Genetic Testing

Genetic Testing for Thalassemia

If HLA typing is performed when stem cell transplant or bone marrow transplant is an option, genetic counseling and education is vital due to ethical implications. A genetic counselor should provide initial and ongoing teaching regarding natural history and clinical manifestations; signs and symptoms of disease that warrant immediate medical attention; and available emotional and social support services. Genetic counselors should also provide available resources in collaboration with outreach coordinators and social workers (e.g., research studies, support groups, advocacy organizations, and patient-to-patient or parent-to-parent connections).

DNA Testing prior to Treatment

Because of the enormous diversity in clinical severity of thalassemia patients, complete DNA testing prior to commencement of treatment is required to determine prognosis, appropriate therapy, and family counseling. Definitive diagnosis and family counseling should be done in conjunction with a thalassemia center

Genetics 101

Having a basic understanding of genetics is invaluable in trying to understand the complexities of thalassemia and its inheritance. Genetics is the study of genes, which are most simply explained as biological instructions. Thousands of genes are passed onto each of us from our mother through the egg and our father through the sperm. These genes instruct our bodies to grow and develop, determining everything from our sex to the color of our eyes and the shapes of our noses.

A complete copy of all the genetic material necessary to create a human being is contained in most all of our body's cells. This genetic material is packaged onto structures called chromosomes. A complete "genetic blueprint" consists of 23 pairs of chromosomes (46 total). Chromosomes are themselves made up of a chemical strand called DNA. Along each DNA strand there are many genes. Each gene is an instruction for making a particular protein. Proteins are responsible for carrying out all the tasks needed to create and maintain a living person.

In thalassemia, a change occurs in the genes that tell the body how to make the globin protein, which makes up part of hemoglobin, the oxygen-carrying component inside our red blood cells. This genetic change leads to decreased or absent production of this very important protein.

The Inheritance of Thalassemia

[Body copy] ecall that hemoglobin is the protein that is affected in thalassemia. Hemoglobin is made of heme, alpha globins, and beta globins. At least 9 different genes direct the production of heme. Changes in these genes may lead to disorders of heme production, a group of conditions separate from the thalassemias. Alpha thalassemia occurs when a mutation in the gene that codes for alpha globin results in reduced or absent production of alpha globins. Beta thalassemia occurs with a corresponding change in the beta globin gene. Therefore, the thalassemias are a result of quantitative mutations in the globin genes.

Below is a karyotype, a picture of all of an individual’s genetic information as seen through a microscope. Notice there are 22 pairs of numbered chromosomes (autosomes) and one pair of sex-determining chromosomes. Also notice that a male carries both an X- and a Y-chromosome, whereas a female has two X-chromosomes. Because a man can pass down either an X- or a Y-chromosome, he is the one who randomly determines the sex of the baby.

Genetic Counseling

Genetic counseling is the communication process of providing information and support to individuals and families with a diagnosis and/or risk of occurrence of an inherited disorder. Culturally sensitive genetic counseling, with an emphasis on reproductive issues, is an integral and necessary component of comprehensive care for patients and parents affected by all forms of thalassemia disease and trait. Services should be provided by a licensed genetic counselor in states with licensure legislation and by an ABGC board-certified or board-eligible genetic counselor in all other states.

Genetic counseling is needed:

  •     at diagnosis and during adolescence
  •     prior to and after any genetic testing
  •     prior to pregnancy and/or as early in pregnancy as possible
  •     Annual follow-ups are needed to reinforce teaching.

Critical components of genetic counseling include:

  •     obtaining a three-generation genetic family history (pedigree)
  •     assessing risk for thalassemia in family members
  • identifying risk factors impacting medical management (e.g., family history of other hemoglobin traits or diseases, hereditary hemochromatosis, G6PD deficiency, inherited thrombophilia, cardiovascular disease or its risk factors, cardiac conduction defects, diabetes, renal disease, ophthalmologic disorders, hearing loss, allergies, ethnicity, consanguinity)
  •     incorporating psychosocial information impacting the family system and relationships (e.g., location of residence, disclosure/nondisclosure of diagnosis, reliable source of emotional/social support)
  •     assisting patients in conveying information about genetic risk to other family members
  •     providing informed consent, pre-, and post-counseling for all genetic testing
  •     alpha-globin genotyping: hemoglobin H–Constant Spring and other structural alphaglobin variants, possible modifying effects of alpha-globin deletions/triplications on betathalassemia
  •     beta-globin genotyping: beta0/beta+, S, D, E, O, and other structural variants

The limitations of drawing genotype/phenotype correlations include:

  •     developmentally appropriate consent/education for minors
  •     reproductive genotype post–stem cell transplant or bone marrow transplant
  •     the possibility of revealing undisclosed adoption or alternative paternity
  •     discussing/facilitating appropriate screening and diagnostic tests for relatives