Review

. 2022 Oct;150(4):947-954.

doi: 10.1016/j.jaci.2022.06.009. Epub 2022 Jun 24.

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

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

Affiliations

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.

PMID: 35753512
PMCID: PMC9547837
DOI: 10.1016/j.jaci.2022.06.009

Review

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

Morgan N Similuk et al. J Allergy Clin Immunol. 2022 Oct.

. 2022 Oct;150(4):947-954.

doi: 10.1016/j.jaci.2022.06.009. Epub 2022 Jun 24.

Authors

Affiliations

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.

PMID: 35753512
PMCID: PMC9547837
DOI: 10.1016/j.jaci.2022.06.009

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.

Trial registration: ClinicalTrials.gov NCT03206099.

Keywords: Genomics; Mendelian disorder; chromosomal microarray analysis; copy number variation; exome sequencing; genetics; immune system; immunology; inborn errors of immunity; secondary findings.

Published by Elsevier Inc.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST: LGB is a member of the Illumina Medical Ethics Board and receives honoraria from Cold Spring Harbor Press. All other authors disclose no other conflicts of interest.

DISCLOSURE OF CONFLICTS OF INTEREST

LGB is a member of the Illumina Medical Ethics Board and receives honoraria from Cold Spring Harbor Press.

Figures

**Figure 1.**
Figure 1 shows the distribution of molecular diagnoses by mode of inheritance. Blue shading indicates the subset of variants which had not been previously reported in the Human Gene Mutation Database Pro or reported in the literature in association with disease. Copy number variation is indicated by dark and light gray, indicating loss and gain, respectively.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical