Morgan N Similuk1, Jia Yan2, Rajarshi Ghosh2, Andrew J Oler3, Luis M Franco4, Michael R Setzer2, Michael Kamen2, Colleen Jodarski2, Thomas DiMaggio5, Joie Davis6, Rachel Gore2, Leila Jamal7, Adrienne Borges2, Nicole Gentile2, Julie Niemela2, Chenery Lowe8, Kathleen Jevtich9, Yunting Yu10, Haley Hullfish11, Amy P Hsu6, Celine Hong12, Patricia Littel13, Bryce A Seifert2, Joshua Milner14, Jennifer J Johnston12, Xi Cheng3, Zhiwen Li3, Daniel Veltri3, Ke Huang3, Krishnaveni Kaladi3, Jason Barnett3, Lingwen Zhang3, Nikita Vlasenko3, Yongjie Fan3, Eric Karlins3, Satishkumar Ranganathan Ganakammal3, Robert Gilmore3, Emily Tran3, Alvin Yun15, Joseph Mackey15, Svetlana Yazhuk15, Justin Lack16, Vasudev Kuram16, Wenjia Cao16, Susan Huse16, Karen Frank17, Gary Fahle18, Sergio Rosenzweig19, Yan Su19, SuJin Hwang19, Weimin Bi20, John Bennett21, Ian A Myles22, Suk See De Ravin23, Ivan Fuss24, Warren Strober24, Bibiana Bielekova25, Adriana Almeida de Jesus26, Raphaela Goldbach-Mansky26, Peter Williamson27, Kelly Kumar28, Caeden Dempsy29, Pamela Frischmeyer-Guerrerio29, Robin Fisch30, Hyejeong Bolan30, Dean D Metcalfe30, Hirsh Komarow30, Melody Carter30, Kirk M Druey31, Irini Sereti32, Lesia Dropulic33, Amy D Klion34, Paneez Khoury34, Elise M O' Connell35, Nicole C Holland-Thomas34, Thomas Brown34, David H McDermott36, Philip M Murphy36, Vanessa Bundy37, Michael D Keller37, Christine Peng37, Helen Kim37, Stephanie Norman37, Ottavia M Delmonte38, Elizabeth Kang13, Helen C Su39, Harry Malech13, Alexandra Freeman6, Christa Zerbe6, Gulbu Uzel6, Jenna R E Bergerson40, V Koneti Rao40, Kenneth N Olivier28, Jonathan J Lyons41, Andrea Lisco32, Jeffrey I Cohen33, Michail S Lionakis5, Leslie G Biesecker12, Sandhya Xirasagar3, Luigi D Notarangelo38, Steven M Holland6, Magdalena A Walkiewicz2. 1. Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md. Electronic address: morgan.similuk@nih.gov. 2. Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 3. Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 4. Functional Immunogenomics Unit, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md. 5. Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 6. Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 7. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md; Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, Md; Johns Hopkins/NIH Genetic Counseling Training Program, Bethesda, Md. 8. Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md. 9. School of Medicine, Uniformed Services University of Health Sciences, Bethesda, Md. 10. College of Medicine, Penn State, University Park, Pa. 11. School of Medicine, University of Miami, Miami, Fla. 12. Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md. 13. Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 14. Institute of Genomic Medicine, Columbia University, New York, NY. 15. Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 16. NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md. 17. Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md. 18. Microbiology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md. 19. Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md. 20. Department of Molecular and Human Genetics, Baylor Genetics, Houston, Tex. 21. Clinical Mycology, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 22. Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 23. Laboratory of Host Defenses, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 24. Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 25. Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 26. Translational Autoinflammatory Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 27. Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 28. Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Md. 29. Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 30. Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 31. Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 32. HIV Pathogenesis Section Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 33. Medical Virology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 34. Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 35. Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 36. Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 37. Division of Allergy and Immunology, Children's National Health System, Washington, DC. 38. Immune Deficiency Genetics Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 39. Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 40. Primary Immune Deficiency Clinic (Autoimmune Lymphoproliferative Syndrome Clinic), Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md. 41. Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Abstract
BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale. Published by Elsevier Inc.
BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale. Published by Elsevier Inc.
Authors: Frederick E Dewey; Michael F Murray; John D Overton; Lukas Habegger; Joseph B Leader; Samantha N Fetterolf; Colm O'Dushlaine; Cristopher V Van Hout; Jeffrey Staples; Claudia Gonzaga-Jauregui; Raghu Metpally; Sarah A Pendergrass; Monica A Giovanni; H Lester Kirchner; Suganthi Balasubramanian; Noura S Abul-Husn; Dustin N Hartzel; Daniel R Lavage; Korey A Kost; Jonathan S Packer; Alexander E Lopez; John Penn; Semanti Mukherjee; Nehal Gosalia; Manoj Kanagaraj; Alexander H Li; Lyndon J Mitnaul; Lance J Adams; Thomas N Person; Kavita Praveen; Anthony Marcketta; Matthew S Lebo; Christina A Austin-Tse; Heather M Mason-Suares; Shannon Bruse; Scott Mellis; Robert Phillips; Neil Stahl; Andrew Murphy; Aris Economides; Kimberly A Skelding; Christopher D Still; James R Elmore; Ingrid B Borecki; George D Yancopoulos; F Daniel Davis; William A Faucett; Omri Gottesman; Marylyn D Ritchie; Alan R Shuldiner; Jeffrey G Reid; David H Ledbetter; Aris Baras; David J Carey Journal: Science Date: 2016-12-23 Impact factor: 47.728
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Authors: Chi A Ma; Jeffrey R Stinson; Yuan Zhang; Jordan K Abbott; Michael A Weinreich; Pia J Hauk; Paul R Reynolds; Jonathan J Lyons; Celeste G Nelson; Elisa Ruffo; Batsukh Dorjbal; Salomé Glauzy; Natsuko Yamakawa; Swadhinya Arjunaraja; Kelsey Voss; Jennifer Stoddard; Julie Niemela; Yu Zhang; Sergio D Rosenzweig; Joshua J McElwee; Thomas DiMaggio; Helen F Matthews; Nina Jones; Kelly D Stone; Alejandro Palma; Matías Oleastro; Emma Prieto; Andrea R Bernasconi; Geronimo Dubra; Silvia Danielian; Jonathan Zaiat; Marcelo A Marti; Brian Kim; Megan A Cooper; Neil Romberg; Eric Meffre; Erwin W Gelfand; Andrew L Snow; Joshua D Milner Journal: Nat Genet Date: 2017-06-19 Impact factor: 38.330
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Authors: Hemmo A F Yska; Kim Elsink; Taco W Kuijpers; Geert W J Frederix; Mariëlle E van Gijn; Joris M van Montfrans Journal: J Clin Immunol Date: 2019-06-28 Impact factor: 8.317
Authors: Aziz Bousfiha; Leila Jeddane; Capucine Picard; Waleed Al-Herz; Fatima Ailal; Talal Chatila; Charlotte Cunningham-Rundles; Amos Etzioni; Jose Luis Franco; Steven M Holland; Christoph Klein; Tomohiro Morio; Hans D Ochs; Eric Oksenhendler; Jennifer Puck; Troy R Torgerson; Jean-Laurent Casanova; Kathleen E Sullivan; Stuart G Tangye Journal: J Clin Immunol Date: 2020-02-11 Impact factor: 8.317