The role of genomics in common variable immunodeficiency disorders

Abstract

The advent of next-generation sequencing (NGS) and 'omic' technologies has revolutionized the field of genetics, and its implementation in health care has the potential to realize precision medicine. Primary immunodeficiencies (PID) are a group of rare diseases which have benefited from NGS, with a massive increase in causative genes identified in the past few years. Common variable immunodeficiency disorders (CVID) are a heterogeneous form of PID and the most common form of antibody failure in children and adults. While a monogenic cause of disease has been identified in a small subset of CVID patients, a genomewide association study and whole genome sequencing have found that, in the majority, a polygenic cause is likely. Other NGS technologies such as RNA sequencing and epigenetic studies have contributed further to our understanding of the contribution of altered gene expression in CVID pathogenesis. We believe that to unravel further the complexities of CVID, a multi-omic approach, combining DNA sequencing with gene expression, methylation, proteomic and metabolomics data, will be essential to identify novel disease-associated pathways and therapeutic targets.

Keywords: CVID; genomics; immunodeficiency.

Figure 1

There are multiple genetic components involved in common variable immunodeficiency disorder (CVID) pathogenesis. Monogenic causes of CVID has been found in approximately 10% of cases, and primarily modify molecules associated with the B cell receptor complex. In most cases there is a polygenic mode of inheritance, whereby variants in multiple genes can contribute to the same or diverse phenotypes. Further genetic complexity may come from transcriptional and epigenetic disturbances.