Year: 2018
Type: article
Study design: Observational Study
Abstract: 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 CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15 to 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 to rare genetic functional variation in the CVID cohort compared to healthy controls.
Source: Frontiers in Immunology
Authors: Guillem de Valles-Ibáñez, Ana Esteve-Solé, Mònica Piquer, E. Azucena González-Navarro, Jessica Hernandez-Rodriguez, Hafid Laayouni, Eva González-Roca, Ana María Plaza-Martin, Ángela Deyà-Martínez, Andrea Martín-Nalda, Mónica Martínez-Gallo, Marina García-Prat, Lucía del Pino-Molina, Ivón Cuscó, Marta Codina-Solà, Laura Batlle-Masó, Manuel Solís-Moruno, Tomàs Marquès-Bonet, Elena Bosch, Eduardo López-Granados, Juan Ignacio Aróstegui, Pere Soler-Palacín, Roger Colobran, Jordi Yagüe, Laia Alsina, Manel Juan, Ferran Casals
Institutions: Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Institut de Biologia Evolutiva, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Sant Joan de Déu, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat Autònoma de Barcelona, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research, Centre for Biomedical Network Research on Rare Diseases, Institució Catalana de Recerca i Estudis Avançats, Barcelona Institute of Science and Technology, Centre for Genomic Regulation
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funders: Howard Hughes Medical Institute, Jeffrey Modell Foundation, Texas Medical Board, Centres de Recerca de Catalunya, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, National Institute of Mental Health, Direcció General de Recerca, Generalitat de Catalunya
Awards: G101141092, G1147610292, G177921026, G2514727360, G3105910846, G3196079523, Factores moduladores de la inmunodeficiencia primaria con susceptibilidad a las infecciones graves por gérmenes intracelulares en la edad pediátrica, G3630544980, G5904217091, G6121499907, G6493900072, Mejoras en el protocolo de tratamiento con linfocitos T transducidos con CART19 (receptor antigénico quimérico anti-CD19) en síndromes linfoproliferativos B: de la valoración epigenética a la introducción de genes suicidas, G743026944, Identificación de variantes genéticas causantes/moduladoras del fenotipo clínico en inmunodeficiencias primarias y con disregulación. Aplicación de la NGS., G8417972586, G8571299638
OpenAlex ID: W2804407076