Novel frameshift variants expand the map of the genetic defects in IRF2BP2

Frontiers in Immunology

Immunology

Emilia Maneiro Pampín¹  María José Acuña Pérez¹  José María García-Aznar¹  Maite García Ramos¹  Nerea Paz Gandiaga²  Javier Gonzalo Ocejo Vinyals³  Erika M. Novoa Bolívar⁴  Roger Colobran⁵  Pere Soler-Palacin⁶  Olga Calavia⁷  Laura Minguell Domingo⁸ 

[1] Department of Immunology, Health in Code, A Coruña, Galicia, Spain;Genetics Division, Universitary Hospital Marqués de Valdecilla, Santander, Canatabria, Spain;Immunology Division, Universitary Hospital Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain;Immunology Division, Universitary Hospital Virgen de la Arrixaca, Murcia, Spain;Immunology Division, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, Spain;Translational Immunology Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain;Department of Clinical and Molecular Genetics, Vall d’Hebron University Hospital (HUVH), Barcelona, Catalonia, Spain;Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain;Pediatric Infectious Diseases and Immunodeficiencies Unit, Children’s Hospital, Barcelona, Catalonia, Spain;Infection and Immunity in Pediatric Patients Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain;Pediatrics Division, Hospital Joan XXIII, Tarragona, Catalonia, Spain;Pediatrics Division, Universitary Hospital Arnau de Vilanova, Lleida, Catalonia, Spain;

关键词: IRF2BP2;    CVID;    colitis;    primary immunodeficiency;    loss-of-function mutations;   

DOI  :  10.3389/fimmu.2023.1279171

 received in 2023-08-17, accepted in 2023-09-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundAt present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations.MethodsWe analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families.ResultsIn this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance.ConclusionsWe describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.

【 授权许可】

Unknown   
Copyright © 2023 García-Aznar, Maneiro Pampín, García Ramos, Acuña Pérez, Paz Gandiaga, Minguell Domingo, Calavia, Soler-Palacin, Colobran, Novoa Bolívar and Ocejo Vinyals