Rare β-Globin Gene Mutations in Pakistan.

Area of Science:

• * Human Genetics
• * Molecular Biology
• * Hematology

Background:

• * Beta-thalassemia (β-thal) is a significant inherited blood disorder globally.
• * The Pakistani population exhibits a diverse spectrum of β-thalassemia mutations.
• * Understanding rare mutations is crucial for accurate genetic diagnosis and carrier screening.

Purpose of the Study:

• * To comprehensively analyze rare β-thalassemia mutations in the Pakistani population.
• * To identify novel mutations and characterize the mutation spectrum.
• * To investigate unexplained cases of transfusion-dependent thalassemia.

Main Methods:

• * Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used to screen 8716 individuals for known β-thal mutations.
• * Genomic sequencing of the β-globin gene and flanking regions was performed for uncharacterized cases.
• * Analysis focused on mutations in coding, 5' untranslated, and splice junction regions.

Main Results:

• * Genomic sequencing identified 19 distinct rare β-thal mutations in 67 (0.82%) individuals, including one novel mutation (HBB: c.136delT).
• * The most frequent rare mutations observed were HBB: c.92+1G>A and HBB: c.113G>A.
• * Interestingly, 21 individuals with transfusion-dependent thalassemia and one known β-thal mutation showed no detectable mutation in the β-globin gene or its immediate flanking regions.

Conclusions:

• * The Pakistani population harbors a highly diverse spectrum of β-thalassemia mutations, including previously unreported ones.
• * The discovery of a novel mutation and frequent rare mutations underscores the need for updated diagnostic panels.
• * Unexplained genetic findings in some patients suggest potential involvement of regulatory elements or other uncharacterized genetic factors in β-thalassemia pathogenesis.