Article ; Online: A large deletion in a non-coding regulatory region leads to NFKB1 haploinsufficiency in two adult siblings.
Clinical immunology (Orlando, Fla.)
2024 Volume 261, Page(s) 110165
Abstract: 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 ... ...
| Abstract | 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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| MeSH term(s) | 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 |
| Chemical Substances | NF-kappa B ; NFKB1 protein, human ; NF-kappa B p50 Subunit |
| Language | English |
| Publishing date | 2024-02-27 |
| Publishing country | United States |
| Document type | Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1459903-x |
| ISSN | 1521-7035 ; 1521-6616 |
| ISSN (online) | 1521-7035 |
| ISSN | 1521-6616 |
| DOI | 10.1016/j.clim.2024.110165 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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