Genetics

DNA

Loeys-Dietz syndrome (LDS) is a genetic disorder that is caused by a gene mutation (change) in the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 genes.

There are six types of Loeys-Dietz syndrome. Each type is caused by mutations in a different gene:

  • Loeys-Dietz syndrome 1 (LDS1) caused by mutations in the TGFBR1 gene (transforming growth factor beta receptor 1)
  • Loeys-Dietz syndrome 2 (LDS2) caused by mutations in the TGFBR2 gene (transforming growth factor beta receptor 2)
  • Loeys-Dietz syndrome 3 (LDS3) caused by mutations in the SMAD3 gene (mothers against decapentaplegic homolog 3)
  • Loeys-Dietz syndrome 4 (LDS4) caused by mutations in the TGFB2 gene (transforming growth factor beta 2)
  • Loeys-Dietz syndrome 5 (LDS5) caused by mutations in the TGFB3 gene (transforming growth factor beta 3)
  • Loeys-Dietz syndrome 6 (LDS6) caused by mutations in the SMAD2 gene (mothers against decapentaplegic homolog 2)

Researchers continue to explore if and how the types of LDS produce different physical manifestations as well as how these similarities and differences can impact medical care.

Genetic testing can confirm a diagnosis of Loeys-Dietz syndrome.

Frequently Asked Questions

The SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, and TGFBR2 genes each contain instructions to build a specific protein that plays a role in the TGF beta pathway. This pathway is a series of molecular actions and interactions involved in the body’s development, growth, immune function, and tissue maintenance.

 

When an LDS-causing mutation occurs in one of these genes, the gene cannot properly pass on its protein-building instructions and the protein becomes dysfunctional. This interferes with the TGF beta pathway's function in the body and ultimately results in the signs and symptoms of LDS.

 

Learn more about genes, mutations, and the TGF beta pathway. 

Approximately 75% of people with LDS are the first members of their family to have the condition. Their de novo (new) mutation occurs at random in a parent’s reproductive cell (egg or sperm) or during conception or embryogenesis (when the embryo develops). There is no parental cause, such as medication or alcohol use, that produces the mutation. 

 

Approximately 25% of people with LDS have a parent with the condition. Their mutation is passed from parent to child in an inheritance pattern known as autosomal dominant. “Autosomal” means the mutation is in a gene that is located on an autosomal chromosome (a long molecule made of DNA and proteins). “Dominant” means that a child can have LDS after receiving a copy of the mutated gene from one parent and a copy of the normal gene from the other parent; they only need to receive one copy of the mutated gene (not two) to have LDS. Due to the autosomal dominant inheritance pattern, people with LDS have a 50% chance of passing their gene mutation and condition to each of their children. However, the degree of any potential vascular, skeletal, skin, or other LDS manifestations in an offspring cannot be predicted.

Through genetic testing, a laboratory is able to examine a person’s genetic information and identify changes that may be related to medical conditions. Testing can confirm a diagnosis of Loeys-Dietz syndrome.

Learn more about genetic testing options, test results, and professionals who can help.

When an individual receives their diagnosis, it can raise important genetic questions for their family members. 

 

For parents of a person with LDS:

  • Approximately 25% of individuals diagnosed with LDS have a parent with LDS.
  • If the individual’s LDS-causing mutation is known (e.g., they receive a positive genetic test result), it is recommended that both parents are genetically tested for the mutation.
  • If the individual’s mutation is unknown, it is recommended that both parents are clinically (physically) examined.

For siblings of a person with LDS:

  • If the individual’s parent is diagnosed with LDS (clinically or through genetic testing), there is a 50% chance that the individual’s sibling inherited the LDS-causing mutation and condition. 
  • If the individual’s parents appear to be clinically (physically) unaffected and receive negative genetic test results, the risk to siblings is low. However, they are still at a greater risk than the rest of the population due to the possibility of parents with reduced penetrance (people with a genetic disorder who do not express the disease manifestations) or mosaicism (a condition where instead of having all cells with the same genetics, a person has two or more genetically different sets of cells).
  • Clinical evaluation and/or genetic testing of the sibling is recommended.  

For children of a person with LDS:

  • There is a 50% chance that an individual’s child inherited the LDS-causing mutation and condition. 
  • Clinical evaluation and/or genetic testing of the child is recommended.

For extended family of a person with LDS:

  • The risk to extended family depends on their relationship (parent/sibling/child) to another family member diagnosed with LDS.

Comprehensive clinical (physical) examination and/or genetic testing are important for a family’s diagnosis. The individual’s family may have LDS but appear not to because of an incomplete clinical examination, symptoms that appear later in life, reduced penetrance, or mosaicism. A genetics professional can help explain these possibilities, organize thorough clinical examination and genetic testing, and discuss next steps. 

 

It is recommended that people with LDS who are of reproductive age and interested in having children meet with a genetics professional to discuss recurrence risk (the likelihood that family members, such as offspring, will have LDS). 

 

Thanks to advancements in genetic testing, there are now a variety of Loeys-Dietz syndrome family planning options. If the familial mutation is known, LDS testing may be performed before and during pregnancy. Testing can help individuals to have a child without Loeys-Dietz syndrome or to receive an early diagnosis for their child. A genetics professional can discuss medical, personal, and financial concerns to help families choose an option that is right for them.

 

Before pregnancy, in vitro fertilization can be performed in a laboratory to combine a previously-collected egg and sperm into an embryo. The embryo can then be tested for LDS via preimplantation genetic testing. Embryos unaffected by LDS can be implanted into the mother or surrogate

 

During pregnancy, prenatal testing can help determine if offspring are likely to have certain birth defects or genetic conditions. For LDS testing, options such as chorionic villus sampling (CVS) and amniocentesis are available as early as week 10 of pregnancy. Test results can be used for pregnancy termination or early diagnosis and monitoring.

 

Do you have questions about genetics, diagnosis, or what comes next for your family?

About Loeys-Dietz Syndrome. Loeys-Dietz Syndrome Foundation. (n.d.). Retrieved October 11, 2022, from https://www.loeysdietz.org/en/medical-information/#diagnosis 

 

Fabregat, I., & Caballero-Díaz, D. (2018). Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Frontiers in Oncology, 8. https://doi.org/10.3389/fonc.2018.00357 

 

Findlay, J. K., Gear, M. L., Illingworth, P. J., Junk, S. M., Kay, G., Mackerras, A. H., Pope, A., Rothenfluh, H. S., & Wilton, L. (2006). Human embryo: A biological definition. Human Reproduction, 22(4), 905–911. https://doi.org/10.1093/humrep/del467 

 

Genetic Alliance; The New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals. Washington (DC): Genetic Alliance; 2009 Jul 8. CHAPTER 1, GENETICS 101. Available from: https://www.ncbi.nlm.nih.gov/books/NBK115568/

 

Kubiczkova, L., Sedlarikova, L., Hajek, R., & Sevcikova, S. (2012). TGF-β – an excellent servant but a bad master. Journal of Translational Medicine, 10(1). https://doi.org/10.1186/1479-5876-10-183 

 

Loewe, L. (2008) Genetic mutation. Nature Education 1(1):113

 

NCI Dictionary of Genetics terms. National Cancer Institute. (n.d.). Retrieved October 11, 2022, from https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/de-novo-mutation 

 

Public Health Agency of Canada. (2013, February 5). Government of Canada. Canada.ca. Retrieved October 11, 2022, from https://www.canada.ca/en/public-health/services/fertility/genetic-testing-screening.html 

 

Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell, 113(6), 685–700. https://doi.org/10.1016/s0092-8674(03)00432-x 

 

U.S. National Library of Medicine. (n.d.). Loeys-Dietz syndrome. MedlinePlus. Retrieved October 11, 2022, from https://medlineplus.gov/genetics/condition/loeys-dietz-syndrome/ 

 

Velchev, J. D., Van Laer, L., Luyckx, I., Dietz, H., & Loeys, B. (2021). Loeys-Dietz Syndrome. Advances in Experimental Medicine and Biology, 251–264. https://doi.org/10.1007/978-3-030-80614-9_11

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