Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

Since the topic of primary immunodeficiencies (PIDs) and the associated diagnostic testing is exhaustive and highly complex [1], this review article will focus primarily on 2 key methodologies used for the laboratory diagnosis of PIDs - flow cytometry and genetic testing, by offering case-based examples.The hallmark of most PIDs is susceptibility to recurrent and life-threatening infections, since the cardinal role of the immune system is host defense. However, the clinical spectrum of PIDs is very diverse and can include other manifestations such as autoimmunity, neoplasia, and congenital anomalies of organs and/or skeleton. Therefore, the traditional role of the laboratory has been to provide supportive data to a largely clinical, radiological and family history-based diagnostic approach. The development of reagents capable of identifying disease-specific mutated proteins along with the ability to evaluate multiple subsets of immune cells and their function, such as respiratory burst, proliferation or phosphorylation, simultaneously, facilitated the incorporation of multi-color and functional flow cytometry into the diagnostic work-up for PIDs.While flow cytometry may be diagnostic for many PIDs where specific proteins and/or defective function can be directly assessed (Table 1)[2-4], the relevance of confirming the diagnosis by genetic testing or mutation analysis still remains germane,[5,6] especially when protein is present but non-functional. Further, genetic testing can provide a venue for genetic counseling by aiding in the identification of carriers, particularly for X-linked diseases, as well as enabling prenatal diagnosis. It is particularly helpful in elucidating the correlation between phenotype and genotype, when there are either allelic variants or unusual presentations present, leading to prognostic insights. But, surpassing all these is the role of genetic testing in identifying asymptomatic individuals who carry a defective gene associated with a p