Genetics 101

Genes are the basic physical and functional units of heredity. Genes are made up of DNA and act as instructions for our body to grow and develop properly. The Human Genome Project has estimated that humans have between 20,000-25,000 genes. Genes are stored in packages called chromosomes.

Every person has two copies of each gene, getting one copy from each parent. Genes tell the cells how to make proteins, which do the work (such as the collagen that provides strength to our skin and the enzymes that digest our food). Most genes are the same in all people, but a small number of genes (less than 1%) are slightly different between people. Small differences in these genes contribute not only to each person’s unique physical features, including skin and hair color, but also how well the organs in our body work.

Some genetic changes are very rare while others are common in the population.  The genetic changes, also called mutations, that cause thoracic aortic aneurysms and dissections to be inherited, or run in families, are very rare.  It is important to note that genes themselves do not cause disease — genetic disorders are caused by mutations that make a gene, and subsequently the protein, function improperly.

A gene mutation is a permanent change, or alteration, in the DNA that makes up a gene.  Mutations can be inherited from a parent or show up for the first time in an individual.  Mutations that are passed from parent to child are called hereditary mutations.  This type of mutation is present throughout a person’s life in virtually every cell of the body.  Sometimes, genetic mutations prevent one or more genes from working properly.  By changing a gene’s instructions, a mutation can cause a normally-occurring protein to malfunction or be missing entirely.  When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition.  A condition caused by mutations in a gene is called a genetic disorder.

For more information about DNA, genes, and how they work, visit Genetics Home Reference.

Genetics of Thoracic Aortic Aneurysm and/or Dissection (TAAD)
The following classifications may help you determine you or your family’s genetic risk of TAAD:

  1. Syndromic TAAD: May be a result of a known genetic connective tissue disorder (Marfan, Loeys-Dietz, Ehlers-Danlos, or Turner syndrome)
  2. Familial Thoracic Aortic Aneurysm and/or Dissection (FTAAD): If you have a positive family history (1+ first degree relative(s) with TAAD)
  3. Sporadic TAAD: If you are the only person in your family to have TAAD with no family history of aortic aneurysms or dissections. Aortic screening is recommended for all 1st degree relatives (parents, children, and siblings)

Genetic Syndromes
Genetic syndromes are genetic diseases that affect more than one system, and some of these syndromes increase the risk for thoracic aortic aneurysm and dissection.  Disorders that confer this increased risk for TAAD include:

Marfan syndrome: A life-threatening genetic disorder that affects connective tissue, which helps to hold the body’s cells and tissues together. This is caused by a mutation in the gene FBN1 which codes for the protein fibrillin-1. The main features of Marfan syndrome can affect the heart, blood vessels, bones, joints, and is found in about 1 in every 5,000 people. Common symptoms include long arms, legs and fingers, curved spine, flat feet, flexible joints, crowded teeth, curved spine, and/or stretch marks unrelated to weight change.

Loeys-Dietz syndrome: is a genetic connective tissue disorder that is caused by a mutation in one of five genes including (TGFβR1, TGFβR2, SMAD-3, TGFβ2, and TGFβ3). Individuals with LDS can experience a variety of features involving the cardiovascular, musculoskeletal, skin and/or gastrointestinal systems. Some common symptoms include but are not limited to aneurysms (dilation of arteries), arterial tortuosity (twisting of arteries), widely spaced eyes, and split or broad uvula (the little flesh found hanging in the back of the mouth).

Ehlers-Danlos syndrome, vascular type: A genetic connective tissue disorder that is caused by defects in a protein called collagen. This defect is caused by alterations in the gene COL3A1. Common symptoms include thin, translucent skin, bruising easily, characteristic facial appearance (thin lips, small chin, thin nose, large eyes), and fragile arteries, muscles and internal organs.

Turner syndrome: A chromosomal disorder in which a female is born with complete or partial absence of the second X chromosome (sex chromosome). The most common feature of this condition is short stature which becomes noticeable from a young age of around 5. Lack of ovarian development is also commonly found in women with Turner’s syndrome; however, other symptoms and characteristics may also be present or vary. This disorder occurs in approximately 1 out of every 2,000 to 4,000 female births.

To learn more about these syndromes, please visit Patient Resources for links to the associated Foundation websites.

Familial Thoracic Aortic Aneurysm and/or Dissection (FTAAD)
Thoracic aortic aneurysm and/or dissection (TAAD) can run in families even when no genetic syndrome like Marfan syndrome is present in affected family members. In these families, multiple people develop TAAD due to an underlying genetic change or mutation. These families have Familial Thoracic Aortic Aneurysm and/or Dissection (FTAAD). In families with FTAAD:

  • Both men and women can be affected.
  • The genetic predisposition is typically passed from generation to generation in an autosomal dominant pattern of inheritance.
  • Children of a parent with FTAAD have up to a 50% chance to develop a thoracic aneurysm and/or dissection or other vascular disease.
  • FTAAD is only a genetic predisposition, who inherit the genetic change may not develop an aneurysm or dissection.
  • In a family there can be a wide range in the age of onset of the thoracic aortic disease.
  • Sometimes other heart or artery features can be inherited with the thoracic aortic disease, such as a bicuspid aortic valve.

Unlike syndromes such as Marfan syndrome, there are typically no outward features to suggest that people with FTAAD have inherited a predisposition for thoracic aortic disease.  Generally, the only disease manifestation is the aortic disease, which is often asymptomatic until there is an aortic rupture or dissection.  This is why family history and aortic imaging are so important in helping identify people at risk for aortic disease.

Several genes have been identified to cause FTAAD including but not limited to: ACTA2,  MYH11, FBN1, TGFBR1, and TGFBR2. Mutations in any one of these genes can cause a predisposition to develop TAAD to be inherited in a family.

Changes in these genes only explain the family history of FTAAD in 25-30% of families affected with FTAAD. We are currently working to identify the genes responsible for disease in the remaining 70-75% of cases.

What should I do if I think that I or a family member may have FTAAD?
If you have a personal or family history of TAAD, talk to your doctor to obtain a referral to a geneticist or genetic counselor. Clinical genetic testing of these genes is available through a DNA diagnostic lab. To find a local genetics provider in your area, visit the National Society of Genetic Counselors website.

Family members at risk for inheriting a predisposition for TAAD need aortic imaging.  First-degree relatives (parents, siblings, and children) of individuals with an aortic aneurysm or dissection should undergo aortic screening by echocardiogram (an ultrasound of the heart). Tell your physician that you need aortic screening that includes the ascending aorta. If good visualization of the ascending aorta cannot be achieved with echocardiogram, consider CT or MRI.

When should children be screened?
Screening of children should be completed if there is an underlying genetic disorder or family history. Echocardiogram is usually sufficient to see the ascending aorta and aortic arch in young children. Talk to your child’s primary care physician or cardiologist about the recommended frequency and timing of imaging.

What happens when an aneurysm is found?
Early detection is key. Aneurysms involving the ascending aorta that are detected early can be monitored and medical therapy initiated.  In some cases, the aneurysm may need to be surgically repaired to prevent life-threatening events such as an acute aortic dissection or rupture of the aorta.

If caught early, the life expectancy of someone with a thoracic aortic aneurysm should approach that of the general population. Your cardiologist and cardiovascular surgeon will determine the optimal treatment of your aortic aneurysms.

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