Dataset Information

Recent advances in elucidating the genetics of common variable immunodeficiency.

ABSTRACT: Common variable immunodeficiency disorders (CVID), a heterogeneous group of inborn errors of immunity, is the most common symptomatic primary immunodeficiency disorder. Patients with CVID have highly variable clinical presentation. With the advent of whole genome sequencing and genome wide association studies (GWAS), there has been a remarkable improvement in understanding the genetics of CVID. This has also helped in understanding the pathogenesis of CVID and has drastically improved the management of these patients. A multi-omics approach integrating the DNA sequencing along with RNA sequencing, proteomics, epigenetic and metabolomics profile is the need of the hour to unravel specific CVID associated disease pathways and novel therapeutic targets. In this review, we elaborate various techniques that have helped in understanding the genetics of CVID.

SUBMITTER: Aggarwal V

PROVIDER: S-EPMC7063417 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recent advances in elucidating the genetics of common variable immunodeficiency.

Aggarwal Vaishali V Banday Aaqib Zaffar AZ Jindal Ankur Kumar AK Das Jhumki J Rawat Amit A

Genes & diseases 20191015 1

Common variable immunodeficiency disorders (CVID), a heterogeneous group of inborn errors of immunity, is the most common symptomatic primary immunodeficiency disorder. Patients with CVID have highly variable clinical presentation. With the advent of whole genome sequencing and genome wide association studies (GWAS), there has been a remarkable improvement in understanding the genetics of CVID. This has also helped in understanding the pathogenesis of CVID and has drastically improved the manage ...[more]

PMID: 32181273

Similar Datasets

Project description: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.

Dataset Information

Recent advances in elucidating the genetics of common variable immunodeficiency.

Publications

Recent advances in elucidating the genetics of common variable immunodeficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets