Utility of Expanded Genetic Analysis for Pediatric Patients with Primary Immunodeficiency

Background Given the heterogenicity among primary immune deficiency (PID) or inborn errors of immunity (IEI) presentations, genetic testing can aid in diagnosis. Despite the convenience of genetic testing, numerous challenges arise, including accessibility and cost. Aims Our goal was to determine if a gene panel approach was sufficient in identifying PID or if expanded testing would be more beneficial. Methods A retrospective chart review analyzed the diagnostic yield for all patients with suspected PID that underwent PID panel testing at our hospital. Subsequently, from January 2021 to August 2024 caregivers of patients with a negative or non-diagnostic PID panel result were consented for additional exome analysis. Expanded analysis was performed via genotypic-based and phenotypic-driven analysis derived from Human Phenotype Ontology terms from chart notes. Variants of potential clinical interest were identified utilizing American College of Medical Genetics and Genomics recommendations for sequence variant interpretation. Variants of interest were cross-referenced to patient phenotype. Results Of the 174 panels run, there was a positive diagnostic yield of 19%. Twelve patients had expanded analysis completed with mean age of symptom presentation of 4.3 years. Expanded analysis identified numerous additional variant of uncertain significance as well as 1 new pathogenic variant. Conclusion This analysis resulted in a minimal increase in diagnostic yield compared to panel testing. Although only 1 new pathogenic variant consistent with the patient's phenotype was identified; the increase in variants of interest from the expanded analysis supports the value of ongoing genomic reanalysis. Given the comparable diagnostic yield, PID panels remain a cost-effective approach at this time.