When recipient testing becomes donor testing: recognizing incidental genetic findings of potential donor origin after allogeneic hematopoietic cell transplantation

As next-generation sequencing (NGS) is increasingly used after allogeneic hematopoietic cell transplantation (allo-HCT), recipient molecular testing may inadvertently characterize donor-derived hematopoiesis in patients with donor-predominant chimerism. Existing donor-disclosure frameworks provide guidance once donor origin is suspected, but less guidance exists for the clinical and laboratory steps needed to interpret, report, and manage post-transplant molecular findings that may reflect donor hematopoiesis. We present two cases illustrating these challenges. In a patient with acute myeloid leukemia, a DDX41 variant of uncertain significance was detected at germline-level variant allele frequency during donor-predominant chimerism and was absent from pre-transplant recipient testing, supporting probable donor origin. In a patient with B-acute lymphoblastic leukemia and myeloid lineage switch, a DNMT3A variant distinct from the recipient’s original mutation was identified at low variant allele frequency following donor engraftment, suggesting clonal hematopoiesis of possible donor origin. These cases demonstrate that post-transplant molecular findings require integration of chimerism status, prior recipient molecular data, variant characteristics, and donor-recipient context. They also highlight a bidirectional disclosure problem in which donor-origin interpretation may be necessary to avoid misclassifying a result as recipient-derived, while discussion of donor origin with the recipient may reveal private genetic information about the donor. We propose practical measures including chimerism-informed molecular review, standardized laboratory report annotation, contextual variant interpretation, and clear donor-notification pathways to help ensure potential donor-origin findings are recognized, interpreted and managed appropriately.