To the Editor:

Telomere Biology Disorders (TBDs) are genetic disorders predominantly characterized by bone marrow failure (BMF), skin abnormalities, liver and lung disease [1]. Pathogenic germline variants in different genes functionally related to telomere maintenance result in TBD due to premature telomere shortening [1]. Current guidelines recommend genetic testing of potential matched-related donors for patients with TBDs evaluated for allogeneic hematopoietic stem cell transplantation (HSCT) [2]. Due to the underlying pathophysiology, the use of variant-carrying but asymptomatic donors is typically avoided even if there is no alternative donor available, as such individuals are expected to carry a substantially increased risk of primary or secondary graft failure [2]. However, evidence supporting this recommendation remains limited [3,4,5] and existing guidelines lack specific recommendations for the clinical dilemma of cases in urgent need for HSCT with only variant-carrying donors being available [2].

We conducted a retrospective analysis of the German Aplastic Anemia and Bone Marrow Failure Syndromes registry (AA-BMF registry; EK332/20, EK225/14) to evaluate whether hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) harboring a pathogenic germline variant may still represent a viable therapeutic option in highly selected cases. For this purpose, we were able to identify three cases in which patients underwent HSCT from a clinically asymptomatic MRD with an, at the time of HSCT, unknown pathogenic germline variant.

After obtaining informed consent, genetic analyses of tissue samples and peripheral blood were performed following HSCT, and clinical data were collected and analyzed. Genetic analyses were conducted using either exome or sanger sequencing on DNA extracted from hair roots (patient 1), fibroblasts (patient 2) or oral mucosa (patient 3) to identify germline variants. Additionally, DNA obtained from blood samples after HSCT was analyzed to detect variations originating from the bone marrow donor. Based on the analyzed exome data, there was no evidence of clonal hematopoiesis with a VAF ≥ 4%. Classification of the variants was carried out following ACMG-criteria (Supplementary Table 1). Telomere length (TL) analysis was performed by flow-FISH [6]. Patient 1 received HSCT from his brother at the age of 7 years for severe AA (Fig. 1A). He showed no signs of acute or chronic graft-versus-host disease after HSCT. However, by the age of 15, he developed esophageal strictures, followed by liver transplantation at the age of 20 years due to progressive hepatopathy. Over time, nail dystrophy and pigmentation abnormalities became evident. At the age of 28, genetic testing identified a homozygous, likely pathogenic variant in the TERT gene c.2266C>T, p.(Arg756Cys). TL was found to be below the 1st percentile across all cellular subsets in graft hematopoiesis (Fig. 1B). 23 years after HSCT, a bone marrow biopsy revealed severe hypocellularity, but blood counts in peripheral blood were still normal. In parallel, the stem cell donating brother was found to carry the same TERT variant in heterozygous state and had been diagnosed with Hodgkin’s lymphoma at the age of 22. The heterozygous parents did not exhibit clinical features of TBD.

Fig. 1
figure 1

A Clinical course of three patients with Telomere Biology Disorders (TBD). HSCT hematopoietic stem cell transplantation, MRD matched related donor, LTx liver transplantation, DNA-icon indicates genetic testing on blood, fibroblasts, hair roots or oral mucosa. B Telomere length of the three patients after BMT. The age of the patients (recipients) is shown on the x-axis. The red line represents the first percentile. The Blue line represents 99th percentile.

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Patient 2 was diagnosed with severe AA at the age of 3 years and received haploidentical HSCT from her father at the age of 5 years (Fig. 1A). At this time, she already suffered from esophageal strictures. Four years later, she developed an interstitial lung disease. No signs of graft-versus-host disease were documented. Other clinical manifestations of TBD were lacrimal duct stenosis and endocrinological symptoms since childhood. Genetic testing revealed a pathogenic heterozygous TERC gene variant (n.50C>A). Subsequently, she developed osteoporosis (aged 16) and enteropathy (aged 20). Her mother, who also carries the TERC variant, developed oral cavity cancer at the age of 32 and was diagnosed with pulmonary fibrosis. TL of donor hematopoiesis was measured below 1% percentile in all cellular subpopulations (Fig. 1B). Surprisingly, genetic analysis of donor hematopoiesis derived peripheral blood cells as well as fibroblasts revealed a heterozygous variant in RTEL1 c.3604C>T, p.(Gln1202*) indicating the diagnosis of TBD in her asymptomatic father who donated the stem cells and a dual diagnosis (TERC and RTEL1) in the patient. Her twin brother, who inherited both variants as well, shows clinical features of TBD. Patient 2 died 16 years after HSCT with normal blood counts from TBD-related interstitial lung disease.

Patient 3 presented with bicytopenia at age 20. He received HSCT from his monozygotic twin at the age of 40 on suspicion of myelodysplastic syndrome (Fig. 1A). Interestingly, poor stem cell mobilization was observed in the brother. Blood counts normalized after HSCT, but symptoms of cytopenia recurred nine years after HSCT, at the age of 49. He then developed acute respiratory failure due to EBV-associated alveolitis. In parallel his brother was diagnosed with mild cytopenia and an unusual high EBV load in the blood. Genetic diagnostics revealed the pathogenetic heterozygous TERT variant c.2851C>T, p.(Arg951Trp) in the patient and the twin brother. TL testing of graft hematopoiesis was measured below the 1st percentile across all cellular subsets (Fig. 1B).

Our report challenges the widely held dogma that variant-carrying family members are categorically deemed unsuitable for HSCT in TBD [2]. While to date, only three cases of HSCT from variant-carrying donors have been described with two patients showing signs of early graft failure [3,4,5] and clinical guidelines generally recommend to avoid variant carriers [2], all three retrospectively identified patients reported here maintained sufficient graft function over extended periods, even though telomeres were shortened below the first percentile in granulocytes and lymphocytes (as measured by flow-FISH) 9-, 21-, and 23-years post-transplant.

A potential explanation for this sustained graft function is that the initial TL of the donor cells, although compromised by a pathogenic variant, was still adequate to compensate for the increased replicative demand and the consecutive early telomere attrition typically observed after HSCT [7,8,9]. Unfortunately, this assumption could not be verified due to the lack of baseline TL measurements from the donors at the time of stem cell collection.

In contrast to the findings of previously published cases, poor stem cell mobilization—a recognized risk factor for graft failure—was reported only in patient 3 [3, 4, 10]. Therefore, administering an adequate number of stem cells might be particularly essential for the observed sustained graft function despite short telomeres and impaired telomere maintenance [6]. Obviously, further research is necessary to determine the extent to which pathogenic variants in specific genes and a potential residual function of affected gene products may contribute to sustained engraftment after HSCT.

The clinical management of TBD patients requiring HSCT in the absence of an HLA-matched unrelated donor remains particularly challenging: While HSCT from MRD has demonstrated significantly superior outcomes, the use of alternative donors — although effective in other hematologic conditions — is more problematic in TBD. Specifically, recent evidence suggests that HLA-mismatched donors and conditioning regimens containing alkylating agents such as cyclophosphamide are associated with substantially lower overall survival in TBD patients [11].

In these selected cases, asymptomatic HLA-matched family members carrying a pathogenic variant may be considered as donors following comprehensive clinical evaluation which should include detailed assessment of bone marrow cellularity and function, supported by in vitro assays such as colony-forming unit analysis to estimate future graft function as well as donor TL. However, such decisions require meticulous clinical, psychosocial, and ethical evaluation, along with a structured, family-centered shared decision-making process.

In conclusion, our retrospective analysis demonstrates that HSCT using matched related donors who are asymptomatic carriers of TBD-associated variants can result in sustained long-term engraftment and may represent a feasible therapeutic option in carefully selected cases.