The role of genomics in common variable immunodeficiency disorders

Area of Science:

• Genetics and Genomics
• Immunology
• Precision Medicine

Background:

• Primary immunodeficiencies (PID) are rare genetic disorders impacting the immune system.
• Common variable immunodeficiency disorders (CVID) represent a significant subset of PID, characterized by antibody deficiency.
• Next-generation sequencing (NGS) has accelerated the identification of genetic causes for PIDs.

Purpose of the Study:

• To review the impact of NGS and 'omic' technologies on understanding PID genetics.
• To highlight the genetic complexity of CVID, suggesting polygenic inheritance.
• To advocate for a multi-omic approach to uncover CVID pathogenesis and therapeutic strategies.

Main Methods:

• Review of current literature on NGS applications in PID and CVID.
• Analysis of findings from genomewide association studies and whole genome sequencing in CVID.
• Discussion of contributions from RNA sequencing and epigenetic studies to CVID research.

Main Results:

• NGS has significantly increased the number of identified causative genes for PIDs.
• CVID is often polygenic, with a monogenic cause identified in only a small fraction of patients.
• Altered gene expression plays a role in CVID pathogenesis, as revealed by RNA sequencing and epigenetic studies.

Conclusions:

• A multi-omic strategy integrating DNA sequencing, gene expression, methylation, proteomics, and metabolomics is essential for CVID research.
• This comprehensive approach will facilitate the identification of novel disease-associated pathways.
• Identifying new pathways will pave the way for targeted therapeutic interventions in CVID.