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Genetics and Loeys-Dietz Syndrome: Random Mutations and Family Affairs

8 min. read

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.

Image 1: DNA

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.

Image 2: TGF beta pathway

Image 2: 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 TGFBR1TGFBR2TGFB2TGFB3SMAD2 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 mutation that is known to cause disease. Your medical professional can use this information to confirm a diagnosis and build a treatment plan that is right for you.

A negative result means that test did not identify a mutation. This may mean that you do not have a genetic disease or that you have a genetic disease caused by a mutation that the test could not find. Your healthcare provider can use your test results, type of test and symptoms to discuss your options.

A variant of unknown significance (VUS) result means that the test identified a mutation that may or may not cause disease. More research and patient information will be needed to understand if the mutation causes disease. DNA banking can be used to store DNA for future testing when genetics and diseases are better understood. In the meantime, your medical professional can use your symptoms and family history to discuss a diagnosis and care plan. 

Where did my mutation come from?

75% of people with LDS are the first in their family to have an LDS-causing mutation. The de novo mutation occurs at random during conception or embryogenesis, the developmental stage of an embryo.

25% of people with LDS inherit the mutation from a parent in an autosomal dominant manner. This means that individuals who inherit one copy of the mutated gene from one parent are affected by LDS.

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 the proband (the first family member to be evaluated or tested for a genetic condition) receives their diagnosis, it can raise important genetic questions for their family.

For parents of a proband with LDS:

●     If the proband’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 proband’s mutation is unknown, it is recommended that both parents are clinically (physically) examined.

For siblings of a proband with LDS:

●     If the proband’s parent is diagnosed with LDS (clinically or through genetic testing), there is a 50% chance that the proband’s sibling inherited the LDS-causing mutation. Clinical evaluation and/or genetic testing of the sibling is recommended.

For children of a proband with LDS:

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

For extended family of a proband with LDS:

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

Comprehensive clinical examination and/or genetic testing are important for a family’s diagnosis. The proband’s family might seem to be unaffected by LDS, but could have LDS and seem unaffected due to incomplete clinical examination, symptoms that appear only later in life or appear very mildly, early death, 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).

Family planning

With advances in genetic testing, there are several family planning options available to people affected by LDS. A genetic counsellor can help families discuss medical, personal, and financial concerns to choose the right option for them.

Before pregnancy, in vitro fertilization can be performed in a laboratory to combine an egg and sperm into an embryo. Then, preimplantation genetic testing can be used to test the embryo. Embryos unaffected by LDS can be implanted into the mother or surrogate.

During pregnancy, testing options are available as early as 10 weeks, include chorionic villus sampling (CVS) and amniocentesis, and can be used for pregnancy termination or early diagnosis and monitoring.

How can I get tested?

Ask a healthcare professional like your family doctor about receiving genetic testing and seeing a genetic counsellor. 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.

Resources

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

·      Prevention Genetics

·      Invitae

·      GeneDx

Blueprint Genetics and Prevention Genetics offer free genetic testing for family members. Learn more here and here.

References

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