Genetics and Loeys-Dietz Syndrome

Loeys-Dietz syndrome (LDS) is a genetic condition that affects the body’s connective tissue. As a genetic condition, it can be traced back to your genes and may be passed on to your children.

What are genes? How can they impact you and your family? Keep reading to find out.

Genetics 101

Our cells use genetic information known as DNA (deoxyribonucleic acid) to build molecules that help the body to function properly. Specific regions of DNA are known as genes, and each gene contains the information needed to build molecules and proteins. Molecules can act together in a series of actions called a biological pathway to accomplish tasks in the cell or the body. These tasks include building other molecules (metabolic pathways), turning genes on or off (gene regulation pathways), and passing signals from outside to inside the cell (signal transduction pathways). These tasks ultimately allow the body to function properly.

The complete set of DNA in a human, known as the human genome, is slightly different for each person. It includes approximately 20,000 to 25,000 genes and less than 1% differs between people. Some genetic differences can be caused by mutations, changes in the DNA sequence that may or may not be harmful to the body. 

What causes LDS?

Loeys-Dietz syndrome is caused by a mutation in one of the following genes:

  • TGFBR1 (transforming growth factor beta receptor 1; LDS type 1)
  • TGFBR2 (transforming growth factor beta receptor 2; LDS type 2)
  • SMAD3 (mothers against decapentaplegic homolog 3; LDS type 3)
  • TGFB2 (transforming growth factor beta 2; LDS type 4)
  • TGFB3 (transforming growth factor beta 3; LDS type 5)
  • SMAD2 (mothers against decapentaplegic homolog 2; LDS type 6)

Each of these genes contains instructions to build a specific protein with the same name as the gene. The proteins interact with each other and other molecules in a signal transduction pathway called the TGF beta pathway. TGFB2 or TGFB3 proteins bind to and bring together receptors TGFBR1 and TGFBR2. These receptors are on the surface of the cell and allow signals from outside of the cell to be transmitted to the inside. TGFBR1 transmits the signal to SMAD2 or SMAD3 proteins, which bind to other proteins and regulate development, growth, immune function and tissue maintenance.

tgf beta pathway
TGF beta pathway

Source: Fabregat I, Cabellero-Diaz D. 2018. Transforming Growth Factor-B-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinegenesis; Figure 1: Canonical (Smad-dependent) and non-canonical (Smad-independent) TGF-B signaling pathways. Frontiers in Oncology. https://doi.org/10.3389/fonc.2018.00357

When an LDS-causing mutation occurs in TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2 or SMAD3, the gene cannot properly pass on its protein-building instructions. The protein does not function properly, disrupts the TGF beta pathway’s role in the body, and ultimately causes the signs and symptoms of LDS.

Genetic Testing and Counselling

What is genetic testing?

Genetic testing allows a laboratory to analyze DNA and identify mutations that can cause disease. Test results are ordered by medical professionals and can confirm a diagnosis like Loeys-Dietz syndrome.

We recommend that you meet with a geneticist or genetic counsellor before and after being tested. Genetics professionals are trained to help people and families make informed decisions. They provide emotional support, give information about genetic disorders, provide you with resources, and discuss the implications of different test results.

What will my test result be?

Genetic testing can produce a positive result, negative result or variant of unknown significance.

A positive result means that the test identified a pathogenic variant (mutation known to cause disease) or likely pathogenic variant (mutation likely to cause disease). These results can be used to confirm a diagnosis.

A negative result indicates that test found a benign variant (mutation not known to cause disease) or likely benign variant (mutation not likely to cause disease), or did not find a mutation. 

A variant of unknown significance (VUS) result means that the test found a mutation that may or may not cause disease. Researchers will need more time, studies, and ​patient data to determine if the mutation is associated with disease. 

After the test, a medical professional can use the test results, type of test, and the individual’s symptoms and family history to discuss an individual’s diagnosis (the testing may or may not confirm a diagnosis) and to create a treatment and monitoring plan that is right for the individual.

In the case of a negative or VUS result, individuals may consider DNA banking (storage) for future genetic testing. Future testing may provide new results as mutations and disease genetics become better understood over time.

Where did my mutation come from?

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.

How will I be affected?

The degree to which people are affected by LDS varies from person to person, even when they have the same type of LDS. However, initial evidence shows that mutations in TGFBR1 and TGFBR2 have greater penetrance than other LDS-causing mutations, meaning that individuals with LDS type 1 and 2 (mutations in TGFBR1 and TGFBR2, respectively) are more likely to exhibit the signs and symptoms of LDS.

How will my family be affected?

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.

Family planning

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.

How can I get diagnosed and tested?

Learn more about receiving a Loeys-Dietz syndrome diagnosis, which can include a clinical (physical) examination and genetic testing.

For genetic testing, ask a healthcare professional like your family doctor about receiving testing and seeing a genetics professional. In Canada, testing may be covered by your provincial health care, private plan, or employee benefits, and genetic counselling in a public clinic is free.

For signs and symptoms of LDS, check out our Head to Toe

 

For peer support, visit a community-run, closed Facebook group: Loeys-Dietz Families

 

For medical professionals near you, click here

 

For medical genetics clinics near you, click here

 

For genetic testing laboratories, check out:

Blueprint Genetics. A patient’s guide to understanding genetic testing. [cited 2021 Sep 14]. Available from: https://blueprintgenetics.com/wp-content/uploads/2016/05/PatientE28099s_guide_to_understanding_genetic_testing-_PATMIN1-01.pdf

 

Canadian Association of Genetic Counsellors. What is a genetic counsellor? [cited 2021 Sep 14]. Available from: https://www.cagc-accg.ca/index.php?page=353

 

Loeys BL, Dietz HC. 2008 [updated 2018 Mar 1]. Loeys-Dietz Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1133/

 

Loewe L. 2008. Genetic mutation. Nature Education. 1(1):113. https://www.nature.com/scitable/topicpage/genetic-mutation-1127/

 

Fabregat I, Cabellero-Diaz D. 2018. Transforming Growth Factor-B-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinegenesis; Figure 1: Canonical (Smad-dependent) and non-canonical (Smad-independent) TGF-B signaling pathways. Frontiers in Oncology. https://doi.org/10.3389/fonc.2018.00357

 

Findlay JK et al. 2007. Human embryo: a biological definition. Human Reproduction. 22(4): 904-911. https://doi.org/10.1093/humrep/del467

 

Genetic Alliance. 2009. Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals. Washington (DC): Genetic Alliance; [updated 2009 Jul 8; cited 2021 Sep 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK115568/

 

Government of Canada. Genetic counselling. [updated 2013 Feb 5; cited 2021 Sep 14] Available from: https://www.canada.ca/en/public-health/services/fertility/genetic-counselling.html

 

Government of Canada. Genetic testing and screening. [updated 2013 Feb 5; cited 2021 Sep 14] Available from: https://www.canada.ca/en/public-health/services/fertility/genetic-testing-screening.html

 

Kubiczkova L et al. 2021. TGF-B – an excellent servant but a bad master. Journal of Translational Medecine. 10(183). https://doi.org/10.1186/1479-5876-10-183

 

MedlinePlus. Loeys-Dietz syndrome? [cited 2021 Sep 14] Available from: https://medlineplus.gov/genetics/condition/loeys-dietz-syndrome/

 

MedlinePlus. What is DNA? [cited 2021 Sep 14] Available from: https://medlineplus.gov/genetics/understanding/basics/dna/

 

Meester JAN et al. 2017. Difference in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Annals of Cardiothoracic Surgery. 6(6). https://www.annalscts.com/article/view/16419

 

National Human Genome Research Institute. Biological Pathways Fact Sheet. [updated 2020 Aug 15; cited 2021 Sep 14] Available from: https://www.genome.gov/about-genomics/fact-sheets/Biological-Pathways-Fact-Sheet

 

News Medical. What are Ligands? [updated 2021 Mar 16; cited September 14, 2021] Available from: https://www.news-medical.net/life-sciences/Ligands-An-Overview.aspx

 

Prevention Genetics. [cited 2021 Sep 14]. Available from: https://www.preventiongenetics.com/

 

Shi Y. 2003. Mechanisms of TGF-B Signalling from Cell Membrane to the Nucleus. Cell. 113(6): 685-700. https://doi.org/10.1016/S0092-8674(03)00432-X

 

Yang H et al. 2020. Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients. Orphanet Journal of Rare Diseases. 15(6). https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1282-3#Bib1

Leave a Comment

Your email address will not be published. Required fields are marked *