Genomics in rare immune disorders From molecular yield to meaningful use

Advances in genomic sequencing have substantially improved the molecular diagnosis of rare diseases, including inborn errors of immunity (IEI). However, the clinical and personal benefits of genomic data are realized inconsistently, reflecting gaps in access, interpretation, and implementation rather than a lack of diagnostic consequence. This dissertation examines genomic medicine in IEI through an integrated lens that spans molecular diagnostic yield, clinical utility, and patient-centered implications of genomic information. Drawing on data from a large, centralized sequencing program, this work combines quantitative analyses, qualitative interviews, and clinical outcome studies to evaluate how genomic information is generated and used in practice.
Early chapters examine patient and family understanding of secondary genomic findings, demonstrating generally adequate understanding with variation in understanding of scope and implications by genetic literacy. Subsequent chapters assess the clinical utility of genomic sequencing in IEI, including exome sequencing of 1,000 families, which yielded molecular diagnoses in approximately one-third of cases and demonstrated the importance of iterative reanalysis. A narrative review presents an integrative model that accounts for genetic, environmental, and temporal influences on disease expression. Later chapters extend these findings to real-world applications, exploring how genomic information shapes reproductive decision-making among individuals with IEI and evaluating associations between comprehensive genomic evaluations and survival outcomes following hematopoietic stem cell transplantation.
Together, these findings highlight both the potency and the uneven realization of genomic medicine. This dissertation advances a model of genomic care that is scientifically rigorous, ethically grounded, and explicitly patient-centered. It suggests that future progress in the field will depend not only on continued technical innovation, but also on improved communication, equitable implementation, and durable strategies for integrating evolving genomic knowledge into clinical decision-making.