Causes of sickle cell disease
Fact-checked by The causes of sickle cell disease (SCD), an inherited blood disorder, are related to hemoglobin, a protein that helps red blood cells carry oxygen throughout the body.
People with sickle cell have genetic mutations that cause them to produce abnormal forms of hemoglobin. Red blood cells containing abnormal forms of the protein can change shape — instead of being round and smooth, they may acquire a crescent or sickle-like shape. This process is known as sickling.
Sickled red blood cells are stiff and sticky, and die more quickly than healthy red blood cells. They can also get caught in small blood vessels, blocking blood flow and limiting oxygen delivery to tissues and organs. This can lead to several complications, including episodes of acute pain known as vaso-occlusive crises.
Understanding what causes SCD and how sickle cell is passed down through families can help guide treatment and family planning decisions.
The role of genes and inheritance
Sickle cell gene mutations occur in a gene called HBB, which encodes a subunit of hemoglobin.
Most people with SCD have mutations that lead to the production of an abnormal version of hemoglobin called hemoglobin S (HbS). When oxygen levels are low, HbS molecules tend to stick to each other to form long, stiff chains within red blood cells — a process known as HbS polymerization — warping their shape and causing sickling.
Everyone inherits two copies of the HBB gene, one from each biological parent. SCD is an autosomal recessive disorder, meaning that both gene copies must carry mutations for a person to develop the condition. However, these mutations don’t need to be the same — one of them may lead to the production of HbS and the other to the production of another abnormal version of the protein.
There are several types of SCD, depending on the specific mutations that are inherited:
- HbSS: Occurs when both HBB copies carry mutations that result in the production of HbS. It is the most common form of SCD, also known as sickle cell anemia.
- HbSC: Occurs when one HBB copy encodes HbS and the other produces another abnormal protein variant called hemoglobin C.
- HbS/beta-thalassemia: Occurs when one HBB copy encodes HbS and the other has a mutation associated with beta thalassemia, an inherited blood disorder that affects hemoglobin production.
Other rarer types of SCD include HbSD, HbSE, and HbSO, which occur when a person inherits one HBB gene copy encoding HbS and another gene copy containing instructions for making other abnormal forms of hemoglobin (hemoglobin D, hemoglobin E, or hemoglobin O).
Sickle cell trait vs. sickle cell disease
People who have one faulty HBB copy encoding HbS and a normal gene copy encoding hemoglobin A, the most common healthy form of the protein found in adults, have sickle cell trait (SCT) rather than SCD. These individuals don’t usually develop symptoms, but have a 50% chance of passing the SCD-causing mutation to their biological children. They are sometimes called sickle cell carriers.
| Sickle cell disease | Sickle cell trait |
|---|---|
| Two mutated HBB copies | One mutated HBB copy |
| No or nearly no production of hemoglobin A | Hemoglobin A is produced |
| Typically causes symptoms | Typically doesn’t cause symptoms |
| People with SCD have a 100% chance of passing a disease-causing mutation to their biological children | Carriers have a 50% chance of passing a disease-causing mutation to their biological children |
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When two sickle cell carriers have a child, there is:
- a 50% chance the child will be a carrier, if the child inherits one faulty HBB copy from either parent
- a 25% chance the child will have SCD, if the child inherits the faulty HBB copy from both parents
- a 25% chance the child will neither be a carrier nor have SCD, if the child inherits the normal gene copy from both parents
Having one normal gene copy enabling the production of hemoglobin A is typically enough to prevent people with SCT from having SCD symptoms. However, this can still happen in rare cases when people with SCT are exposed to certain conditions that promote HbS polymerization and red blood cell sickling, including:
- dehydration
- low oxygen levels, which can happen after strenuous exercise
- high altitudes, for instance, when flying or mountain climbing
- very high or very low body temperature
Who is most affected by sickle cell disease?
Certain racial and ethnic backgrounds are risk factors for SCD, although people of any ethnicity can have the condition. Those at higher risk include people with ancestors from:
- Africa
- Central or South America
- the Mediterranean
- the Middle East
- South Asia
These are areas where malaria, a mosquito-borne infectious disease, was historically more common. Having SCT helps reduce the risk of severe malaria. Over time, communities in these regions evolved to have higher rates of HBB mutations. However, this also increased the likelihood of SCD.
In the U.S., over 90% of people with sickle cell are non-Hispanic Black or African American. People with Hispanic or Latino backgrounds make up about 3% to 9% of the U.S. sickle cell population.
Can sickle cell disease be prevented?
As a genetic blood disorder, there is nothing that can prevent SCD from developing if a baby inherits it. Sickle cell isn’t contagious or a result of any specific behaviors during pregnancy.
Newborn screening, a common practice in many countries, can help doctors diagnose the condition early, promoting earlier treatment and better outcomes. It can also help identify SCT. If a baby has SCT, at least one of their parents is a carrier, except in very rare cases.
Genetic counseling can help sickle cell patients and their relatives understand SCD genetics and inheritance and their family planning options. Depending on the circumstances, a genetic counselor may suggest:
- genetic testing of the parents, if they don’t know whether they are carriers, before pregnancy
- prenatal testing to identify sickle cell before birth
- using a form of in vitro fertilization that allows doctors to genetically screen fertilized eggs and select an embryo without disease-causing HBB mutations to transfer into the womb
- using a sperm or egg donor
- adopting a child
Sickle Cell Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
