Diagnosing common variable immunodeficiency disorders in the era of genome sequencing

Abstract

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. There is no single clinical feature or laboratory test that can confirm the diagnosis with certainty, since by definition, there is no known cause for these conditions. Over the last 17 years, an increasing number of genetic defects have been identified in patients with a CVID phenotype. If a causative mutation is identified, patients are removed from the umbrella diagnosis of CVID and are deemed to have a CVID-like disorder caused by a specific primary immunodeficiency/inborn error of immunity (PID/IEI). Currently, causative mutations are identified in about 25% of patients with a CVID phenotype in non-consanguineous populations. In the remaining patients, the explanation for these disorders remains unclear. There are many advantages in identifying the causative genetic defect, as it may lead to specific forms of treatment, in addition to subcutaneous or intravenous immunoglobulin (SCIG/IVIG). It will allow family studies and may allow future reduction in the prevalence of PIDs by preimplantation genetic diagnosis (PGD). Next generation sequencing (NGS) has revolutionised genetic testing. It allows rapid sequencing of multiple genes simultaneously. NGS has made routine diagnostic sequencing of disorders with genetic heterogeneity such as CVID, cost-effective. Given the profound benefits of identifying the underlying mutation, we advocate all patients with a CVID phenotype should now be routinely offered diagnostic genetic sequencing after appropriate counselling.