Double Heterozygosity for Hb Durham-N.C. (HBB: c.344T>C) [β114(G16)Leu→Pro] and the IVS-I-110 (HBB: c.93-21G>A)...

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Thalassemia is a group of inherited blood disorders characterized by reduced or absent hemoglobin synthesis.
• Genetic mutations in the beta-globin gene (HBB) are a primary cause of beta-thalassemia.
• Unstable hemoglobin variants can also lead to hematological abnormalities.

Observation:

• A 10-month-old girl presented with severe thalassemia, including very low hemoglobin levels, microcytosis, and hypocromia.
• Genetic analysis revealed compound heterozygosity for a common IVS-I-110 beta-thalassemia mutation and a de novo Hb Durham-N.C. (Hb Brescia) variant.
• The patient exhibited significant red blood cell abnormalities, including increased RDW, reticulocytosis, anisocytosis, poikilocytosis, and basophilic stippling.

Findings:

• The beta-thalassemia mutation was inherited from the mother, while the Hb Durham-N.C. mutation arose de novo.
• This represents the first described case of a severe thalassemic phenotype in a compound heterozygote with an unstable hemoglobin variant and a common beta-thalassemia allele.
• The study identified specific HBB gene mutations: c.93-21G>A for beta-thalassemia and c.344T>C for Hb Durham-N.C.

Implications:

• This case underscores that rare dominant or recessive mutations can occur in any individual, even if infrequently.
• Understanding compound heterozygosity for common and rare HBB mutations is crucial for accurate diagnosis and genetic counseling.
• The identification of de novo mutations emphasizes the importance of comprehensive genetic evaluation in unexplained severe phenotypes.