A large deletion in a non-coding regulatory region leads to NFKB1 haploinsufficiency in two adult siblings.

Male Adult Humans Middle Aged Siblings Haploinsufficiency / genetics DNA Copy Number Variations NF-kappa B / genetics Common Variable Immunodeficiency / genetics Regulatory Sequences, Nucleic Acid NF-kappa B p50 Subunit / genetics
Copy number variation (CNV) Hypogammaglobulinemia Inborn error of immunity (IEI) NFKB1 Noncoding region Nuclear factor k light-chain enhancer of activated B cells (NFκB) Primary immunodeficiency Promoter p105 p50

Journal

Clinical immunology (Orlando, Fla.)
ISSN: 1521-7035
Titre abrégé: Clin Immunol
Pays: United States
ID NLM: 100883537

Informations de publication

Date de publication:
Apr 2024
Historique:
received: 10 10 2023
revised: 19 01 2024
accepted: 26 02 2024
medline: 18 3 2024
pubmed: 1 3 2024
entrez: 29 2 2024
Statut: ppublish

Résumé

Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost ¼ of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.

Identifiants

DOI: 10.1016/j.clim.2024.110165 PMID: 38423196
pubmed: 38423196
pii: S1521-6616(24)00056-1
doi: 10.1016/j.clim.2024.110165
pii:
doi:

Substances chimiques

NF-kappa B 0
NFKB1 protein, human 0
NF-kappa B p50 Subunit 0

Types de publication

Case Reports Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

110165

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare they have no conflicts of interest.

Auteurs

Mathieu Fusaro (M)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital - Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: mathieu.fusaro@inserm.fr.

Cyrille Coustal (C)

Internal Medicine and Multi-Organic Diseases Department, Hôpital Saint Éloi, CHU Montpellier, Montpellier, France.

Laura Barnabei (L)

Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR 1163, F-75015 Paris, France.

Quentin Riller (Q)

Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR 1163, F-75015 Paris, France.

Marion Heller (M)

Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital - Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Duong Ho Nhat (D)

Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR 1163, F-75015 Paris, France.

Cécile Fourrage (C)

INSERM-UMR 1163, Imagine Institute, Paris, France; Bioinformatics Core Facility, INSERM-UMR 1163, Imagine Institute, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3633, INSERM, University Paris Cité, Paris, France.

Sophie Rivière (S)

Internal Medicine and Multi-Organic Diseases Department, Hôpital Saint Éloi, CHU Montpellier, Montpellier, France.

Frédéric Rieux-Laucat (F)

Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR 1163, F-75015 Paris, France.

Alexandre Thibault Jacques Maria (ATJ)

Internal Medicine & Onco-Immunology (MedI2O), Institute for Regenerative Medicine and Biotherapy (IRMB), Montpellier University Hospital, Montpellier, France; IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France.

Capucine Picard (C)

Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital - Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Pediatric Immuno-Hematology and Rheumatology Unit, Necker Hospital for Sick Children - AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies CEREDIH, Necker University, Hospital for Sick Children - AP-HP, Paris, France.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Personnes › Fratrie › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteur de transcription NF-kappa B › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Déficit immunitaire commun variable › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Séquences d'acides nucléiques régulatrices › A large deletion in a non-coding regulatory...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteur de transcription NF-kappa B › Sous-unité p50 de NF-kappa B › A large deletion in a non-coding regulatory...