Kyoto, Japan — Scientists at Kyoto University have identified germline abnormalities in the genes SLF2 and SMC5 as the cause of a previously unrecognized inherited bone marrow failure syndrome and a genetic predisposition to myelodysplastic syndromes (MDS). Their findings connect two genes first associated with a rare neurodevelopmental condition to the maintenance of blood-forming stem cells, revealing how defects in chromosome regulation can progressively weaken the bone marrow.
Inherited bone marrow failure syndromes, or IBMFS, are a diverse group of disorders caused by genetic changes present from birth. These conditions impair hematopoietic stem cells, the self-renewing cells responsible for generating red blood cells, immune cells and platelets. As the stem-cell pool becomes depleted or dysfunctional, patients may develop anemia, infections, bleeding problems and other complications. They also face an increased risk of MDS, a group of blood cancers characterized by ineffective blood production and the accumulation of abnormal blood cells.
For physicians, diagnosing IBMFS can be difficult because many patients do not carry mutations in the genes traditionally associated with the disorder. Young people who develop unexplained cytopenias, bone marrow abnormalities or MDS are often suspected of having an underlying germline condition, but the responsible genetic change may remain hidden even after extensive testing. The Kyoto University study suggests that SLF2 and SMC5 should now be considered among the genes that may explain these cases.
The researchers were led to the discovery while following patients with Atelis Syndrome, a recently described neurodevelopmental disorder linked to germline variants in SLF2 or SMC5. Several of the patients developed MDS at unusually young ages, while clinical examinations also revealed features consistent with inherited bone marrow failure. This unexpected combination prompted the team to investigate whether the same mutations affecting neurological development were also damaging the blood-forming system.
To test the mutations directly, the scientists generated induced pluripotent stem cells, or iPSCs, from a patient carrying pathogenic SLF2 variants. These cells can be reprogrammed from mature tissue into a stem-like state and then directed to form specialized cell types, including hematopoietic progenitor cells. Using CRISPR-Cas9 gene editing, the team corrected the patient’s SLF2 variants in otherwise genetically identical cells. These corrected lines, known as isogenic controls, allowed the researchers to compare diseased and repaired cells while minimizing the confounding effects of unrelated genetic differences.
The patient-derived cells displayed impaired blood-forming potential when differentiated into hematopoietic progenitors. Their abnormalities were observed in laboratory experiments and in animal models designed to assess stem-cell function in a living environment. In contrast, correcting the SLF2 variants restored key cellular properties, providing direct evidence that the mutations—not merely another inherited feature of the patient’s genome—were responsible for the bone marrow defects.
The study also points to a molecular explanation for the progressive nature of the syndrome. SLF2 and SMC5 participate in the organization and protection of chromosomes, processes that are essential when stem cells divide and preserve their genetic material. When these proteins are disrupted, hematopoietic stem cells appear to experience cellular stress and activate p53, a central tumor-suppressor protein. Although p53 can protect the body by stopping damaged cells from multiplying, chronic activation can cause stem-cell exhaustion, growth arrest or premature aging.
In the bone marrow, this process may create a damaging cycle. Genetic instability or defective chromosome maintenance triggers p53-dependent surveillance, removing or disabling stem cells that might otherwise replenish the blood system. Over time, the remaining stem cells become less capable of producing healthy blood cells. At the same time, surviving cells carrying additional abnormalities may gain a growth advantage, increasing the likelihood of progression toward MDS. The researchers’ results therefore link chromosome dysfunction, p53 activation and hematopoietic stem-cell aging in a single disease mechanism.
The findings could have immediate implications for genetic diagnosis and patient monitoring. Recognizing SLF2 and SMC5 mutations in children or young adults with unexplained bone marrow failure may allow clinicians to provide earlier surveillance for MDS and to make more informed decisions about treatment, including stem-cell transplantation. The work also demonstrates the value of patient-derived iPSCs and precise gene correction as tools for investigating rare diseases. By restoring the normal gene sequence in laboratory-grown cells, researchers can distinguish causal mutations from harmless genetic variation and begin testing possible therapeutic strategies.
“Our results show that genes originally linked to a neurodevelopmental disorder also play a critical role in maintaining hematopoietic stem-cell function,” said first author Sho Shibata. Corresponding author Kazuhisa Chonabayashi noted that correcting the variants reversed the cellular abnormalities, offering direct evidence that the mutations cause bone marrow failure. Published in Leukemia on 7 August 2026, the study expands the genetic landscape of IBMFS and inherited MDS susceptibility while offering researchers a new route for solving cases that have previously resisted diagnosis.
Subject of Research: Cells
Article Title: SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome
News Publication Date: 7 August 2026
Web References: https://doi.org/10.1038/s41375-026-03061-7
References: Leukemia, DOI: 10.1038/s41375-026-03061-7
Image Credits: Kyoto University / Sho Shibata
Keywords: inherited bone marrow failure syndrome, IBMFS, myelodysplastic syndrome, MDS, SLF2, SMC5, hematopoietic stem cells, HSC aging, p53, CRISPR-Cas9, induced pluripotent stem cells, iPSCs, Atelis Syndrome, germline mutations
