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| Pàgina inicial > Articles > Articles publicats > Evaluating the Genetics of Common Variable Immunodeficiency : |
(Universitat Pompeu Fabra) (Hospital Clínic i Provincial de Barcelona) (Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Universitat Pompeu Fabra) (Universitat Pompeu Fabra) (Universitat Pompeu Fabra) (Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Hospital Clínic i Provincial de Barcelona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
| Data: | 2018 |
| Resum: | Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p. C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. |
| Ajuts: | Ministerio de Economía y Competitividad SAF2012-35025 Ministerio de Economía y Competitividad ES-2013-064333 Ministerio de Economía y Competitividad SAF2015-68472-C2-2-R Ministerio de Ciencia e Innovación BFU2016-77961-P Ministerio de Economía y Competitividad BES-2012-051794 Ministerio de Economía y Competitividad PI14/00405 Ministerio de Economía y Competitividad PI12/01990 Ministerio de Economía y Competitividad PI15/01094 Ministerio de Economía y Competitividad PI13/00676 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR-866 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR-702 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Common variable immunodeficiency ; Primary immunodeficiency ; Exome sequencing ; Loss-of-function ; Rare disease genetics |
| Publicat a: | Frontiers in immunology, Vol. 9 (may 2018) , ISSN 1664-3224 |
