Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome.
• DBA is typically linked to genes involved in ribosomal biogenesis, but the genetic cause remains unknown in many patients.
• IKZF1 encodes the Ikaros transcription factor, essential for hematopoietic development, and its variants are linked to leukemia and immunodeficiency.

Purpose of the Study:

• To investigate the genetic etiology of Diamond-Blackfan anemia-like features in identical twins.
• To determine the functional impact of a novel germline IKZF1 variant.
• To explore the role of IKZF1 in hematopoiesis and DBA pathogenesis.

Main Methods:

• Genetic sequencing to identify variants.
• Functional assays to assess the impact of the IKZF1 variant on gene expression.
• Analysis of transcriptional networks involved in hematopoietic development.

Main Results:

• Identified a germline IKZF1 variant (rs757907717 C > T) in identical twins with DBA-like features and autoimmune gastrointestinal disease.
• The variant results in a missense substitution (p.R381C/p.R423C) affecting IKZF1 isoforms.
• The IKZF1 variant alters global gene expression and perturbs transcriptional networks crucial for hematopoietic development, including erythropoiesis and immune function.

Conclusions:

• The identified germline IKZF1 variant is associated with a DBA-like syndrome.
• This variant contributes to hematopoiesis alterations, including dysregulation of erythropoiesis and immune system networks.
• IKZF1 variants represent a potential novel genetic cause for Diamond-Blackfan anemia and related disorders.