osteopathic physicians, Physical therapy, Medicine, In patient, Family Practice, business, Carpal tunnel syndrome
Abstract

Carpal tunnel syndrome (CTS) is a common cause of medical and workforce-related expenses in the United States. It is also frustrating for patients who have difficulty using the affected hand, impairing their activities of daily living and decreasing their quality of life. By utilizing the philosophy of osteopathic medicine, providers can better implement a treatment plan by working with the patient to find one that incorporates all aspects of the patient’s environment. By using the practice of osteopathic manipulative therapy (OMT), osteopathic physicians can often effectively treat the patient’s symptoms without side effects found in medications. This is especially useful in patients who may be unable to take certain medications, such as pregnant patients. Other treatment modalities are also reviewed in this manuscript.

Published
2021
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18. Neptune: an environment for the delivery of genomic medicine

Author

Venner Eric, Victoria Yi, David Murdock, Sara E. Kalla, Tsung-Jung Wu, Aniko Sabo, Shoudong Li, Qingchang Meng, Xia Tian, Mullai Murugan, Michelle Cohen, Christie Kovar, Wei-Qi Wei, Wendy K. Chung, Chunhua Weng, Georgia L. Wiesner, Gail P. Jarvik, Donna Muzny, Richard A. Gibbs, Debra Abrams, Samuel E. Adunyah, Ladia Albertson-Junkans, Berta Almoguera, Darren C. Ames, Paul Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J. Babb, Adithya Balasubramanian, Hana Bangash, Melissa Basford, Lisa Bastarache, Samantha Baxter, Meckenzie Behr, Barbara Benoit, Elizabeth Bhoj, Suzette J. Bielinski, Sarah T. Bland, Carrie Blout, Kenneth Borthwick, Erwin P. Bottinger, Mark Bowser, Harrison Brand, Murray Brilliant, Wendy Brodeur, Pedro Caraballo, David Carrell, Andrew Carroll, Lisa Castillo, Victor Castro, Gauthami Chandanavelli, Theodore Chiang, Rex L. Chisholm, Kurt D. Christensen, Wendy Chung, Christopher G. Chute, Brittany City, Beth L. Cobb, John J. Connolly, Paul Crane, Katherine Crew, David R. Crosslin, Jyoti Dayal, Mariza De Andrade, Jessica De la Cruz, Josh C. Denny, Shawn Denson, Tim DeSmet, Ozan Dikilitas, Michael J. Dinsmore, Sheila Dodge, Phil Dunlea, Todd L. Edwards, Christine M. Eng, David Fasel, Alex Fedotov, Qiping Feng, Mark Fleharty, Andrea Foster, Robert Freimuth, Christopher Friedrich, Stephanie M. Fullerton, Birgit Funke, Stacey Gabriel, Vivian Gainer, Ali Gharavi, Andrew M. Glazer, Joseph T. Glessner, Jessica Goehringer, Adam S. Gordon, Chet Graham, Robert C. Green, Justin H. Gundelach, Heather S. Hain, Hakon Hakonarson, Maegan V. Harden, John Harley, Margaret Harr, Andrea Hartzler, M. Geoffrey Hayes, Scott Hebbring, Nora Henrikson, Andrew Hershey, Christin Hoell, Ingrid Holm, Kayla M. Howell, George Hripcsak, Jianhong Hu, Elizabeth Duffy Hynes, Joy C. Jayaseelan, Yunyun Jiang, Yoonjung Yoonie Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E. Justice, Divya Kalra, Elizabeth W. Karlson, Brendan J. Keating, Melissa A. Kelly, Eimear E. Kenny, Dustin Key, Krzysztof Kiryluk, Terrie Kitchner, Barbara Klanderman, Eric Klee, David C. Kochan, Viktoriya Korchina, Leah Kottyan, Emily Kudalkar, Alanna Kulchak Rahm, Iftikhar J. Kullo, Philip Lammers, Eric B. Larson, Matthew S. Lebo, Magalie Leduc, Ming Ta (Michael) Lee, Niall J. Lennon, Kathleen A. Leppig, Nancy D. Leslie, Rongling Li, Wayne H. Liang, Chiao-Feng Lin, Jodell E. Linder, Noralane M. Lindor, Todd Lingren, James G. Linneman, Cong Liu, Wen Liu, Xiuping Liu, John Lynch, Hayley Lyon, Alyssa Macbeth, Harshad Mahadeshwar, Lisa Mahanta, Bradley Malin, Teri Manolio, Maddalena Marasa, Keith Marsolo, Michelle L. McGowan, Elizabeth McNally, Jim Meldrim, Frank Mentch, Hila Milo Rasouly, Jonathan Mosley, Shubhabrata Mukherjee, Thomas E. Mullen, Jesse Muniz, David R. Murdock, Shawn Murphy, Melanie F. Myers, Bahram Namjou, Yizhao Ni, Robert C. Onofrio, Aniwaa Owusu Obeng, Thomas N. Person, Josh F. Peterson, Lynn Petukhova, Cassandra J. Pisieczko, Siddharth Pratap, Cynthia A. Prows, Megan J. Puckelwartz, Ritika Raj, James D. Ralston, Arvind Ramaprasan, Andrea Ramirez, Luke Rasmussen, Laura Rasmussen-Torvik, Soumya Raychaudhuri, Heidi L. Rehm, Marylyn D. Ritchie, Catherine Rives, Beenish Riza, Dan M. Roden, Elisabeth A. Rosenthal, Avni Santani, Schaid Dan, Steven Scherer, Stuart Scott, Aaron Scrol, Soumitra Sengupta, Ning Shang, Himanshu Sharma, Richard R. Sharp, Rajbir Singh, Patrick M.A. Sleiman, Kara Slowik, Joshua C. Smith, Maureen E. Smith, Duane T. Smoot, Jordan W. Smoller, Sunghwan Sohn, Ian B. Stanaway, Justin Starren, Mary Stroud, Jessica Su, Casey Overby Taylor, Kasia Tolwinski, Sara L. Van Driest, Sean M. Vargas, Matthew Varugheese, David Veenstra, Eric Venner, Miguel Verbitsky, Gina Vicente, Michael Wagner, Kimberly Walker, Theresa Walunas, Liwen Wang, Qiaoyan Wang, Scott T. Weiss, Quinn S. Wells, Peter S. White, Ken L. Wiley, Janet L. Williams, Marc S. Williams, Michael W. Wilson, Leora Witkowski, Laura Allison Woods, Betty Woolf, Julia Wynn, Yaping Yang, Ge Zhang, Lan Zhang, and Hana Zouk

Subjects
Computer science, business.industry, Process (engineering), MEDLINE, High-Throughput Nucleotide Sequencing, Genomics, Data science, Article, Personalization, Variety (cybernetics), Workflow, Neptune, Pharmacogenomics, Health care, Electronic Health Records, Humans, business, Software, Genetics (clinical)
Abstract

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Published
2021
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19. Natural History of TANGO2 Deficiency Disorder: Baseline Assessment of 73 Patients

Author

Christina Y. Miyake, Erica J. Lay, Claudia Soler-Alfonso, Kevin E. Glinton, Kimberly M. Houck, Mustafa Tosur, Nancy E. Moran, Sara B. Stephens, Fernando Scaglia, Taylor S. Howard, Jeffrey J. Kim, Tam Dam Pham, Santiago O. Valdes, Na Li, Chaya N. Murali, Lilei Zhang, Maina Kava, Deane Yim, Cheyenne Beach, Gregory Webster, Leonardo Liberman, Christopher M. Janson, Prince J. Kannankeril, Samantha Baxter, Moriel Singer-Berk, Jordan Wood, Samuel J. Mackenzie, Michael Sacher, Lina Ghaloul-Gonzalez, Claudia Pedroza, Shaine A. Morris, Saad A. Ehsan, Mahshid S. Azamian, and Seema R. Lalani

Subjects
Genetics (clinical)
Abstract

TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delays, seizures, intermittent ataxia, hypothyroidism and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.Data were collected from an ongoing natural history study of TDD patients enrolled between February 2019 - May 2022. Data were obtained through phone-based parent interviews and medical record review.Data were collected from 73 patients (56% male) from 57 unrelated families in 17 different countries. The median age of participants at time of data collection was 9.0 years (IQR 5.3-15.9 years, range fetal - 31 years). A total of 24 different TANGO2 alleles were observed. Patients demonstrated normal development in early infancy with progressive delays in developmental milestones thereafter. Symptoms including ataxia, dystonia and speech difficulties typically starting between the ages of 1-3 years. A total of 48 (66%) patients suffered metabolic crises and, of these, 29/48 (73%) developed cardiac crises. Metabolic crises were significantly decreased after initiation of B-complex or multivitamins.We provide the most comprehensive review of natural history of TDD and provide important observational data suggesting B-complex or multivitamins may prevent metabolic crises.

Published
2022

20. seqr : a web-based analysis and collaboration tool for rare disease genomics

Author

Samantha Baxter, Daniel G. MacArthur, Shifa Zhang, Ikeoluwa Osei-Owusu, Lawrence J. Babb, Christina Austin-Tse, Kevin Nguyen, Harindra Arachchi, Lynn Pais, Matthew Solomonson, Katherine R. Chao, Stacy Mano, Gabrielle Lemire, Michael Wilson, Ben Weisburd, Heidi L. Rehm, Grace E. VanNoy, Alysia Kern Lovgren, Emily O'Heir, Stephanie DiTroia, William Phu, Hana Snow, Eleina M. England, Anne H. O’Donnell-Luria, and Melanie O’Leary

Subjects
Data sharing, Annotation, business.industry, Computer science, Web application, Collaboration tool, Identification (biology), Genomics, business, Exome, Data science, Rare disease
Abstract

Exome and genome sequencing have become the tools of choice for rare disease diagnosis, leading to large amounts of data available for analyses. To identify causal variants in these datasets, powerful filtering and decision support tools that can be efficiently used by clinicians and researchers are required. To address this need, we developed seqr - an open source, web-based tool for family-based monogenic disease analysis that allows researchers to work collaboratively to search and annotate genomic callsets. To date, seqr is being used in several research pipelines and one clinical diagnostic lab. In our own experience through the Broad Institute Center for Mendelian Genomics, seqr has enabled analyses of over 10,000 families, supporting the diagnosis of more than 3,800 individuals with rare disease and discovery of over 300 novel disease genes. Here we describe a framework for genomic analysis in rare disease that leverages seqr’s capabilities for variant filtration, annotation, and causal variant identification, as well as support for research collaboration and data sharing. The seqr platform is available as open source software, allowing low-cost participation in rare disease research, and a community effort to support diagnosis and gene discovery in rare disease.

Published
2021
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21. Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis

Author

Giuseppe Carlucci, Max L. Senders, Jun Tang, Alexis Broisat, Thomas Reiner, Geert Raes, Claudia Calcagno, Samantha Baxter, Amr Alaarg, Willem J. M. Mulder, Seigo Ishino, Zahi A. Fayad, Brenda L. Sanchez-Gaytan, Jason S. Lewis, Mark E. Lobatto, Laura Zendman, Sophie Hernot, Nick Devoogdt, Jan C. van de Voort, Carlos Pérez-Medina, Yiming Zhao, Anu E. Meerwaldt, Philip M. Robson, Nicolas A. Karakatsanis, Anna Palmisano, Gilles Boeykens, Francois Fay, Sotirios Tsimikas, Biomaterials Science and Technology, Clinical sciences, Supporting clinical sciences, Medical Imaging, Department of Bio-engineering Sciences, Cellular and Molecular Immunology, Translational Imaging Research Alliance, ACS - Atherosclerosis & ischemic syndromes, Graduate School, 01 Internal and external specialisms, Radiology and Nuclear Medicine, and Medical Biochemistry

Subjects
Aging, Pathology, Scavenger Receptors, Mice, Knockout, ApoE, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, Multimodal Imaging, 030218 nuclear medicine & medical imaging, Neovascularization, Mice, 0302 clinical medicine, Lectins, Receptors, Medicine, Macrophage, Stage (cooking), Plaque, Atherosclerotic, screening and diagnosis, C-Type, medicine.diagnostic_test, Scavenger Receptors, Class E, Magnetic Resonance Imaging, Plaque, Atherosclerotic, Detection, Phenotype, Radiology Nuclear Medicine and imaging, Positron emission tomography, Cell Surface, Disease Progression, Biomedical Imaging, Rabbits, medicine.symptom, Cardiology and Cardiovascular Medicine, Mannose Receptor, ApoE, medicine.drug, medicine.medical_specialty, Knockout, Clinical Sciences, Vascular Cell Adhesion Molecule-1, Receptors, Cell Surface, Inflammation, Article, 03 medical and health sciences, Humans, Animals, Genetic Predisposition to Disease, Lectins, C-Type, Radiology, Nuclear Medicine and imaging, Multiparametric Magnetic Resonance Imaging, Lighting, Fluorodeoxyglucose, Animal, business.industry, Magnetic resonance imaging, Single-Domain Antibodies, Atherosclerosis, molecular imaging, 4.1 Discovery and preclinical testing of markers and technologies, Disease Models, Animal, nanobody, Good Health and Well Being, Early Diagnosis, Mannose-Binding Lectins, PET/MRI, Cardiovascular System & Hematology, Positron-Emission Tomography, Disease Models, Radiopharmaceuticals, Molecular imaging, atherosclerosis, business, Class E
Abstract

ObjectivesThis study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers.BackgroundNoninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated.MethodsWe screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe-/- mice and atherosclerotic rabbits using a combination of invivo PET/MRI readouts and exvivo radioactivity counting, autoradiography, and histological analyses.ResultsThe 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR-PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features.ConclusionsWe have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocolthat allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approachallowsthemultiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.

Published
2019

22. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Ian B. Stanaway, Dan M. Roden, Divya Kalra, Dustin Key, Debra J. Abrams, David Fasel, Victor Castro, Brad Malin, Berta Almoguera, Beenish Riza, Meckenzie A. Behr, Eric Venner, Christine M. Eng, Joy Jayaseelan, Scott J. Hebbring, Michelle L. McGowan, Steven E. Scherer, Theresa L. Walunas, Mark Bowser, James D. Ralston, Wei-Qi Wei, Liwen Wang, David R. Murdock, Wayne H. Liang, Julia Wynn, Nancy D. Leslie, Laura J. Rasmussen-Torvik, Ming Ta (Michael) Lee, Frank D. Mentch, Lan Zhang, Alanna Kulchak Rahm, Josh F. Peterson, Jodell E. Linder, Joshua C. Smith, Soumitra Sengupta, Brendan J. Keating, Gina Vicente, Andrew Carroll, Nora B. Henrikson, Anne E. Justice, Heather S. Hain, Wen Liu, Andrea H. Ramirez, Matthew S. Lebo, Hana Zouk, Georgia L. Wiesner, Andrea L. Hartzler, Cassandra J. Pisieczko, Catherine M. Rives, Jessica Goehringer, Maegan V. Harden, John Lynch, Chiao-Feng Lin, Peter White, Phil Dunlea, Shawn N. Murphy, Mullai Murugan, Harshad Mahadeshwar, Mark Fleharty, Andrea Foster, Arvind Ramaprasan, Christopher A. Friedrich, Justin H. Gundelach, Hayley Lyon, Niall J. Lennon, Eric W. Klee, David R. Crosslin, Ge Zhang, Rongling Li, Ozan Dikilitas, Xiuping Liu, Christin Hoell, Aniwaa Owusu Obeng, Katherine D. Crew, Lisa M. Castillo, Justin Starren, Jonathan D. Mosley, Carrie L. Blout, Himanshu Sharma, Elizabeth M. McNally, Sarah T. Bland, Megan J. Puckelwartz, Matthew Varugheese, Keith Marsolo, Betty Woolf, Sharon Aufox, Janet L. Williams, Kimberly Walker, Murray H. Brilliant, Birgit Funke, Laura Allison Woods, Marylyn D. Ritchie, Brittany City, Todd Lingren, Hila Milo Rasouly, Lawrence J. Babb, Alex Fedotov, Robert C. Onofrio, Margaret Harr, Suzette J. Bielinski, Michael W. Wilson, Shubhabrata Mukherjee, Robert R. Freimuth, Chet Graham, Todd L. Edwards, Quinn S. Wells, Marc S. Williams, Jordan W. Smoller, Wendy K. Chung, Avni Santani, Paul K. Crane, George Hripcsak, QiPing Feng, Ali G. Gharavi, Yizhao Ni, Iftikhar J. Kullo, Michael Wagner, Philip E. Lammers, Michael J. Dinsmore, Thomas N. Person, Victoria Yi, Samuel E. Adunyah, Tim DeSmet, Eric B. Larson, Elizabeth Hynes, David C. Kochan, Eimear E. Kenny, Magalie S. Leduc, Lisa Mahanta, David Carrell, Paul S. Appelbaum, Viktoriya Korchina, Beth L. Cobb, Lynn Petukhova, Jessica De la Cruz, Patrick M. A. Sleiman, Stuart A. Scott, Tsung-Jung Wu, Gail P. Jarvik, Erwin P. Bottinger, Ken Wiley, Josh C. Denny, Melissa A. Basford, Samuel J. Aronson, David L. Veenstra, Yaping Yang, Kayla Marie Howell, John J. Connolly, Jessica Su, Yoonjung Yoonie Joo, Miguel Verbitsky, Sean M. Vargas, Cong Liu, Barbara Benoit, Andrew Hershey, Richard A. Gibbs, Cynthia A. Prows, Hana Bangash, Wendy Brodeur, Gauthami Chandanavelli, Sara L. Van Driest, Kurt D. Christensen, Elizabeth J. Bhoj, Vivian S. Gainer, Adam S. Gordon, Robert C. Green, Hakon Hakonarson, Krzysztof Kiryluk, Elisabeth A. Rosenthal, Rajbir Singh, James G. Linneman, Harrison Brand, Theodore Chiang, Sheila Dodge, Ingrid A. Holm, M. Geoffrey Hayes, Yunyun Jiang, Ning Shang, Samantha Baxter, Noralane M. Lindor, Kathleen A. Leppig, Teri A. Manolio, Sara E. Kalla, Pedro J. Caraballo, Ritika Raj, Aaron Scrol, Jyoti G. Dayal, Richard R. Sharp, Christie Kovar, Soumya Raychaudhuri, Sunghwan Sohn, Emily Kudalkar, Maddalena Marasa, Stacey Gabriel, Dan Schaid, Ladia Albertson-Junkans, Rex L. Chisholm, Maureen E. Smith, Donna M. Muzny, Casey Overby Taylor, Jianhong Hu, Elizabeth W. Karlson, Lisa Bastarache, Darren C. Ames, Joseph T. Glessner, Leora Witkowski, Siddharth Pratap, Qiaoyan Wang, Melissa A. Kelly, Adithya Balasubramanian, Kara Slowik, Terrie Kitchner, Barbara J. Klanderman, Shawn Denson, Mary Stroud, Alyssa Macbeth, Melanie F. Myers, Jesse Muniz, Kasia Tolwinski, Scott T. Weiss, Chunhua Weng, Stephanie M. Fullerton, John B. Harley, Christopher G. Chute, Heidi L. Rehm, Sheethal Jose, Andrew M. Glazer, Navya Shilpa Josyula, Kenneth M. Borthwick, Thomas E. Mullen, Mariza de Andrade, Leah C. Kottyan, Luke V. Rasmussen, James Meldrim, and Bahram Namjou

Subjects
0301 basic medicine, Standardization, Test data generation, business.industry, Computer science, Sequence Analysis, DNA, 030105 genetics & heredity, Precision medicine, Data science, Clinical decision support system, Biobank, Article, 3. Good health, Data sharing, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, Genetic Testing, Prospective Studies, Sample collection, Personalized medicine, Precision Medicine, business, Genetics (clinical)
Abstract

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Published
2019
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23. Multimodal Positron Emission Tomography Imaging to Quantify Uptake of 89Zr-Labeled Liposomes in the Atherosclerotic Vessel Wall

Author

Erik S.G. Stroes, Carlos Pérez-Medina, Sean Carlin, Zahi A. Fayad, Andreas Kjaer, Jason Bini, Julia Witjes, Chang Ho Wessel, Luuk Giesen, Francois Fay, Tina Binderup, Thomas Reiner, Mark E. Lobatto, Philip M. Robson, Gert Storm, Willem J. M. Mulder, Mootaz Eldib, Samantha Baxter, Jason S. Lewis, Claudia Calcagno, Precision Medicine, ICMS Core, Biomaterials Science and Technology, Radiology and Nuclear Medicine, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, Afd Pharmaceutics, and Pharmaceutics

Subjects
Male, Noninvasive imaging, Biodistribution, UT-Hybrid-D, Biomedical Engineering, Pharmaceutical Science, Bioengineering, Vascular permeability, 02 engineering and technology, 01 natural sciences, Article, In vivo, medicine, Animals, Tissue Distribution, Aorta, Abdominal, Radioisotopes, Pharmacology, Liposome, medicine.diagnostic_test, 010405 organic chemistry, Chemistry, business.industry, Organic Chemistry, 22/2 OA procedure, Magnetic resonance imaging, Atherosclerosis, 021001 nanoscience & nanotechnology, Plaque, Atherosclerotic, 0104 chemical sciences, Positron emission tomography, Positron-Emission Tomography, Liposomes, Rabbits, Zirconium, 0210 nano-technology, Nuclear medicine, business, Ex vivo, Biotechnology
Abstract

Nanotherapy has recently emerged as an experimental treatment option for atherosclerosis. To fulfill its promise, robust noninvasive imaging approaches for subject selection and treatment evaluation are warranted. To that end, we present here a positron emission tomography (PET)-based method for quantification of liposomal nanoparticle uptake in the atherosclerotic vessel wall. We evaluated a modular procedure to label liposomal nanoparticles with the radioisotope zirconium-89 (89Zr). Their biodistribution and vessel wall targeting in a rabbit atherosclerosis model was evaluated up to 15 days after intravenous injection by PET/computed tomography (CT) and PET/magnetic resonance imaging (PET/MRI). Vascular permeability was assessed in vivo using three-dimensional dynamic contrast-enhanced MRI (3D DCE-MRI) and ex vivo using near-infrared fluorescence (NIRF) imaging. The 89Zr-radiolabeled liposomes displayed a biodistribution pattern typical of long-circulating nanoparticles. Importantly, they markedly accumulated in atherosclerotic lesions in the abdominal aorta, as evident on PET/MRI and confirmed by autoradiography, and this uptake moderately correlated with vascular permeability. The method presented herein facilitates the development of nanotherapy for atherosclerotic disease as it provides a tool to screen for nanoparticle targeting in individual subjects' plaques.

Published
2019
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24. Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach

Author

Hyuk Jee, Anne H. O’Donnell-Luria, Michael S. Hershfield, Eugene P. Chambers, Aman Sharma, Samantha Baxter, Fatma Dedeoglu, Sofia Rosenzweig, Yuelong Huang, Qing Zhou, Z. Huang, Pui Y. Lee, Lauren A. Henderson, Maria L. Taylor, Ivona Aksentijevich, and Peter A. Nigrovic

Subjects
0301 basic medicine, Adenosine Deaminase, In silico, Immunology, Population, Computational biology, Biology, Genome, Article, Correlation, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Humans, Genetic Predisposition to Disease, education, 030203 arthritis & rheumatology, education.field_of_study, Carrier signal, Receiver operating characteristic, Genetic Variation, ADENOSINE DEAMINASE 2, 030104 developmental biology, HEK293 Cells, Immune System Diseases, Intercellular Signaling Peptides and Proteins, Function (biology), Algorithms
Abstract

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aim to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database (gnomAD). We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77/85 (91%) of DADA2-associated variants reduced ADA2 enzymatic function by > 75%. Analysis of 100 ADA2 variants in gnomAD showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; p < 0.0001). Using < 25% residual enzymatic activity as the cut-off to define potential pathogenicity, integration of our results with gnomAD population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSION: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.

Published
2021

25. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Author

Ma Elena Gonzalez, Marit E. Jørgensen, Edmund Chan, Eric Boerwinkle, Craig L. Hanis, Tim M. Strom, Young-Jin Kim, Alanna C. Morrison, Abigail Sveden, Zachary Zappala, Jianjun Liu, Markku Laakso, Russell P. Tracy, Andrew D. Morris, Farook Thameem, Ruth J. F. Loos, Robert Sladek, Moriel Singer-Berk, Jason Flannick, Stephen S. Rich, Angélica Martínez-Hernández, Rob M. van Dam, Wendy S. Post, Michael Boehnke, Peter M. Nilsson, Humberto García-Ortiz, Clicerio González-Villalpando, Samantha Baxter, Yoon Shin Cho, Sergio Islas-Andrade, Colin N. A. Palmer, Claudia H. T. Tam, Nicholas A. Watts, Lizz Caulkins, Rachel Son, Daniel G. MacArthur, Toni I. Pollin, Juan Manuel Malacara Hernandez, Jong-Young Lee, Bruce M. Psaty, Ravindranath Duggirala, Erwin P. Bottinger, Nancy L. Heard-Costa, Donna M. Lehman, Carlos A. Aguilar-Salinas, Juyoung Lee, Haichen Zhang, Mark I. McCarthy, Brian Tomlinson, Leslie A. Lange, Cecilia Contreras-Cubas, Johanna Kuusisto, Danish Saleheen, Juliana C.N. Chan, Andrew Dahl, Konstantin Strauch, Noël P. Burtt, Tien Yin Wong, Niels Grarup, Jerome I. Rotter, Ronald C.W. Ma, Julia K. Goodrich, Anne H. O’Donnell-Luria, Jose C. Florez, Miriam S. Udler-Aubrey, Kristin A. Maloney, James G. Wilson, Ramachandran S. Vasan, Bong-Jo Kim, Leif Groop, Noah Zaitlen, Kerrin S. Small, Heikki A. Koistinen, Donald W. Bowden, Wing-Yee So, Jaakko Tuomilehto, Oluf Pedersen, John C. Chambers, Mi Yeong Hwang, Karen L. Mohlke, John Blangero, Eleina M. England, Elvia Mendoza-Caamal, James B. Meigs, Federico Centeno-Cruz, Michael Preuss, Ralph A. DeFronzo, Joanne B. Cole, Jordan Wood, Allan Linneberg, Benjamin Glaser, Lorena Orozco, Jaspal S. Kooner, Valeriya Lyssenko, Sohee Han, Gil Atzmon, Ma. Eugenia Garay-Sevilla, Tiinamaija Tuomi, Brian E. Henderson, Christopher J. O'Donnell, Hyun Min Kang, Teresa Tusié-Luna, Nir Barzilai, Thomas Meitinger, Christian Gieger, Ben Weisburd, Alexander P. Reiner, Tim D. Spector, Myron D. Gross, E. Shyong Tai, Yik Ying Teo, for Amp-T D-Genes Consortia, Xueling Sim, Emilio J. Cordova, Cristina Revilla-Monsalve, Daniel R. Witte, Francisco Barajas-Olmos, Claudia Schurmann, Lori L. Bonnycastle, Josep M. Mercader, Adolfo Correa, Torben Hansen, Kyong Soo Park, Ching-Yu Cheng, Soo Heon Kwak, Nathalie Chami, Christopher A. Haiman, Xavier Soberón, Josée Dupuis, and Maggie C.Y. Ng

Subjects
Genetics, 0303 health sciences, Genetic variants, Disease, 030204 cardiovascular system & hematology, Biology, medicine.disease, Penetrance, 3. Good health, Biomarker (cell), 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Genotype, medicine, Exome sequencing, 030304 developmental biology, Monogenic Diabetes
Abstract

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

Published
2020
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27. matchbox: An open-source tool for patient matching via the Matchmaker Exchange

Author

Harindra Arachchi, Anne H. O’Donnell-Luria, Monica H. Wojcik, Alicia B. Byrne, Samantha Baxter, Daniel G. MacArthur, Anthony A. Philippakis, Melissa A. Haendel, Elise Valkanas, Heidi L. Rehm, Benjamin Weisburd, Julius O.B. Jacobsen, Damian Smedley, Arachchi, Harindra, Wojcik, Monica H, Weisburd, Benjamin, Jacobsen, Julius OB, Valkanas, Elise, Baxter, Samantha, Byrne, Alicia B, O'Donnell-Luria, Anne H, Haendel, Melilssa, Smedley, Damian, MacArthur, Daniel G, Philippakis, Anthony A, and Rehm, Heidi L

Subjects
0301 basic medicine, Matching (statistics), Process (engineering), rare diseas, Information Storage and Retrieval, Web Browser, Biology, matchbox, Article, Bridge (nautical), Access to Information, World Wide Web, Novel gene, 03 medical and health sciences, Rare Diseases, novel gene, Genetics, Humans, Genetic Predisposition to Disease, open-source, Genetic Association Studies, Genetics (clinical), Information Dissemination, Patient Selection, Scale (chemistry), Phenotype, 030104 developmental biology, Open source, Matchmaker Exchange, Software
Abstract

Rare disease investigators constantly face challenges in identifying additional cases to build evidence for gene‐disease causality. The Matchmaker Exchange (MME) addresses this limitation by providing a mechanism for matching patients across genomic centers via a federated network. The MME has revolutionized searching for additional cases by making it possible to query across institutional boundaries, so that what was once a laborious and manual process of contacting researchers is now automated and computable. However, while the MME network is beginning to scale, the growth of additional nodes is limited by the lack of easy‐to‐use solutions that can be implemented by any rare disease database owner, even one without significant software engineering resources. Here we describe matchbox, which is an open‐source, platform‐independent, portable bridge between any given rare disease genomic center and the MME network, which has already led to novel gene discoveries. We also describe how matchbox greatly reduces the barrier to participation by overcoming challenges for new databases to join the MME. Refereed/Peer-reviewed

Published
2018
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28. RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions

Author

Zoi Karoulia, Marylene Leboeuf, Romain Remark, Miriam Merad, Brandon Hogstad, Poulikos I. Poulikakos, Marie-Luise Berres, Wing-hong Kwan, Howard Lin, Kenneth L. McClain, Jerry E. Chipuk, Hélène Salmon, Madhavika N. Serasinghe, Camille Bigenwald, Stefan Jordan, Veronika Kana, Karen Phaik Har Lim, Carl E. Allen, EF Brandt, Jun Tang, Tsz-Kwong Man, Willem J. M. Mulder, Rikhia Chakraborty, Samantha Baxter, ACS - Atherosclerosis & ischemic syndromes, and Medical Biochemistry

Subjects
Proto-Oncogene Proteins B-raf, 0301 basic medicine, MAPK/ERK pathway, MAP Kinase Signaling System, Immunology, Apoptosis, C-C chemokine receptor type 7, Article, Mice, 03 medical and health sciences, Chemokine receptor, Phagocytosis, Langerhans cell histiocytosis, Cell Movement, medicine, Animals, Humans, Immunology and Allergy, Kinase activity, Protein kinase A, Dendritic cell migration, Research Articles, Chemistry, Dendritic Cells, medicine.disease, 3. Good health, Mice, Inbred C57BL, Histiocytosis, Langerhans-Cell, 030104 developmental biology, Langerhans Cells, Mutation, Cancer research
Abstract

Hogstad et al. show that the somatic BRAFV600E mutation in myeloid dendritic cell precursors in Langerhans cell histiocytosis promotes lesion formation through impaired dendritic cell migration and resistance to apoptosis, which can be rescued with targeted MAPK pathway inhibition., Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

Published
2018

29. Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study

Author

Dayna-Lynn Nevay, Abdul Noor, Seema Panchal, Joyce So, Salma Shickh, Hanna Faghfoury, Emma Reble, Nicholas A. Watkins, Yvonne Bombard, Rita Kodida, Sam Khalouei, Oana Morar, Christine Elser, Melanie Care, Melyssa Aronson, Ruth Godoy, Jillian Murphy, Kara Semotiuk, Dakota Kleinman, Josh Silver, Spring Holter, Mariana Gutierrez Salazar, Kathleen-Rose Zakoor, Sheri Horsburgh, Stephanie DiTroia, Conxi Lázaro, Jessica Gu, Jamie Goltz, David Chitayat, Susan Armel, Arnon Adler, Raymond H. Kim, Marta Szybowska, Jordan Lerner-Ellis, Samantha Baxter, Chloe Mighton, and Chantal F. Morel

Subjects
Proband, Adult, Male, medicine.medical_specialty, Canada, Adolescent, Disease, Undiagnosed Diseases, DNA sequencing, Article, Young Adult, Internal medicine, Molecular genetics, Exome Sequencing, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Genetic Testing, Prospective cohort study, Genetics (clinical), Aged, Whole Genome Sequencing, business.industry, Genome, Human, Cancer, Middle Aged, medicine.disease, Mutation, Medical genetics, Female, business
Abstract

BackgroundExome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.MethodsPatients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.ResultsOverall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.ConclusionsThis study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

Published
2020

30. AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

Author

Jiguang Peng, Jiale Xiang, Samantha Baxter, and Zhiyu Peng

Subjects
0303 health sciences, Genome, Human, Concordance, 030305 genetics & heredity, Null (mathematics), Disease mechanisms, Computational Biology, Computational biology, Genomics, Biology, Pathogenicity, Interpretation (model theory), Frameshift mutation, 03 medical and health sciences, User-Computer Interface, Loss of Function Mutation, Genetics, Humans, Fraction (mathematics), Genetics (clinical), Software, 030304 developmental biology
Abstract

Null variants are prevalent within the human genome, and their accurate interpretation is critical for clinical management. In 2018, the ClinGen Sequence Variant Interpretation (SVI) Working Group refined the only criterion with a very strong pathogenicity rating (PVS1). To streamline PVS1 interpretation, we have developed an automatic classification tool with a graphical user interface called AutoPVS1. The performance of AutoPVS1 was assessed using 56 variants manually curated by the ClinGen's SVI Working Group; it achieved an interpretation concordance of 93% (52/56). A further analysis of 28,586 putative loss-of-function variants by AutoPVS1 demonstrated that at least 27.7% of them do not reach a very strong strength level, 17.5% because of variant-specific issues and 10.2% due to disease mechanism considerations. Notably, 41.0% (1,936/4,717) of splicing variants were assigned a decreased preliminary PVS1 strength level, a significantly greater fraction than in frameshift variants (13.2%) and nonsense variants (10.8%). Our results reinforce the necessity of considering variant-specific issues and disease mechanisms in variant interpretation and demonstrate that AutoPVS1 meets an urgent need by enabling biocurators to easily assign accurate, reliable and reproducible PVS1 strength levels in the process of variant interpretation. AutoPVS1 is publicly available at http://autopvs1.genetics.bgi.com/.

Published
2019

31. Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species

Author

Filip K. Swirski, Tina Binderup, Andreas Kjaer, Mandy M. T. van Leent, Serge K. Lyashchenko, Willem J. M. Mulder, Mark E. Lobatto, Sarayu Ramachandran, Matthias Nahrendorf, Claudia Calcagno, Carlos Pérez-Medina, Samantha Baxter, Zahi A. Fayad, Georgios Soultanidis, Philip M. Robson, Venkatesh Mani, Nicolas A. Karakatsanis, Francois Fay, Abraham J. P. Teunissen, Seigo Ishino, Jun Tang, Yiming Zhao, Juan F. Granada, Giuseppe Carlucci, Joost Malkus, Max L. Senders, Raphaël Duivenvoorden, Yohana C. A. Frederico, Edward A. Fisher, Thomas Reiner, Barbara A. Hutten, Brenda L. Sanchez-Gaytan, Precision Medicine, Nephrology, ACS - Amsterdam Cardiovascular Sciences, Graduate School, ACS - Atherosclerosis & ischemic syndromes, AII - Inflammatory diseases, 01 Internal and external specialisms, Radiology and Nuclear Medicine, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, ACS - Diabetes & metabolism, Epidemiology and Data Science, and Medical Biochemistry

Subjects
0301 basic medicine, Male, Treatment response, Simvastatin, Swine, Plaque progression, Inflammation, 02 engineering and technology, Hdl metabolism, Bioinformatics, Article, 03 medical and health sciences, Apolipoproteins E, Imaging, Three-Dimensional, Research Support, N.I.H., Extramural, Species Specificity, In vivo, Journal Article, medicine, Animals, Tissue Distribution, Tissue distribution, business.industry, Research Support, Non-U.S. Gov't, General Medicine, 021001 nanoscience & nanotechnology, Multiple species, Atherosclerosis, Magnetic Resonance Imaging, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Nanomedicine, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Positron-Emission Tomography, Female, Immunotherapy, Rabbits, medicine.symptom, 0210 nano-technology, business, Lipoproteins, HDL, Large animal
Abstract

Item does not contain fulltext Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Published
2019
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32. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019
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33. More than a fancy exome: unique capabilities of genome sequencing for pediatric rare disease diagnosis

Author

Lynn Pais, Samantha Baxter, Vijay S. Ganesh, Ben Weisburd, Heidi L. Rehm, Stephanie DiTroia, Julia K. Goodrich, Anne H. O’Donnell-Luria, Emily O'Heir, Katrin Õunap, Alan H. Beggs, Pankaj B. Agrawal, Daniel G. MacArthur, Monica H. Wojcik, Sander Pajusalu, and Katherine R. Chao

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Computational biology, Biology, Molecular Biology, Biochemistry, Exome, DNA sequencing, Rare disease
Published
2021
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34. Insights into genetics, human biology and disease gleaned from family based genomic studies

Author

Deborah A. Nickerson, Pengfei Liu, Nara Sobreira, Jessica X. Chong, Eric Boerwinkle, Davut Pehlivan, Samantha Baxter, Nan Wu, V. Reid Sutton, David Valle, Jill A. Rosenfeld, Dimitri Avramopoulos, Tamar Harel, Anne H. O’Donnell-Luria, Murat Gunel, Jennifer E. Posey, Tara C. Matise, Richard P. Lifton, James R. Lupski, Heidi L. Rehm, Donna M. Muzny, Claudia M.B. Carvalho, Steven Buyske, Zeynep Coban Akdemir, Daniel G. MacArthur, C. D. Boehm, Mark Gerstein, Kimberly F. Doheny, Janson White, Richard A. Gibbs, Sushant Kumar, Shalini N. Jhangiani, Michael J. Bamshad, Shrikant Mane, P. Dane Witmer, and Ada Hamosh

Subjects
0301 basic medicine, Genomics, Locus (genetics), Computational biology, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, Databases, Genetic, Exome Sequencing, Humans, Genetic Predisposition to Disease, Allele, Genetics (clinical), Exome sequencing, Genome, Human, Genetic Diseases, Inborn, Oligogenic Inheritance, Human genetics, United States, Pedigree, 030104 developmental biology, National Institutes of Health (U.S.), Mendelian inheritance, symbols, Human genome
Abstract

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel “disease gene” discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

Published
2019

35. Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Author

Claudia M. van Tiel, Roy Schrijver, Dorothee Atzler, Aldo Jongejan, Oliver Soehnlein, Marnix Lameijer, Menno P.J. de Winther, Francois Fay, Suzanne A. B. M. Aarts, Barbara Zarzycka, Bram Slütter, Christian Weber, Jun Tang, Perry D. Moerland, Norbert Gerdes, Boris Bleijlevens, Myrthe den Toom, Raphaël Duivenvoorden, Esther Lutgens, Tom Seijkens, Linda Beckers, Pascal J. H. Kusters, Remco T. A. Megens, Marion J.J. Gijbels, Gijs Kooij, Cornelis van 't Veer, Johan Kuiper, Gerry A. F. Nicolaes, Gert Vriend, Louis Boon, Edward A. Fisher, Willem J. M. Mulder, Samantha Baxter, Johan Duchene, Maria Aslani, Marten A. Hoeksema, Biomedische Technologie, Promovendi CD, Biochemie, Moleculaire Genetica, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, RS: CARIM - R2.06 - Intermediate cardiac metabolism, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, RS: CARIM - R1.01 - Blood proteins & engineering, Medical Biochemistry, ACS - Amsterdam Cardiovascular Sciences, Graduate School, Other departments, Center of Experimental and Molecular Medicine, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, Nephrology, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Molecular cell biology and Immunology, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
0301 basic medicine, Apolipoprotein E, MECHANISM, rHDL, recombinant high-density lipoprotein, Cell Culture Techniques, 030204 cardiovascular system & hematology, PHENOTYPE, THERAPY, Monocytes, ACTIVATION, immunology, Mice, DC, dendritic cell, 0302 clinical medicine, Cell Movement, TRAF, tumor necrosis factor receptor-associated factor, CD40, Medicine, Propiophenones, Aniline Compounds, biology, nanotechnology, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, BMDM, bone marrow-derived macrophage, Plaque, Atherosclerotic, 3. Good health, medicine.anatomical_structure, Apoe, apolipoprotein E, Tumor necrosis factor alpha, medicine.symptom, Cardiology and Cardiovascular Medicine, CD40-TRAF6 INTERACTIONS, Signal Transduction, Bioinformatics, CD40 Ligand, INHIBITION, Inflammation, CVD, cardiovascular disease, Article, 03 medical and health sciences, Immune system, Animals, Humans, TNF Receptor-Associated Factor 6, SMI, small molecule inhibitor, business.industry, Monocyte, Macrophages, Germinal center, drug development, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Immunoglobulin class switching, inflammation, CELLS, Cancer research, biology.protein, IMMUNE-SYSTEM, atherosclerosis, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract

Background Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. Objectives This study evaluates the potential of TRAF-STOP treatment in atherosclerosis. Methods The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe−/−) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages. Results TRAF-STOP treatment of young Apoe−/− mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe−/− mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair “classical” immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe−/− mice. Conclusions TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis., Central Illustration

Published
2018
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36. Evaluation: A Qualitative Pilot Study of Novel Information Technology Infrastructure to Communicate Genetic Variant Updates

Author

Matthew Varugheese, Stephanie Klinkenberg-Ramirez, Lisa P. Newmark, David W. Bates, Lynn A. Volk, Heidi L. Rehm, Stephanie E. Pollard, Pamela M. Neri, Samantha Baxter, Sara J Samaha, and Samuel J. Aronson

Subjects
0301 basic medicine, Genetic counseling, Point-of-Care Systems, Health Informatics, Pilot Projects, 030105 genetics & heredity, Clinical decision support system, Health informatics, Grounded theory, 03 medical and health sciences, Health Information Management, Nursing, Health care, medicine, Humans, Precision Medicine, Genetic testing, medicine.diagnostic_test, business.industry, Communication, Genetic Variation, Precision medicine, Focus group, Computer Science Applications, 030104 developmental biology, business, Medical Informatics, Research Article
Abstract

SummaryPartners HealthCare Personalized Medicine developed GeneInsight Clinic (GIC), a tool designed to communicate updated variant information from laboratory geneticists to treating clinicians through automated alerts, categorized by level of variant interpretation change.The study aimed to evaluate feedback from the initial users of the GIC, including the advantages and challenges to receiving this variant information and using this technology at the point of care.Healthcare professionals from two clinics that ordered genetic testing for cardiomyopathy and related disorders were invited to participate in one-hour semi-structured interviews and/ or a one-hour focus group. Using a Grounded Theory approach, transcript concepts were coded and organized into themes.Two genetic counselors and two physicians from two treatment clinics participated in individual interviews. Focus group participants included one genetic counselor and four physicians.Analysis resulted in 8 major themes related to structuring and communicating variant knowledge, GIC’s impact on the clinic, and suggestions for improvements. The interview analysis identified longitudinal patient care, family data, and growth in genetic testing content as potential challenges to optimization of the GIC infrastructure.Participants agreed that GIC implementation increased efficiency and effectiveness of the clinic through increased access to genetic variant information at the point of care.Development of information technology (IT) infrastructure to aid in the organization and management of genetic variant knowledge will be critical as the genetic field moves towards whole exome and whole genome sequencing. Findings from this study could be applied to future development of IT support for genetic variant knowledge management that would serve to improve clinicians’ ability to manage and care for patients.Citation: Klinkenberg-Ramirez S, Neri PM, Volk LA, Samaha SJ, Newmark LP, Pollard S, Varugheese M, Baxter S, Aronson SJ, Rehm HL, Bates DW. Evaluation: A qualitative pilot study of novel information technology infrastructure to communicate genetic variant updates.

Published
2016

37. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

Author

Mark E. Lobatto, Willem J. M. Mulder, Zahi A. Fayad, Wei Leong, Sarian M. van Rijs, Claudia Calcagno, Gustav J. Strijkers, Francois Fay, Carlos Pérez-Medina, Samantha Baxter, Erik S.G. Stroes, Sarayu Ramachandran, Hendrik B. Sager, Gert Storm, Brenda L. Sanchez-Gaytan, Mounia S. Braza, Thomas Reiner, Matthias Nahrendorf, David P. Cormode, Edward A. Fisher, Laurien Hassing, Jun Tang, Filip K. Swirski, Yaritzy M Astudillo, Raphaël Duivenvoorden, Susanne E. M. van der Staay, Biomaterials Science and Technology, Radiology and Nuclear Medicine, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, CCA -Cancer Center Amsterdam, Biomedical Engineering and Physics, and Experimental Vascular Medicine

Subjects
Apolipoprotein B, proliferation, Inflammation, macrophage, 030204 cardiovascular system & hematology, high-density lipoprotein, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Engineering, medicine, polycyclic compounds, Macrophage, cardiovascular diseases, radiochemistry, Research Articles, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, business.industry, Monocyte, organic chemicals, nutritional and metabolic diseases, SciAdv r-articles, ApoE knockout mice, Phenotype, 3. Good health, Molecular Imaging, medicine.anatomical_structure, Nanomedicine, chemistry, Simvastatin, inflammation, Immunology, biology.protein, lipids (amino acids, peptides, and proteins), medicine.symptom, atherosclerosis, business, Macrophage proliferation, medicine.drug, Research Article
Abstract

Nanoparticle-based delivery of simvastatin inhibits plaque macrophage proliferation in apolipoprotein E–deficient mice., Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

Published
2015

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