Double the trouble, quadruple the confusion: Demystifying the genetics of alpha thalassemia

Inheritance of most genetic conditions involves 2 copies of a gene, 1 copy inherited from each parent. However, there are exceptions to this rule, one of those being alpha thalassemia. Instead of having 1 gene (with 2 copies), there are 2 genes (with 4 copies total) which influences the inheritance of alpha thalassemia. This complicates things a bit—let’s dive in.

Alpha thalassemia is caused by decreased hemoglobin production and leads to anemia, too few working red blood cells, which can have varying degrees of severity depending on the type.

There are 2 genes that influence the severity of alpha thalassemia: HBA1 and HBA2. These genes produce a protein called alpha-globin, which is a critical component of hemoglobin. Hemoglobin is a protein found in our red blood cells that helps carry oxygen throughout our body. Typically, people have 2 working copies of each gene (4 copies total). 

The number of copies of genes that are non-functional are directly related to disease severity in alpha thalassemia; the fewer working copies, the more severe the disease. Alpha thalassemia typically results from deletions of HBA1 or HBA2 but may result from other types of variants as well.

Individuals with either 0 or 1 working of the HBA1/2 genes have clinical symptoms. Those with 0 working copies of HBA1/2 have a condition known as hemoglobin Bart syndrome (HbBart), and those with 1 working copy have hemoglobin H (HbH) disease.

Silent carriers: 3 working copies

If 1 copy of HBA1/2 is deleted/non-working, these individuals are referred to as silent carriers. Silent carriers are at risk of having a child with hemoglobin H disease only if their partner is a 2 gene cis carrier.

Carrier: 2 working copies: ––/αα or α–/α–

If 2 copies of the HBA1/2 are not working, the deletions may be cis or trans. Cis carriers have 1 chromosome with 2 working HBA1/2 genes and 1 chromosome without any working copies of HBA1/2. Trans carriers have 1 working copy of HBA1/2 on each copy of chromosome 16.

Cis vs trans carrier status: a closer look

At first glance, one may not see a difference between a cis and a trans carrier of alpha thalassemia; however, there are significantly different implications for the children of cis vs trans carriers.

Let’s illustrate the different risks to children based on parental carrier status. To maintain simplicity, let’s think about the offspring of 2 partners who are both cis carriers and 2 partners who are both trans carriers. Be aware there are many other combinations with other genotypes resulting in different outcomes.

Risks to children - 2 cis carriers

Normal (4 working copies): 25% chance

Cis carrier (2 working copies on same chromosome): 50% chance

Affected with Hb Bart Disease (0 working copies - most severe form of alpha thalassemia): 25% chance

Risks to children - 2 trans carriers

Trans carrier (2 working copies, on different chromosomes): 100% chance of children with no clinical symptoms

Summary of risks

Ultimately, the difference between cis and trans carriers is that cis carriers are at risk to have a fetus with fatal Hb Bart syndrome while trans carriers are not.

Alpha thalassemia is a potentially severe condition, and its complicated genetics can make discussion challenging. Ensuring that conversations contain accurate genetic information can have a large impact on families at-risk or affected with alpha thalassemia.

It is vital clinicians understand which testing options can differentiate between cis and trans carrier status. 1 test that can distinguish between the 2 is the Quest Diagnostics Alpha-Globin Common Mutation Analysis (test code 11175).