Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

Autor:	Similuk MN; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md. Electronic address: morgan.similuk@nih.gov., Yan J; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Ghosh R; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Oler AJ; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Franco LM; Functional Immunogenomics Unit, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., Setzer MR; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Kamen M; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Jodarski C; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., DiMaggio T; Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Davis J; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Gore R; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Jamal L; 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., Borges A; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Gentile N; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Niemela J; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Lowe C; Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md., Jevtich K; School of Medicine, Uniformed Services University of Health Sciences, Bethesda, Md., Yu Y; College of Medicine, Penn State, University Park, Pa., Hullfish H; School of Medicine, University of Miami, Miami, Fla., Hsu AP; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Hong C; Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md., Littel P; Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Seifert BA; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Milner J; Institute of Genomic Medicine, Columbia University, New York, NY., Johnston JJ; Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md., Cheng X; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Li Z; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Veltri D; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Huang K; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Kaladi K; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Barnett J; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Zhang L; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Vlasenko N; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Fan Y; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Karlins E; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Ganakammal SR; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Gilmore R; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Tran E; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Yun A; Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Mackey J; Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Yazhuk S; Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Lack J; NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md., Kuram V; NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md., Cao W; NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md., Huse S; NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md., Frank K; Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md., Fahle G; Microbiology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md., Rosenzweig S; Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md., Su Y; Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md., Hwang S; Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md., Bi W; Department of Molecular and Human Genetics, Baylor Genetics, Houston, Tex., Bennett J; Clinical Mycology, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Myles IA; Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., De Ravin SS; Laboratory of Host Defenses, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Fuss I; Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Strober W; Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Bielekova B; Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Almeida de Jesus A; Translational Autoinflammatory Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Goldbach-Mansky R; Translational Autoinflammatory Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Williamson P; Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Kumar K; Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Md., Dempsy C; Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Frischmeyer-Guerrerio P; Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Fisch R; Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Bolan H; Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Metcalfe DD; Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Komarow H; Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Carter M; Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Druey KM; Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Sereti I; HIV Pathogenesis Section Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Dropulic L; Medical Virology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Klion AD; Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Khoury P; Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., O' Connell EM; Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Holland-Thomas NC; Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Brown T; Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., McDermott DH; Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Murphy PM; Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Bundy V; Division of Allergy and Immunology, Children's National Health System, Washington, DC., Keller MD; Division of Allergy and Immunology, Children's National Health System, Washington, DC., Peng C; Division of Allergy and Immunology, Children's National Health System, Washington, DC., Kim H; Division of Allergy and Immunology, Children's National Health System, Washington, DC., Norman S; Division of Allergy and Immunology, Children's National Health System, Washington, DC., Delmonte OM; Immune Deficiency Genetics Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Kang E; Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Su HC; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Malech H; Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Freeman A; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Zerbe C; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Uzel G; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Bergerson JRE; Primary Immune Deficiency Clinic (Autoimmune Lymphoproliferative Syndrome Clinic), Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Rao VK; Primary Immune Deficiency Clinic (Autoimmune Lymphoproliferative Syndrome Clinic), Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Olivier KN; Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Md., Lyons JJ; Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Lisco A; HIV Pathogenesis Section Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Cohen JI; Medical Virology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Lionakis MS; Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Biesecker LG; Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md., Xirasagar S; Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Notarangelo LD; Immune Deficiency Genetics Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Holland SM; Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md., Walkiewicz MA; Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Jazyk:	angličtina
Zdroj:	The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Oct; Vol. 150 (4), pp. 947-954. Date of Electronic Publication: 2022 Jun 24.
DOI:	10.1016/j.jaci.2022.06.009
Abstrakt:	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.)
Databáze:	MEDLINE
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