Management change following NGS diagnosis of inborn errors of immunity: The Australasian experience

Inborn errors of immunity (IEIs) are rare monogenic disorders with diverse, often life-limiting manifestations. Next-generation sequencing (NGS) has transformed IEI diagnostics, but data on therapeutic impact remain limited. We conducted a multicenter retrospective study through the Clinical Immunogenomics Research Consortium of Australasia, encompassing 12 hospitals across Australia and New Zealand. Probands with confirmed monogenic IEIs diagnosed by panel, whole-exome, or whole-genome sequencing were included. Among 205 probands with pathogenic variants in 86 genes, NGS findings prompted management changes in 84%: 71.7% major and 12.2% minor. Major changes included recommendation/planning for hematopoietic stem cell transplant (40.8%), initiation of targeted therapies (39.5%), and immunoglobulin replacement or prophylactic antimicrobials (18.4% each). Cascade testing identified 32 affected relatives, including four from probands who themselves did not have a discernible management change, demonstrating the broader impact of molecular diagnosis. Overall, NGS-based diagnosis drove substantial management changes and further defined the Australasian IEI landscape, supporting early genomic testing as a cornerstone of precision care.