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ABSTRACT Introduction Genetic testing of patients with clinically diagnosed or suspected primary immunodeficiencies (PIDs) constitutes standard of care. Choice of testing modality and patient attributes can impact the likelihood of securing a diagnosis. Areas covered Published diagnostic rates for gene panel testing, exome sequencing (WES), and whole genome sequencing are compared among cohorts identified within PubMed. Performance of the testing platforms is reviewed in PIDs taken as a whole, followed by separate cohorts of patients with suspected PIDs, specific PIDs, and clinical phenotypes that can be associated with underlying PIDs. Expert opinion Massively parallel high-throughput sequencing clearly represents the most expedient method for diagnosis of PIDs. For patients from highly consanguineous backgrounds, WES and whole genome sequencing should be performed to obtain optimal diagnostic yield. For patients for whom familial consanguinity is unlikely, choice of platform depends upon the phenotype. In patients with suspected PIDs, assessment for copy number variants is important, whether as part of gene panel bioinformatic analyses or combined with WES. Diagnostic rates overall for massively parallel sequencing are high for clinically diagnosed and suspected PIDs. WES may have a slightly higher overall yield, but gene panel testing represents a cost-effective and efficient reasonable initial step.