Alpha-thalassemia

Inheritance

How does alpha-thalassemia run in families?

Alpha-thalassemia is caused by deletions or mutations in the HBA1 and/or HBA2 genes, meaning pieces of the gene are missing or changed. Both of these genes tell the body to make a protein called alpha globin, which is a component of hemoglobin. Hemoglobin is the protein in red blood cells responsible for carrying and delivering oxygen to cells throughout the body. We each have two copies, called alleles, of HBA1 and HBA2, for a total of four alleles. One copy of HBA1 and one copy of HBA2 come from mom in the egg cell. The other copies of HBA1 and HBA2 come from dad through the sperm cell.

Because two genes are involved, the inheritance of alpha-thalassemia is complex, but usually follows an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means that those who have one changed allele do not have disease, and those with two changed alleles have disease. Therefore, individuals can have changes to one gene and have no symptoms. If two of these individuals (carriers) have a child together who inherited changed genes from each parent, the child will have the disease. In this way, the disease can appear in a family despite no one else in the extended family having that same disease. Inheritance is more complicated with alpha-thalassemia because there are two genes involved. An individual can inherit between 0 and 4 changed copies of HBA1 and/or HBA2. Typically, those with more changed copies have more health complications as compared to people with fewer copies of the changed genes.

When one or more of these alleles has a change, the body cannot produce alpha globin correctly, resulting in a reduced ability of red blood cells to carry oxygen throughout the body. If three or four alleles are changed, the cells produce an abnormal form of hemoglobin called hemoglobin H or hemoglobin Bart, respectively. These types of hemoglobin do not easily release oxygen. Therefore, they cannot transport oxygen to the cells. People with two alleles changed have hemoglobin trait and might have anemia. People with only one allele changed are called silent carriers.

Because of the complexity of the inheritance of alpha-thalassemia, genetic testing and interpretation of test results is best performed by genetic professionals, including genetic counselors. Genetic counselors can be found on the National Society of Genetic Counselors website.

References
  • Alpha thalassemia. (2009). Genetics Home Reference. https://ghr.nlm.nih.gov/condition/alpha-thalassemia
  • Origa, R., Moi, P., Galanello, R., & Cao, A. (2013). Alpha-Thalassemia. GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed (2/29/2016).
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What does it mean to have inherited a "variant" or "variant of uncertain significance" in the gene for alpha-thalassemia?

Are there forms of alpha-thalassemia that aren't genetic?

Does it matter if the affected child or parent is male or female?

What does it mean to have inherited a "variant" or "variant of uncertain significance" in the gene for alpha-thalassemia?

Genetics is a growing field, and scientists and doctors do not know everything there is to know about all conditions, including all possible changes in the genes that cause diseases. Therefore, sometimes when individuals have genetic testing the results can fall into a category called 'variants' or 'variants of uncertain significant'. For HBA1 and HBA2, the genes associated with alpha-thalassemia, almost 100% of these changes are known. However, a 'variant' result is still possible.

Our genes, such as HBA1 and HBA2, are stretches of DNA. Our DNA is composed of 'letters', four small molecules abbreviated A, T, C, and G. With genetic testing, the HBA1 and HBA2 genes are searched to see if stretches of the 'letters' are missing. This is the most common type of change in these genes. The genes are also sequenced, meaning each 'letter' of the gene is read to look for 'misspellings'. Sometimes these changes do not affect how the gene functions and do not cause disease. Sometimes we know that a particular change does cause disease. Other times there is a new or rare change, and scientists have not yet figured out if that particular change causes disease, causes a mild form of the disease, or does not cause disease. Therefore, some changes have 'uncertain significance'.

As more genetic testing is performed on patients, more information will become available for those with 'variant' results. A geneticist or genetic counselor may recommend a return visit in the future to review new information and what it might mean for you. Genetic counselors can be found on the National Society of Genetic Counselors website.

Are there forms of alpha-thalassemia that aren't genetic?

All forms of alpha-thalassemia are genetic. Alpha-thalassemia is caused by alterations or changes to the genetic instructions for an important protein in red blood cells, which carry oxygen to the cells of the body.

References
  • Origa, R., Moi, P., Galanello, R., & Cao, A. (2013). Alpha-Thalassemia. GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed (2/29/2016).
Does it matter if the affected child or parent is male or female?

Both males and females are equally likely to inherit alpha-thalassemia and pass it on to children. Symptoms in males and females are similar. However, females can experience pregnancy related symptoms, including preeclampsia, congestive heart failure, threatened miscarriage and worsening anemia.

References
  • Origa, R., Moi, P., Galanello, R., & Cao, A. (2013). Alpha-Thalassemia. GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed (2/29/2016).

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