Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.

Autor: Garcia-Prat M; Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Pediatric Infectious Diseases and Immunodeficiencies Unit, Children's Hospital, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain., Batlle-Masó L; Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Pediatric Infectious Diseases and Immunodeficiencies Unit, Children's Hospital, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain., Parra-Martínez A; Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Pediatric Infectious Diseases and Immunodeficiencies Unit, Children's Hospital, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain., Franco-Jarava C; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Martinez-Gallo M; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Aguiló-Cucurull A; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Perurena-Prieto J; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Castells N; Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Medicine Genetics Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Urban B; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Dieli-Crimi R; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain., Soler-Palacín P; Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. pere.soler@vallhebron.cat.; Pediatric Infectious Diseases and Immunodeficiencies Unit, Children's Hospital, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. pere.soler@vallhebron.cat.; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain. pere.soler@vallhebron.cat., Colobran R; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain. roger.colobran@vallhebron.cat.; Translational Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. roger.colobran@vallhebron.cat.; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. roger.colobran@vallhebron.cat.; Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. roger.colobran@vallhebron.cat.; Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Bellaterra, Catalonia, Spain. roger.colobran@vallhebron.cat.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2024 Jan 24; Vol. 44 (2), pp. 54. Date of Electronic Publication: 2024 Jan 24.
DOI: 10.1007/s10875-024-01659-z
Abstrakt: The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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