Gene test interpretation: Hemoglobin C (Hb C) variant in the hemoglobin beta locus (HBB)

INTRODUCTION — This monograph summarizes the interpretation and possible interventions based on a genetic test result that reveals the hemoglobin C (Hb C) variant in the hemoglobin beta locus (HBB), which encodes the beta globin chain of hemoglobin.

Hb C is a structural variant; homozygosity causes chronic hemolytic anemia with small, dense red blood cells. Hb C is the third most common hemoglobin variant in the world with genetic origins in Africa, southern Europe, and Thailand. It is most common in regions such as Burkina Faso, Mali, Ghana, Togo, and Benin. However, all parts of the world have individuals who are carriers of Hb C due to demographic mobility. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Scope'.)

Settings for Hb C testing — The settings in which Hb C testing is appropriate and the care of individuals with Hb C disease are discussed separately in UpToDate [1]. (See 'Resources' below.)

In order to optimally use genetic testing results, one should be familiar with the indications for the testing and the information sought by the health care provider and/or patient family. Genetic testing for hemoglobinopathies is commonly used in at least three categories [2]:

●Patients suspected of having a hemoglobin disorder who have an unclear diagnosis after clinical laboratory evaluation or a presentation with atypical or discordant clinical and laboratory features.

●Reproductive counseling, with preconception or prenatal evaluation of females at risk of being carriers. If positive, paternal testing is performed to determine the risk of fetal disease.

●Newborn screening programs that identify unknown hemoglobin variants that may be clinically significant, rare, or novel. Optimal use of this information requires a review of the clinical and laboratory information, an understanding of the genes that were tested, and the review of the pathologic significance of the findings.

How to read the report

●Accuracy – Confirm that the correct person was tested and that the test was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory), as summarized in the table (table 1).

●Genotype – Confirm presence of the Hb C variant, whether it is heterozygous or homozygous, and whether any other variants affecting hemoglobin are present.

Determine whether a complete blood count (CBC) has been done and obtain one if not available. Determine whether protein-based hemoglobinopathy testing has been performed (hemoglobin electrophoresis or high performance liquid chromatography [HPLC]). In many cases it will be helpful to have this information for confirmation, especially if the person has anemia. Hemoglobin analysis may be omitted in some cases such as a suspected Hb C carrier with a normal CBC (no anemia) and normal red blood cell (RBC) indices.

Hb C variant — The Hb C variant is a point mutation in the HBB gene that changes glutamic acid to lysine at amino acid 7 of the beta globin chain (p.Glu7Lys; c.19G>A). The point mutation affects the same amino acid codon as the sickle cell variant (figure 1). However, the consequences for the hemoglobin molecule and RBCs are very different. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb C'.)

Hb C disease is autosomal recessive; heterozygotes are unaffected and do not need special treatment (see 'Hb C trait' below). Homozygosity for Hb C (Hb C disease) or compound heterozygosity for Hb C and another variant such as beta thalassemia or the sickle cell variant produces a hemoglobinopathy. (See 'Hb C disease' below and 'Other combinations with Hb C' below.)

The patterns on protein-based hemoglobin analysis vary in early childhood as adult hemoglobin (Hb A) production is established and fetal hemoglobin (Hb F) production declines (table 2).

Hb C disease is a chronic hemolytic anemia without vaso-occlusive complications. If an individual with a diagnosis of Hb C disease has symptoms of vaso-occlusion (dactylitis as a child, vaso-occlusive pain, acute chest syndrome, stroke), their diagnosis should be questioned and they should be evaluated for the sickle cell variant. Hb C Harlem is a rare variant that consists of the sickle cell mutation plus another mutation that causes hemoglobin to have the same mobility as Hb C on gel electrophoresis. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease' and "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb C-Harlem'.)

Hb C DISEASE — Hb C disease refers to homozygosity for the Hb C variant. Individuals with Hb C disease can present in infancy (after six months), older childhood, or adulthood. They have mild hemolytic anemia and often splenomegaly. More severe disease can occur when Hb C is combined with a beta thalassemia variant. (See "Pathophysiology of thalassemia", section on 'Beta thalassemia'.)

Laboratory findings include anemia and Hb C crystals inside red blood cells (RBCs) (picture 1); target cells may also be seen. Markers of nonimmune hemolysis may be present, as summarized in the table (table 3).

The following interventions are appropriate in individuals with Hb C disease (algorithm 1):

●Annual clinical monitoring, with attention paid to symptoms of gallstones and examination of spleen size. (See "Splenomegaly and other splenic disorders in adults", section on 'How to examine the spleen'.)

●Use of a method other than HbA1C testing to assess for diabetes and/or monitor glycemic control (chronic hemolysis falsely lowers HbA1C). (See "Screening for type 2 diabetes mellitus", section on 'Fasting plasma glucose' and "Measurements of chronic glycemia in diabetes mellitus", section on 'Other biomarkers'.)

●Supplemental folic acid (typical dose, 1 mg daily; can be omitted if adequate dietary folate is ensured).

●Notification of first-degree relatives so that they can be evaluated if appropriate. (See 'First-degree relatives' below.)

●For individuals who are planning childbearing, reproductive counseling and partner testing to determine the risk of a child having a hemoglobinopathy. (See 'Reproductive counseling' below.)

OTHER COMBINATIONS WITH Hb C — Hb C in combination with other hemoglobinopathy variants can cause clinically significant disease. The details of evaluation and management depend on the nature of the other hemoglobin variant(s). Two common examples are Hb SC disease and Hb C-beta thalassemia (algorithm 1).

●Hb SC disease – Hb C in combination with the sickle cell variant causes Hb SC disease, a form of sickle cell disease (SCD) that is typically milder than Hb SS disease but can cause any of the SCD complications and may require various SCD interventions. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

●Hb C-beta thalassemia – Hb C in combination with a beta⁺ thalassemia variant causes Hb C-beta⁺ thalassemia, a form of Hb C disease that is typically milder than Hb C disease but can cause chronic hemolytic anemia. Less common is Hb C-beta⁰ thalassemia, a more severe chronic hemolytic anemia.

Notification of first-degree relatives and preconception counseling and partner testing are appropriate. (See 'First-degree relatives' below and 'Reproductive counseling' below.)

Hb C TRAIT — Hb C trait refers to heterozygosity for the Hb C variant. (See 'Hb C variant' above.)

This is a benign carrier condition that does not require any interventions (algorithm 1). However, notification of first-degree relatives and preconception counseling and partner testing are appropriate. (See 'First-degree relatives' below and 'Reproductive counseling' below.)

CONSIDERATIONS FOR FIRST-DEGREE RELATIVES

Reproductive counseling — Individuals with Hb C, including Hb C trait, Hb C disease, or a compound hemoglobinopathy with Hb C, should receive reproductive counseling, ideally before conception. Partner testing should be offered to determine the risk of Hb C disease or other hemoglobinopathy in the child. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

The likelihood of having an affected child, an unaffected carrier child, or a child with no hemoglobinopathy variants depends on both parental genotypes (figure 2).

First-degree relatives — Individuals with Hb C, including Hb C trait, Hb C disease, or a compound hemoglobinopathy including Hb C, should inform their first-degree relatives to allow their testing and counseling, if appropriate. Such testing is especially important if they are considering childbearing.

The first test is typically a complete blood count (CBC) with review of the red blood cell (RBC) indices and reticulocyte count if available, followed by testing for hemolysis and a protein-based hemoglobin analysis method in most cases. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)

RESOURCES

UpToDate topics and other sources

●Hb C disease and Hb C trait – (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb C'.)

●Hb SC disease – (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

●Hemoglobinopathy testing – (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

Locating a specialist

●Hematologists – American Society of Hematology (ASH)

●Genetic counselors – The National Society of Genetic Counselors (NSGC)

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)