The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation

Zebisch, Armin; Winter, Gerlinde; Kashofer, Karl; Hatzl, Stefan; Uhl, Barbara; Wurm, Sonja; Wölfler, Albert; Greinix, Hildegard; Höefler, Gerald; Sill, Heinz

doi:10.1038/s41409-019-0691-1

Cited by 4 publications

(1 citation statement)

References 12 publications

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“…Zebisch and coworkers described a family in which a 60-year-old female affected with MDS was transplanted from her 58-year-old apparently healthy sister; the graft function was poor, and laboratory investigations demonstrated the presence of the same ASXL1 mutation, p.Pro808His, in the donor sister (Zebisch et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

Taha

Foroni²,

Valli³

et al. 2022

Front. Genet.

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Background: Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive ribosomopathy mainly characterized by exocrine pancreatic insufficiency, skeletal alterations, neutropenia, and a relevant risk of hematological transformation. At least 90% of SDS patients have pathogenic variants in SBDS, the first gene associated with the disease with very low allelic heterogeneity; three variants, derived from events of genetic conversion between SBDS and its pseudogene, SBDSP1, provided the alleles observed in about 62% of SDS patients.Methods: We performed a reanalysis of the available WES files of a group of SDS patients with biallelic SBDS pathogenic variants, studying the results by next bioinformatic and protein structural analysis. Parallelly, careful clinical attention was given to the patient focused in this study.Results: We found and confirmed in one SDS patient a germline heterozygous missense variant (c.100T>C; p.Phe34Leu) in the EIF6 gene. This variant, inherited from his mother, has a very low frequency, and it is predicted as pathogenic, according to several in silico prediction tools. The protein structural analysis also envisages the variant could reduce the binding to the nascent 60S ribosomal.Conclusion: This study focused on the hypothesis that the EIF6 germline variant mimics the effect of somatic deletions of chromosome 20, always including the locus of this gene, and similarly may rescue the ribosomal stress and ribosomal dysfunction due to SBDS mutations. It is likely that this rescue may contribute to the stable and not severe hematological status of the proband, but a definite answer on the role of this EIF6 variant can be obtained only by adding a functional layer of evidence. In the future, these results are likely to be useful for selected cases in personalized medicine and therapy.

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Section: Discussionmentioning

confidence: 99%

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

Taha

Foroni²,

Valli³

et al. 2022

Front. Genet.

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Allogeneic hematopoietic cell transplantation in elderly patients with myelodysplastic syndromes: Considerations and challenges

Schulz,

Pavletic,

Mina

2024

Seminars in Hematology

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Germline mutations: many roles in leukemogenesis

Chen

Kazi

Porter

et al. 2020

Current Opinion in Hematology

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Purpose of review The purpose of this review is to summarize the current understanding of germline mutations as they contribute to leukemia development and progression. We also discuss how these new insights may help improve clinical management of germline mutations associated with leukemia. Recent findings Germline mutations may represent important initial mutations in the development of leukemia where interaction with somatic mutations provide further hits in leukemic progression. In addition, germline mutations may also contribute to leukemogenesis by impacting bone marrow stem-cell microenvironment and immune cell development and function. Summary Leukemia is characterized by the clonal expansion of malignant cells secondary to somatic or germline mutations in a variety of genes. Understanding somatic mutations that drive leukemogenesis has drastically improved our knowledge of leukemia biology and led to novel therapeutic strategies. Advances have also been made in identifying germline mutations that may affect leukemic development and progression. This review will discuss the biological and clinical relationship of germline mutations with clonal hematopoiesis, bone marrow microenvironment, and immunity in the progression of leukemia.

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The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation

Cited by 4 publications

References 12 publications

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

Allogeneic hematopoietic cell transplantation in elderly patients with myelodysplastic syndromes: Considerations and challenges

Germline mutations: many roles in leukemogenesis

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