With the rapid advancement of precision genomics, the role of genetic predisposition genes in the diagnosis and treatment of hematologic malignancies has become increasingly evident. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), germline genetic variants not only influence disease susceptibility and immune status, but also profoundly affect post-transplant immune reconstitution, complication risks, and long-term survival outcomes. Consequently, incorporating genetic predisposition genes into systematic pre-transplant evaluation has emerged as a critical strategy for improving both the safety and efficacy of transplantation.

Professor Zhihui Li from the hematopoietic stem cell transplantation team at GoBroad Healthcare Group provides an in-depth interpretation of the clinical value of genetic predisposition genes in guiding transplant decision-making.

Patients with Homozygous IEI Mutations: Superior Survival Outcomes with Unrelated Donors

Studies have shown that patients harboring homozygous mutations in genes associated with inborn errors of immunity (IEI) achieve significantly better survival outcomes when transplanted with unrelated donors compared with related donors. The underlying reason lies in the familial aggregation of IEI-associated mutations. Related donors are more likely to carry the same homozygous or heterozygous pathogenic variants, resulting in donor-derived hematopoietic and immune cells with latent functional defects.

After transplantation, these hidden immune deficiencies may impair effective immune reconstitution, increasing the risk of severe infections and non-relapse-related mortality. In contrast, the likelihood that an unrelated donor carries the same homozygous IEI mutation is extremely low. Such donors typically possess intact immune function, facilitating robust and stable immune reconstitution, thereby reducing transplant-related complications and improving long-term survival.

Pre-Transplant Genetic Testing: From an “Optional Tool” to a Foundational Component

Based on these findings, testing for genetic predisposition genes should be considered a fundamental component of pre-transplant evaluation. For patients with hematologic malignancies who are candidates for allo-HSCT, systematic screening of genes related to hematopoiesis and immune function is recommended, with particular attention to IEI-associated genes and variants linked to cellular and humoral immunodeficiencies.

Genetic testing results not only support comprehensive risk assessment, but also directly inform donor selection and transplant strategy development, enabling more rational and evidence-based clinical decisions.

Genetics-Guided Donor Selection and Risk-Stratified Management

In donor selection, patients carrying homozygous IEI-related mutations should preferentially receive grafts from unrelated donors to minimize potential genetic and immunologic risks. For patients with pathogenic germline variants affecting cellular or humoral immunity, priority should be given to donors with intact immune function who do not harbor the same high-risk variants, regardless of whether the donor is related or unrelated.

At the same time, these patients should be classified as a high-risk transplant population and managed accordingly after transplantation. Risk-stratified post-transplant care should include intensified dynamic monitoring of immune reconstitution, enhanced infection prevention and early intervention strategies, and the use of immunologic supportive therapies when necessary, in order to reduce transplant-related complications.

Toward Personalized Transplantation: Genetics-Driven Optimization of Clinical Decision-Making

Overall, genetic predisposition information introduces a new dimension to decision-making in allogeneic hematopoietic stem cell transplantation. From donor selection to post-transplant management, individualized strategies based on germline genetic risk can enable safer and more precise transplantation.

Looking ahead, the systematic integration of genetic assessment into the transplant workflow has the potential to further improve transplant success rates and deliver greater long-term survival benefits for patients.