دورية أكاديمية
أعرض في EDS

Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.

التفاصيل البيبلوغرافية
العنوان: Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.
المؤلفون: Baxter SK; Department of Pediatrics (Pediatric Rheumatology), University of Washington, Seattle, Wash; Seattle Children's Hospital and Research Institute, Seattle, Wash; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash., Walsh T; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash., Casadei S; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash., Eckert MM; Seattle Children's Hospital and Research Institute, Seattle, Wash., Allenspach EJ; Department of Pediatrics (Pediatric Rheumatology), University of Washington, Seattle, Wash; Seattle Children's Hospital and Research Institute, Seattle, Wash., Hagin D; Seattle Children's Hospital and Research Institute, Seattle, Wash; Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, University of Tel Aviv, Tel Aviv, Israel., Segundo G; Department of Pediatrics (Allergy and Immunology), Universidade Federal de Uberlandia, Minas Gerais, Brazil., Lee MK; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash., Gulsuner S; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash., Shirts BH; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Wash., Sullivan KE; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa., Keller MD; Division of Allergy and Immunology, Children's National Hospital, Washington, DC., Torgerson TR; Department of Pediatrics (Pediatric Rheumatology), University of Washington, Seattle, Wash; Seattle Children's Hospital and Research Institute, Seattle, Wash., King MC; Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, Wash. Electronic address: mcking@uw.edu.
المصدر: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Jan; Vol. 149 (1), pp. 327-339. Date of Electronic Publication: 2021 Apr 20.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Mosby Country of Publication: United States NLM ID: 1275002 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-6825 (Electronic) Linking ISSN: 00916749 NLM ISO Abbreviation: J Allergy Clin Immunol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: St Louis, Mosby.
مواضيع طبية MeSH: Diabetes Mellitus, Type 1/*congenital , Diarrhea/*genetics , Genetic Diseases, X-Linked/*genetics , Immune System Diseases/*congenital, Adolescent ; Child ; Child, Preschool ; Diabetes Mellitus, Type 1/diagnosis ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/therapy ; Diarrhea/diagnosis ; Diarrhea/therapy ; Female ; Gene Expression ; Genetic Diseases, X-Linked/diagnosis ; Genetic Diseases, X-Linked/therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Immune System Diseases/diagnosis ; Immune System Diseases/genetics ; Immune System Diseases/therapy ; Infant ; Infant, Newborn ; Male ; Mutation
مستخلص: Background: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes.
Objective: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management.
Methods: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis.
Results: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation.
Conclusions: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.
(Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: R35 CA197458 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Immune dysregulation; autoimmunity; genetics; inborn errors of immunity; molecular diagnosis; pediatric; precision medicine; primary immunodeficiency disorders; sequencing
SCR Disease Name: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome
تواريخ الأحداث: Date Created: 20210417 Date Completed: 20220303 Latest Revision: 20230102
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8526646
DOI: 10.1016/j.jaci.2021.04.005
PMID: 33864888
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-6825
DOI:10.1016/j.jaci.2021.04.005