Contributors: Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Hôpital Saint Eloi CHU Montpellier; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Structure Fédérative de Recherche Necker (UAR 3633 / US24); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB); Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM); Service d'immuno-hématologie pédiatrique CHU Necker; Research in CP laboratory was supported by the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH) and ERA-Net for Research Programmes on Rare Diseases (E-Rare: EuroCID, ANR RANR187; n◦061-2016-050). M.F. is supported by Fondation pour la Recherche Médicale (grant ID: FDM202006011216). Research in FRL’s laboratory was supported by fundings from the Institut National de la Santé et de la Recherche Médicale (INSERM), the French government (managed by French National Research Agency (Agence Nationale de la Recherche) through the “Investissements d’avenir” program (Institut Hospitalo-Universitaire Imagine, grant reference: ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant reference: ANR-18-RHUS-0010)), and other grants from the Agence National de la Recherche (ANR-18-CE17-0001 “Action”), and the Fondation pour la Recherche Médicale (grant reference: Equipe FRM EQU202103012670). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its “Investments for the Future” program.; ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010); ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018); ANR-18-CE17-0001,ACTION,Cytopénies Auto-immunes: génétique et mécanismes physiopathologiques du syndrome d'Evans pédaitrique(2018); ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017); ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
نبذة مختصرة : International audience ; 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.
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