A novel deletion/insertion caused by a replication error in the β-globin gene locus control region

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Beta-globin locus control region (β-LCR) deletions cause (εγδβ)(0)-thalassemia, a rare genetic disorder.
• Patients with these deletions exhibit a normal hemoglobin phenotype despite a thalassemic hematological profile.
• Multiplex-ligation probe amplification (MLPA), long-range PCR, and DNA sequencing are key methods for detecting and characterizing β-LCR deletions.

Observation:

• A novel 11,155 bp deletion in the β-LCR was identified in a French Caucasian patient.
• This deletion spans from DNase I hypersensitive site 2 (HS2) to HS4 of the β-LCR.
• A 197 bp insertion of inverted sequences from the HS2-HS3 inter-region was observed, suggesting complex replication-associated rearrangements.

Findings:

• The identified β-LCR deletion leads to (εγδβ)(0)-thalassemia.
• The deletion removes critical regulatory elements (HS2-HS4) within the β-LCR.
• The presence of an insertion indicates a complex mutational mechanism.

Implications:

• Carriers of this β-LCR deletion may be misdiagnosed with α-thalassemia trait.
• Comprehensive analysis of the α- and β-globin gene clusters is essential for accurate diagnosis.
• Preventing misdiagnosis is critical for appropriate genetic counseling and patient management.