Targeted Deep Sequencing of Shwachman-Diamond syndrome bone marrow samples
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ABSTRACT:
PROVIDER: EGAC00001001851 | EGA |
REPOSITORIES: EGA
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Project description:Shwachman-Diamond Syndrome (SDS) is a rare and clinically-heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Although SDS was described over 50 years ago, the molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from SDS patients. We generated a single cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor-beta (TGF?) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGF? inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGF?3 and other TGF? pathway members were elevated in SDS patient blood plasma. These data establish the TGF? pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.
| S-EPMC6715362 | biostudies-literature
Project description:Data Access Committee EGAC00001001852
| EGAC00001001852 | EGA
Project description:Targeted sequencing of myeloid malignancy-associated genes as well as EIF6 in bone marrow samples in Shwachman-Diamond syndrome patients. Paired bone marrow fibroblasts serve as a germline control.
| EGAS00001004879 | EGA
Project description:Data Access Committee EGAC00001001868
| EGAC00001001868 | EGA
Project description:Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children. Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.
| S-EPMC1275624 | biostudies-literature
Project description: Not available
| S-EPMC3850156 | biostudies-literature
Project description:To define the mechanistic basis of clonal hematopoiesis in SDS, we investigated somatic
mutations acquired by patients with SDS followed longitudinally. This dataset includes single cell sequencing data from SDS bone marrow as well as serial samples from a single patient that went on to develop AML.
| EGAS00001004881 | EGA
Project description:Shwachman-Diamond syndrome (SDS) is an autosomal-recessive marrow failure syndrome with a predisposition to leukemia. SDS patients harbor biallelic mutations in the SBDS gene, resulting in low levels of SBDS protein. Data from nonhuman models demonstrate that the SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. The complete abrogation of Sbds expression in these models results in severe cellular and lethal physiologic abnormalities that differ from the human disease phenotype. Because human SDS cells are characterized by partial rather than complete loss of SBDS expression, we interrogated SDS patient cells for defects in ribosomal assembly. SDS patient cells exhibit altered ribosomal profiles and impaired association of the 40S and 60S subunits. Introduction of a wild-type SBDS cDNA into SDS patient cells corrected the ribosomal association defect, while patient-derived SBDS point mutants only partially improved subunit association. Knockdown of eIF6 expression improved ribosomal subunit association but did not correct the hematopoietic defect of SBDS-deficient cells. In summary, we demonstrate an SBDS-dependent ribosome maturation defect in SDS patient cells. The role of ribosomal subunit joining in marrow failure warrants further investigation.
| S-EPMC3537309 | biostudies-literature
Project description:Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.
| S-EPMC8753194 | biostudies-literature
Project description:To define the mechanistic basis of clonal hematopoiesis in Shwachman-Diamond syndrome (SDS), we investigated somatic mutations acquired by patients with SDS followed longitudinally. This dataset includes the initial discovery cohort whole exome sequencing from bone marrow samples used to identify novel somatic mutations in patients with SDS. Paired fibroblasts serve as a germline control.
| EGAS00001004880 | EGA