TABLE 2.

Evaluation of patients for primary immunodeficiencies^a

Criteria in diagnosis of PIDs	Confounders in diagnosis of PIDs
Family history of PID	Large numbers of new genetic defects identified in a relatively short span of time, making it challenging for many specialty practitioners to stay updated
Syndromic defect (e.g., ataxia telangiectasia)	Considerable variability in genotype-phenotype correlations
Unusual infection (susceptibility to a single microorganism, e.g., Mendelian susceptibility to mycobacterial disease) or recurrent infections	Expanding phenotypic spectrum for known genetic defects
Significant autoimmunity (autoimmune cytopenias or multiple organ-specific autoimmunity)	Somatic mosaicism; digenic PIDs (two genetic defects associated with a PID); two-hit hypothesis (underlying monogenic defect that is phenotypically unmasked by infection or other triggering event)
Laboratory anomaly (e.g., hypogammaglobulinemia)	Need for functional characterization of new genetic findings; role of epigenetic changes in modulating phenotype, copy number variations (CNV) contributing to phenotype
Genetic diagnosis via whole-exome sequencing or whole-genome sequencing	Phenocopies of PIDs (autoantibodies to immunologically relevant proteins that cause clinical conditions phenotypically similar to those caused by known monogenic defects)

^aPatients with primary immunodeficiencies (PIDs) may present for evaluation in multiple ways, and the six criteria provided represent some of the possible contexts that should be considered during clinical assessment. There are several confounders that could pose a challenge to the diagnostic evaluation for PIDs, and some of these are presented in this table.