Gene test interpretation: Sickle cell variant in the hemoglobin beta locus (HBB)

INTRODUCTION — This monograph discusses interpretation and possible interventions based on a genetic test result that reveals the sickle cell variant in the hemoglobin beta locus (HBB, also called beta globin gene). It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the individual who was tested. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)

HOW TO READ THE REPORT — Obtain a hard copy or digital report rather than a verbal statement. Confirm the correct person (not a relative) was tested. If the sickle cell variant is identified, determine if the individual is heterozygous or homozygous and whether other variants were identified.

Testing can be done using targeted genetic testing for the sickle cell variant or full sequencing of the hemoglobin beta locus (HBB) gene. The latter would allow other variants in HBB to be detected, since variants in HBB other than the sickle cell variant (beta thalassemia variants, hemoglobin C) can have important implications for the tested individual. Additional information may be inferred from protein-based hemoglobin analysis (high performance liquid chromatography [HPLC] or immunoelectrophoresis [IEF]).

Genetic testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. If testing was not done in a CLIA-certified laboratory or was done by direct-to-consumer testing or for a research study and the results would impact clinical care (positive result, negative result in an individual with a positive personal or family history), confirm the result by repeat genetic testing or hemoglobin analysis in a CLIA-certified laboratory. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

The sickle prep (SickleDex) or solubility test alone are not sufficient to confirm or exclude the diagnosis of sickle cell trait or sickle cell disease.

Positive testing for the sickle cell variant may be reported as:

●Sickle cell variant; hemoglobin S (Hb S)

●c.20A>T (DNA sequence change)

●p.Glu7Val (protein sequence change, previously called pGlu6Val using an earlier amino acid numbering system)

The tables provide caveats related to genetic testing (table 1) and a glossary (table 2).

DISEASE ASSOCIATIONS — The sickle cell variant is a point mutation in the hemoglobin beta locus (HBB). It introduces a single amino acid substitution that leads to a physical change in the beta globin chains of the hemoglobin molecule, producing hemoglobin S (Hb S) [2].

Red blood cells with Hb S can undergo sickling, but this generally will not occur unless >50 percent of the cell's hemoglobin is Hb S. The inheritance pattern is autosomal recessive (table 2). Other physiologic changes that contribute to sickling in certain organs are discussed separately. (See "Pathophysiology of sickle cell disease".)

Whether an individual with the sickle cell variant will have sickle cell trait or sickle cell disease depends on the status of the HBB gene inherited from the other parent. This is summarized in the table (table 3) and illustrated in the algorithm (algorithm 1).

●Sickle cell trait – When an individual is heterozygous for the sickle cell variant and the other HBB gene lacks a hemoglobinopathy variant, the individual has sickle cell trait. They are essentially an unaffected carrier, although there are some clinical implications that require counseling. (See 'People with sickle cell trait' below.)

●Sickle cell disease – When an individual has the sickle cell variant in combination with another disease-associated HBB variant, they have sickle cell disease, which carries a risk of serious end-organ damage.

•Homozygous Hb S – Individuals with homozygosity (Hb SS) have sickle cell anemia (a form of sickle cell disease), often identified by newborn screening or testing. The affected child usually develops clinical findings during infancy, such as anemia and vaso-occlusive pain (dactylitis) in the hands. They are at risk for severe end-organ damage, including stroke, and they should receive comprehensive care from a hematologist or other expert in order to reduce these risks. (See 'People with sickle cell disease' below.)

•Compound heterozygosity – Individuals with heterozygosity for the sickle cell variant and another disease-associated HBB variant (Hb C, beta thalassemia) also have sickle cell disease. Some will present similarly to individuals who are homozygous for Hb SS; others may have a milder course and may be unaware of their diagnosis. However, they are at risk for serious end-organ damage and should receive comprehensive care by a hematologist or other expert to reduce these risks. (See 'People with sickle cell disease' below.)

An individual with the sickle cell variant may also have variants affecting the alpha globin loci (HBA1 or HBA2), which may be reported as alpha thalassemia trait or hemoglobin H disease. Unlike a second HBB variant, a variant affecting alpha globin generally reduces the severity of the sickle cell variant. Individuals with sickle cell trait and an alpha thalassemia variant have sickle cell trait, not sickle cell disease.

The clinical implications for the patient and family members should be discussed with a hematologist, genetic counselor, or other expert. (See 'Considerations for relatives' below and 'Resources' below.)

PEOPLE WITH SICKLE CELL TRAIT — Sickle cell trait refers to heterozygosity for the sickle cell variant (hemoglobin S [Hb S]) in combination with a normal beta globin gene on the other allele (algorithm 1). (See 'Disease associations' above.)

Sickle cell trait is a benign carrier condition. It affects millions of individuals, the vast majority of whom are asymptomatic and may be unaware they have sickle cell trait. Their lifespan is normal, and they do not have a disease.

Individuals with sickle cell trait should be aware of a few rare medical complications (table 3) [3]:

●Increased risk of complications of dehydration. Heat-induced and exercise-induced injury and death can be mitigated with universal precautions (proper conditioning and adequate hydration) rather than altering participation for physical activities or training [4]. (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)

●Increased risk of complications associated with high altitudes, airplane travel, or increased atmospheric pressure (scuba diving).

●Increased risk of urologic and kidney disease (urinary tract infection, chronic kidney disease). Hematuria, even if transient, should be evaluated due to an increased risk of a rare cancer. (See "Sickle cell trait", section on 'Urologic and kidney disease'.)

●Hyposthenuria (reduced urinary concentrating ability) may lead to bedwetting, polyuria/nocturia, or dehydration.

●Increased risk of splenic infarction. (See "Splenomegaly and other splenic disorders in adults", section on 'Focal splenic lesions'.)

●Slightly increased risk of venous thromboembolism (VTE), especially pulmonary embolism. This is important for education but should not limit access to contraceptives or otherwise alter management. (See "Sickle cell trait", section on 'Reproductive issues'.)

●Complications of traumatic hyphema (blood in the anterior chamber of the eye), warranting hospital admission and ophthalmologist consultation. (See "Traumatic hyphema: Management".)

●Underestimation of glycosylated hemoglobin (HbA1c; A1C) for a given serum glucose level. Sickle cell trait does not confer an increased risk for diabetes. If screening or monitoring of diabetes is indicated, glucose measurements, which are not affected by the sickle cell variant, may be used instead of HbA1c. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'A1C' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Glycemic management' and "Sickle cell trait", section on 'Inadequate evidence or conflicting results on the risk of hypertension, diabetes, heart disease, or stroke'.)

●Slightly increased risk of renal medullary carcinoma, a rare type of kidney cancer. (See "Sickle cell disease effects on the kidney", section on 'Renal medullary carcinoma'.)

●Possibility of sickle cell trait or disease in relatives. (See 'Considerations for relatives' below.)

Counseling may require additional visits or referral to a hematologist or genetic counselor. (See 'Resources' below.)

PEOPLE WITH SICKLE CELL DISEASE — Sickle cell disease refers to homozygosity for the sickle cell variant (Hb SS) or compound heterozygosity for the sickle cell variant with another beta globin variant (algorithm 1). Some people such as those with Hb SS or sickle-beta⁰-thalassemia may have obvious clinical findings, whereas others may be unaware of their status (eg, sickle cell variant in combination with hemoglobin C [Hb SC disease] or mild beta thalassemia). (See "Hemoglobin variants including Hb C, Hb D, and Hb E" and "Overview of compound sickle cell syndromes".)

If the diagnosis is in question, the individual should have a hemoglobin analysis. (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)

All individuals with sickle cell disease require multidisciplinary comprehensive care (table 3) to maximize life expectancy and reduce the risk of complications involving the kidney, joints, eye, and pregnancy, among others [5]. (See "Overview of the management and prognosis of sickle cell disease" and "Evaluation and management of fever in children and adults with sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)

CONSIDERATIONS FOR RELATIVES

Preconception counseling — Preconception genetic counseling and partner testing is appropriate for all individuals who carry the sickle cell variant and are considering childbearing.

The sickle cell variant can occur in all ethnic and racial groups, and any partner may have an undetected asymptomatic beta globin variant. Partner testing should include the sickle cell variant, beta thalassemia variants, hemoglobin C, and other beta globin variants. This is essential to determine the risk of sickle cell disease in the child(ren). Certain variants are found more frequently in specific populations, but the presence or absence of a hemoglobinopathy variant cannot be inferred from racial or ethnic background. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

Screening before pregnancy allows the provider to review diagnostic approaches and reproductive technologies to help couples with pregnancy decisions. Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)

Reproductive screening and counseling — If both parents have sickle cell trait, the risk of sickle cell trait in their child is 50 percent, and the risk of homozygous sickle cell disease is 25 percent (figure 1). Similar considerations apply if other hemoglobin beta locus (HBB) variants are present in one or both parents.

For carrier couples at risk for sickle cell disease in a fetus, prenatal diagnostic testing (chorionic villus sampling [CVS], amniocentesis) is available; this allows diagnosis of sickle cell disease after conception and facilitates counseling. Cell-free DNA (sampling fetal DNA from the maternal circulation) is being explored. The decision to perform invasive prenatal diagnostic testing requires early in-depth discussion with the family concerning the associated risks versus the benefits of obtaining a diagnosis.

At-risk relatives — Individuals with the sickle cell variant should inform their at-risk relatives about this family history and the role of genetic counseling and testing.

●First-degree relatives of an individual with sickle cell trait have a 50 percent chance of inheriting the variant (figure 1).

●All biological children of an individual with homozygous sickle cell disease (Hb SS) will inherit one copy of the sickle cell variant.

●In both cases, the relative's risk of having sickle cell disease depends on the beta globin gene they inherit from the other parent.

Counseling (and testing, if appropriate) can be facilitated by a genetic counselor, hematologist, or other expert. (See 'Locating a genetics expert' below.)

RESOURCES

UpToDate topics

Sickle cell trait and sickle cell disease:

●Prenatal testing – (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Diagnosis – (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing".)

●Sickle cell trait – (See "Sickle cell trait".)

●Other sickle cell syndromes – (See "Hemoglobin variants including Hb C, Hb D, and Hb E" and "Overview of compound sickle cell syndromes".)

●Management – (See "Overview of the management and prognosis of sickle cell disease".)

Genetics:

●Terminology – (See "Genetics: Glossary of terms".)

●Counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

●Testing – (See "Genetic testing".)

Other sources of information

●American Society of Hematology (ASH) Resources for clinicians [6]

●Centers for Disease Control (CDC) website [7]

Locating a genetics expert

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

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