Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles.
Seth A BrodiePayal P KhinchaNeelam GiriAaron J BoukMia SteinbergJieqiong DaiLea JessopFrank X DonovanSettara C ChandrasekharappaKelvin C de AndradeIrina MaricSteven R EllisLisa MirabelloBlanche P AlterSharon A SavagePublished in: Cold Spring Harbor molecular case studies (2021)
IKZF1 encodes Ikaros, a zinc finger-containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C > T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C > T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.
Keyphrases
- bone marrow
- acute lymphoblastic leukemia
- copy number
- gene expression
- transcription factor
- genome wide
- dna repair
- genome wide identification
- mesenchymal stem cells
- dna methylation
- amino acid
- case report
- chronic kidney disease
- acute myeloid leukemia
- early onset
- big data
- multiple sclerosis
- autism spectrum disorder
- young adults
- gestational age
- iron deficiency
- oxide nanoparticles
- heat stress