Clinical and Laboratory Characterization of the c.*233G>C Beta Globin Gene Substitution: Evidence Against a Thalassemic Phenotype

Purpose:

The c.*233G>C nucleotide substitution in the HBB gene was recently proposed as a novel β thalassemia allele based on genetic analysis of 11 thalassemic individuals. Based on this single report, the c.*233G>C allele has been provisionally included as a β (+) thal allele in a commonly used β globin database (HbVar).

The c.*233G>C is frequently seen in HBB gene sequencing for hemoglobinopathies. A clinical review was performed to determine the phenotype and hematologic characteristics of the c.*233G>C nucleotide substitution.

Methods:

At a tertiary-care pediatric institution, a retrospective review was performed of all HBB gene sequencing tests over a 30-month period. A chart review was performed for all cases with the c.*233G>C variant.

Results:

Of a total of 104 HBB cases, the c.*233G>C variant was identified in 18 individuals; 17 were heterozygotes and 1 was a homozygote (Patient 17) (Table 1). HBB gene sequencing was performed as part of the work-up for suspected variant hemoglobin (Hb) but can detect non-coding alterations including β thalassemia alleles as well.

Red cell indices in our series (Table 1) do not demonstrate the characteristics of heterozygous β thalassemia (microcytosis, mildly elevated RBC count, and mild anemia). MCV and RBC count data available for 9 individuals showed MCV values in the normocytic or macrocytic range and RBC counts within the normal range for all 9 patients. Of 13 patients with recorded Hb values, only one patient (Patient 14) was anemic but was found to have iron deficiency.

The patients in our series did not have elevated Hb A₂, which in patients with β thalassemia is typically above the normal range (>4%); the 9 patients who could be evaluated for Hb A₂ had values ranging from 2.4% to 3.7%. The remaining individuals were either too young to be evaluated for Hb A₂ or possessed a variant Hb that co-eluted with HbA₂.

The 13 patients in our series who were heterozygous for a Hb variant showed no excess in the variant Hb relative to Hb A. In patients with compound heterozygosity with a β thalassemia allele, the amount of the variant hemoglobin typically exceeds the amount of Hb A.

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Conclusions:

Red cell indices and Hb proportions in this series of 18 individuals with c.*233G>C substitution are not consistent with a thalassemic phenotype. Our analysis supports a hypothesis that c.*233G>C substitution is not a β (+) thalassemia allele but is rather a fairly common benign polymorphism. This information has important implications in the diagnosis and genetic counseling of individuals with the c.*233G>C substitution.

References:

1. Sirdah et al. The spectrum of β-thalassemia mutations in Gaza Strip, Palestine. Blood Cells, Molecules and Diseases. 2013; 50: 247-251.

2. HbVar: A Database of Human Hemoglobin Variants and Thalassemias. http://globin.cse.psu.edu/hbvar/menu.html.