Review: Diagnosing Common Variable Immunodeficiency Disorder in the Era of Genome Sequencing
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Common variable immunodeficiency disorders (CVID) are an enigmatic group of often heritable conditions, which may manifest for the first time in early childhood or as late as the eighth decade of life. In the last 5 years, next generation sequencing (NGS) has revolutionised identification of genetic disorders. However, despite the best efforts of researchers around the globe, CVID conditions have been slow to yield their molecular secrets. We have previously described the many clinical advantages of identifying the genetic basis of primary immunodeficiency disorders (PIDs). In a minority of CVID patients, monogenic defects have now been identified. If a causative mutation is identified, these conditions are reclassified as CVID-like disorders. Here we discuss recent advances in the genetics of CVID and discuss how NGS can be optimally deployed to identify the causal mutations responsible for the protean clinical manifestations of these conditions. Diagnostic criteria such as the Ameratunga et al. criteria will continue to play an important role in patient management as well as case selection and sequencing strategy design until the genetic conundrum of CVID is solved.
KeywordsCVID NGS IVIG CVID-like disorders
We are extremely grateful to our patients for allowing us to undertake these studies for the benefit of others. We hope this discovery will benefit them and any future families with these disorders. We thank AMRF, A+ Trust, IDFNZ, ASCIA, and the Australian National Health and Medical Research Council (NHMRC, Program Grant 1054925) and Project 1127198 for grant support. We also receive support from Bloody Long Way (BLW). C.S. is supported by NHMRC postgraduate scholarship 1075666. We thank Dr. Kitty Croxson, ADHB, and LabPlus management for ongoing support. Bioinformatic analysis was supported by the New Zealand eScience Infrastructure. All studies were approved by Auckland Hospital (3435), NZ Ministry of Health (MEC/06/10/134), and the Walter and Eliza Hall Institute (WEHI) Human Research Ethics Committee (HREC 10/02).
Compliance with Ethical Standards
Conflict of Interest
All authors declare they have no conflicts of interest.
RA- wrote the first draft.
KL- wrote bioinformatics section.
STW, DG, and RS edited and revised the manuscript.
CS and VB contributed to the text.
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