Chronic Granulomatous Disease and Myelodysplastic Syndrome in a Patient with a Novel Mutation in CYBB.
Bárbara C S ReisDaniela P CunhaAna Paula S BuenoFlavia A A CarvalhoJuliana DutraFabiana V MelloMaria Cecília Menks RibeiroCristiane B MilitoElaine Sobral da CostaZilton Farias Meira de VasconcelosPublished in: Genes (2021)
Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis with variable risk of evolution to acute leukemias. Both disorders are rare and have distinct pathophysiologic mechanisms, with no known association. A 7-month-old boy presenting with recurrent infections and anemia at age 2 months underwent immunological, hematological and genetic investigation that culminated in the diagnosis of both CGD and MDS. Next generation sequencing was performed and identified a silent variant predicted as of Uncertain Significance, located in the splicing site at the end of exon 5 in CYBB. CYBB variants account for at least two thirds of CGD cases, but no previous descriptions of this variant were found in ClinVar or The Human Gene Mutation Database (HGMD) databases. We were able to demonstrate an exon 5 skipping on the proband's cDNA, which strongly suggests the disruption of the NADPH oxidase complex, abrogating the formation of reactive oxygen species from neutrophils. Moreover, erythroid cell lineage could be also affected by NADPH oxidase complex damages. Further investigation is needed to evaluate the potential effect of CYBB gene alterations in hematopoiesis, as well as in MDS and CGD association.
Keyphrases
- copy number
- stem cells
- single cell
- genome wide
- chronic kidney disease
- emergency department
- liver failure
- cell therapy
- gene expression
- intensive care unit
- risk assessment
- transcription factor
- dna methylation
- interstitial lung disease
- respiratory failure
- induced pluripotent stem cells
- bone marrow
- aortic dissection
- mechanical ventilation
- circulating tumor cells
- idiopathic pulmonary fibrosis
- iron deficiency
- cell wall