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.

This study was funded by grants SAF2012-35025 and SAF2015-68472-C2-2-R from the Ministerio de Economía y Competitividad (Spain) and FEDER (EU) to FC; by Direcció General de Recerca, Generalitat de Catalunya (2014SGR-866 and 2017SGR-702) to FC and EB; to EB by grant BFU2016-77961-P from Ministerio de Economía, Industria y Competitividad (Spain) AEI (Spain) and FEDER (EU); by Instituto de Salud Carlos III, grant PI14/00405, cofinanced by the European Regional Development Fund (ERDF) to RC; partially funded by CERCA Programme/Generalitat de Catalunya (JIA), and SAF2015-68472-C2-1-R grant from the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) to JIA; GV-I was supported by grant BES-2012-051794; JH-R was supported by grant BES-2013-064333. TMB is supported by U01 MH106874 grant, Howard Hughes International Early Career, Obra Social “La Caixa” and Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya. All phases of this study were supported by the projects PI12/01990 and PI15/01094 to LA and PI13/00676 to MJ. This work was also supported by the Jeffrey Modell Foundation. This study makes use of data generated by the Medical Genome Project. A full list of the investigators who contributed to the generation of the data is available from http://www.medicalgenomeproject.com/en. Funding for the project was provided by the Spanish Ministry of Economy and Competitiveness, projects I + D + i 2008, Subprograma de actuaciones Científicas y Tecnológicas en Parques Científicos y Tecnológicos (ACTEPARQ 2009) and ERFD.