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

Exome / genetics Female Genetic Testing / methods Genomics Humans Male Phenotype Prospective Studies
Genomics Mendelian disorder chromosomal microarray analysis copy number variation exome sequencing genetics immune system immunology inborn errors of immunity secondary findings

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
10 2022
Historique:
received: 17 12 2021
revised: 07 05 2022
accepted: 02 06 2022
pubmed: 27 6 2022
medline: 12 10 2022
entrez: 26 6 2022
Statut: ppublish

Résumé

Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. 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. 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. 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. This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.jaci.2022.06.009 PMID: 35753512 PMC: PMC9547837
pubmed: 35753512
pii: S0091-6749(22)00839-9
doi: 10.1016/j.jaci.2022.06.009
pmc: PMC9547837
mid: NIHMS1823027
pii:
doi:

Banques de données

ClinicalTrials.gov
['NCT03206099']

Types de publication

Journal Article Review Research Support, N.I.H., Intramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

947-954

Subventions

Organisme : Intramural NIH HHS
ID : ZIA AI001222
Pays : United States

Informations de copyright

Published by Elsevier Inc.

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Auteurs

Morgan N Similuk (MN)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md. Electronic address: morgan.similuk@nih.gov.

Jia Yan (J)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Rajarshi Ghosh (R)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Andrew J Oler (AJ)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Luis M Franco (LM)

Functional Immunogenomics Unit, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md.

Michael R Setzer (MR)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Michael Kamen (M)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Colleen Jodarski (C)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Thomas DiMaggio (T)

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Joie Davis (J)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Rachel Gore (R)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Leila 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.

Adrienne Borges (A)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Nicole Gentile (N)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Julie Niemela (J)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Chenery Lowe (C)

Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.

Kathleen Jevtich (K)

School of Medicine, Uniformed Services University of Health Sciences, Bethesda, Md.

Yunting Yu (Y)

College of Medicine, Penn State, University Park, Pa.

Haley Hullfish (H)

School of Medicine, University of Miami, Miami, Fla.

Amy P Hsu (AP)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Celine Hong (C)

Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md.

Patricia Littel (P)

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Bryce A Seifert (BA)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Joshua Milner (J)

Institute of Genomic Medicine, Columbia University, New York, NY.

Jennifer J Johnston (JJ)

Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md.

Xi Cheng (X)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Zhiwen Li (Z)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Daniel Veltri (D)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Ke Huang (K)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Krishnaveni Kaladi (K)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Jason Barnett (J)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Lingwen Zhang (L)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Nikita Vlasenko (N)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Yongjie Fan (Y)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Eric Karlins (E)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Satishkumar Ranganathan Ganakammal (SR)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Robert Gilmore (R)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Emily Tran (E)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Alvin Yun (A)

Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Joseph Mackey (J)

Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Svetlana Yazhuk (S)

Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Justin Lack (J)

NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md.

Vasudev Kuram (V)

NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md.

Wenjia Cao (W)

NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md.

Susan Huse (S)

NIAID Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc, Frederick, Md.

Karen Frank (K)

Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md.

Gary Fahle (G)

Microbiology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md.

Sergio Rosenzweig (S)

Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md.

Yan Su (Y)

Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md.

SuJin Hwang (S)

Immunology Service, Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md.

Weimin Bi (W)

Department of Molecular and Human Genetics, Baylor Genetics, Houston, Tex.

John Bennett (J)

Clinical Mycology, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Ian A Myles (IA)

Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Suk See De Ravin (SS)

Laboratory of Host Defenses, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Ivan Fuss (I)

Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Warren Strober (W)

Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Bibiana Bielekova (B)

Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Adriana Almeida de Jesus (A)

Translational Autoinflammatory Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Raphaela Goldbach-Mansky (R)

Translational Autoinflammatory Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Peter Williamson (P)

Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Kelly Kumar (K)

Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Md.

Caeden Dempsy (C)

Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Pamela Frischmeyer-Guerrerio (P)

Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Robin Fisch (R)

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Hyejeong Bolan (H)

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Dean D Metcalfe (DD)

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Hirsh Komarow (H)

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Melody Carter (M)

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Kirk M Druey (KM)

Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Irini Sereti (I)

HIV Pathogenesis Section Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Lesia Dropulic (L)

Medical Virology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Amy D Klion (AD)

Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Paneez Khoury (P)

Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Elise M O' Connell (EM)

Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Nicole C Holland-Thomas (NC)

Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Thomas Brown (T)

Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

David H McDermott (DH)

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Philip M Murphy (PM)

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Vanessa Bundy (V)

Division of Allergy and Immunology, Children's National Health System, Washington, DC.

Michael D Keller (MD)

Division of Allergy and Immunology, Children's National Health System, Washington, DC.

Christine Peng (C)

Division of Allergy and Immunology, Children's National Health System, Washington, DC.

Helen Kim (H)

Division of Allergy and Immunology, Children's National Health System, Washington, DC.

Stephanie Norman (S)

Division of Allergy and Immunology, Children's National Health System, Washington, DC.

Ottavia M Delmonte (OM)

Immune Deficiency Genetics Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Elizabeth Kang (E)

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Helen C Su (HC)

Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Harry Malech (H)

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Alexandra Freeman (A)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Christa Zerbe (C)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Gulbu Uzel (G)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Jenna R E 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.

V Koneti 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.

Kenneth N Olivier (KN)

Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Md.

Jonathan J Lyons (JJ)

Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Andrea Lisco (A)

HIV Pathogenesis Section Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Jeffrey I Cohen (JI)

Medical Virology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Michail S Lionakis (MS)

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Leslie G Biesecker (LG)

Center for Precision Health Research, National Human Genome Research Institute, Bethesda, Md.

Sandhya Xirasagar (S)

Bioinformatics and Computational Biosciences Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Luigi D Notarangelo (LD)

Immune Deficiency Genetics Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Steven M Holland (SM)

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

Magdalena A Walkiewicz (MA)

Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Md.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Exome › Clinical exome sequencing of 1000 families...
questionsmedicales.fr › Établissements, main d'oeuvre et services de soins de santé › Services de santé › Services de médecine préventive › Services de diagnostic › Dépistage génétique › Clinical exome sequencing of 1000 families...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Clinical exome sequencing of 1000 families...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Clinical exome sequencing of 1000 families...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Clinical exome sequencing of 1000 families...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › Clinical exome sequencing of 1000 families...