Last updated:
9/8/2025
Years published: 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Sophia Adelson, MS, Leah Rossi, MS and Fiona Seung, MS, Stanford University MS Program in Human Genetics and Genetic Counseling, Anusha Kindler, MS, CGC, Stanford Center for Inherited Cardiovascular Disease and Dianna M. Milewicz, MD, PhD, University of Texas Health Science Center at Houston McGovern Medical School, for the preparation of this report.
Nonsyndromic heritable thoracic aortic disease (nsHTAD), also known as familial thoracic aortic aneurysm and dissection (FTAAD) is a rare genetic vascular disorder characterized by aneurysm, dissection, or dilatation of the thoracic aorta, affecting the root, ascending aorta, arch, or descending aorta, in families with no other problems in the body. It is a subtype of heritable thoracic aortic disease (HTAD), a condition that affects the aorta. The aorta is the large blood vessel that carries blood from the heart to the rest of the body.1,2,3,4 In people with HTDA the aorta can become weak and progressively enlarges (aneurysm formation). As the aneurysm grows, the risk for a tear (dissection) in the aorta increases which can be life-threatening.1,3-5
nsHTAD can occur at any age 2-4,6 but is usually diagnosed in older adults.1 Additionally, an aneurysm is commonly identified incidentally during imaging of the heart and/or chest, or when a tear or dissection of the aorta causes a serious emergency.7,8 Some people may not have symptoms until the aorta dissections,3,6 and chest pain is the most common symptom.7
When thoracic aortic aneurysms are part of a broader condition called a syndrome, which is a recognizable pattern of physical traits, the condition is known as syndromic thoracic aortic aneurysm or dissections (s-TAADs) or syndromic heritable thoracic disease. Marfan syndrome and Loeys-Dietz syndrome are two examples of syndromes where thoracic aortic aneurysms are a defining feature.1,3,4,7
Genetic testing can sometimes identify a change (variant) in a gene in people with nsHTAD, but in many families, no variant is found, even when inheritance is clearly present. That’s because current testing can’t detect all genetic causes of the disease. Researchers are still uncovering new variants that help explain these familial cases.
Heritable thoracic aortic disease (HTDA) is caused by changes (variants) in genes that help build and maintain the aortic wall. 1,3,4,6,7,9 It is usually inherited from a parent in an autosomal dominant pattern, meaning a person only needs one copy of the changed gene to have the condition.3,4,6,7,9 Some people may develop HTAD due to a new gene change with no family history.3,4,9 Scientists have identified several genes linked to HTAD, but for many people, the exact cause is still unknown.6,7
There are two main groups of genes involved in nsHTAD. One group includes genes such as FBN1, COL3A1 and LOX that affect the connective tissue in the aorta.3,9,24 The other group includes genes that are involved in TGF-beta signaling (TGFBR1, TGFBR2, TGFB2 and SMAD3)1,3,9 and those involved in smooth muscle contraction (ACTA2, MYH11, MYLK and PRKG1).3,6,9,10
Medical treatments can slow the enlargement of the aorta but there are no medications that prevent aortic dissections. Doctors may prescribe medications to lower blood pressure or reduce strain on the aorta.1,3,4,7,9 Regular check-ups with imaging tests help monitor aortic size.1,3,4,6,7,9 Ultimately, the aorta enlarges to a size that surgery is needed to prevent an aortic dissection.1,3,4,6,7,9 With proper care, people with nsHTAD can live long, healthy lives.1,3,4,6,7,9
Introduction
Heritable thoracic aortic disease (HTAD) is an umbrella term that includes syndromic conditions (like Marfan syndrome and Loeys-Dietz syndrome) and nonsyndromic heritable thoracic aortic disease (nsHTAD). Syndromic HTAD affects the aorta and other parts of the body, while nonsyndromic HTAD only affects the aorta.1 This report focuses on nonsyndromic heritable thoracic aortic disease (nsHTAD)
Nonsyndromic HTAD can cause changes in the aorta at any point in life, even in childhood. The age at which the disease starts and how it presents can vary widely.4 Aortic aneurysms typically do not cause any symptoms. For the rare aneurysms that cause symptoms, the symptoms depend on where the aneurysm is, how big it is and how fast it is growing.
Symptoms can include:
An aortic dissection is when the aorta tears, causing sudden, severe pain in the chest or upper back that feels like “ripping” or “tearing.” The pain may move from one area to another. An aortic dissection can also make skin pale, cause a weak pulse and lead to numbness, tingling, or even paralysis in the arms or legs.11
For someone with nsHTAD, doctors may find a genetic cause in the family, but sometimes the cause is unknown. Even without a clear genetic diagnosis, nsHTAD might still be suspected if there is a strong family history or if someone has an aortic dissection at a young age (before 60) and no other reason is found.4 Over 20% of people with a thoracic aortic aneurysm who don’t have a known vascular connective tissue disorder have a parent, sibling or child (first-degree relative) with an aneurysm.15
nsHTAD can be caused by changes (pathogenic variants) in certain genes. These genes provide instructions for making proteins that help the aorta stay strong and flexible. When these genes have disease-causing variants, the proteins do not work properly, and the aorta can become weak.
Most cases of nsHTAD are caused by variants in genes involved in vascular smooth muscle function. Genes with a definitive or strong association with nsHTAD include ACTA2, MYH11, MYLK, PRKG1, MAT2A, MFAP5, FOXE3 and THSD4.4,16 About 20-30% of people with a family history of HTAD and no syndromic presentation have an underlying genetic cause.4 It is important to note that MFAP5 and FOXE3 have moderate gene-disease validity, TGFB3 and MAT2A have limited gene-disease validity, and THSD4 has not been sufficiently evaluated meaning the genes are still being researched for the purpose of proving their association with nsHTAD.4
Inheritance
Nonsyndromic HTAD is typically inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Nonsyndromic HTAD affects males and females in about equal numbers though there are some sex-specific differences in its predisposition and outcomes. nsHTAD can present in earlier ages with more severe symptoms in males compared to females but some genes show equal severity in both sexes.17 nsHTAD occurs worldwide with no ethnic predisposition.15,18 The exact prevalence of people with nsHTAD is unknown
Diagnosis of nsHTAD involves several steps including a physical exam, reviewing medical and family history, imaging tests (such as echocardiograms, CT scans, or MRIs) and genetic testing.4
There are different ways to evaluate the weakness and enlargement (aneurysm) or tearing (dissection) of the aorta. Aortic dissections are often classified using the Stanford or the DeBakey systems.22,23 The Stanford system divides dissections into two types: type A, where the dissection starts in the ascending aorta, and type B, where the dissection starts in the descending aorta. The Debakey system has three types (type I, II, and III) based on where the tear starts and which parts of the aorta are affected.23 In 2020, new criteria were proposed to describe aortic dissections in more detail, focusing on the exact location of the tear and how far the dissection has spread.16
Imaging tests help doctors check the size and shape of the aorta and track the size of the aortic tear over time. Aortic aneurysms are diagnosed using imaging tests like echocardiography (a test that uses sound waves to create a picture), CT scans, MRI, transesophageal echocardiogram (TEE), chest X-rays, or angiography. Aortic dissections can be diagnosed with CT scans or TEE.11
Genetic testing can identify variants in genes linked to nonsyndromic HTAD and syndromic HTAD. The American College of Cardiology and the American Heart Association recommend genetic testing for the following people with thoracic aortic disease (TAD): an aortic dissection (tear) under the age of 60 years; a family history of the condition; or people showing signs of syndromes like Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, or smooth muscle dysfunction syndrome. Family history of TAD increases the likelihood of identifying a gene variant causing HTAD in an individual with TAD. Diagnosis usually begins with genetic testing and evaluation by a genetic counselor who may order testing of multiple HTAD-related genes. If results are unclear or if symptoms suggest another genetic condition, more advanced testing such as exome or genome sequencing may be ordered. For individuals with TAD and features of Turner syndrome—such as short stature and ovarian insufficiency— chromosome tests like a karyotype or chromosomal microarray may be ordered.4 A team of specialists, including a cardiologist, medical geneticist and genetic counselor is often involved to ensure an accurate diagnosis and the best care plan.
There are no FDA-approved medications designed solely for non-syndromic or syndromic HTAD, but doctors use treatments that are proven to slow the enlargement of the aorta. These include:
Medications
Imaging and Monitoring
Surgical Treatment
Non-syndromic HTAD is best managed by a team of specialists including cardiologists, geneticists and cardiovascular surgeons.3,4 Since the condition can run in families, genetic counseling is strongly recommended. Genetic counselors can help families understand their risks, provide information about genetic testing and guide them in making informed healthcare decisions.3,4,7,9
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
1. Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL. Inherited Thoracic Aortic Disease. Circulation. 2020-05-12;doi:10.1161/CIRCULATIONAHA.119.043756
2. Milewicz DM, Chen H, Park E-S, et al. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. The American Journal of Cardiology. 1998/08/15;82(4)doi:10.1016/S0002-9149(98)00364-6
3. Mulder BJM, van de Laar IMBH, De Backer J. Heritable Thoracic Aortic Disorders. Clinical Cardiogenetics. 2016;doi:10.1007/978-3-319-44203-7_17
4. Milewicz DM, Cecchi AC. Heritable Thoracic Aortic Disease Overview. 2003 Feb 13 [Updated 2023 May 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1120/ Accessed Sept 8, 2025.
5. Isselbacher EM, Cardenas CLL, Lindsay ME. Hereditary Influence in Thoracic Aortic Aneurysm and Dissection. Circulation. 2016 Jun 14;133(24)doi:10.1161/CIRCULATIONAHA.116.009762
6. Milewicz DM, Carlson AA, Regalado ES. Genes Predisposing to Thoracic Aortic Aneurysms and Dissections: Associated Phenotypes, Gene-Specific Management, and Genetic Testing. Cardiology clinics. 2010 May;28(2)doi:10.1016/j.ccl.2010.01.017
7. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(41):2873-2926. doi:10.1093/eurheartj/ehu281
8. Duarte VE, Yousefzai R, Singh MN. Genetically Triggered Thoracic Aortic Disease: Who Should be Tested? Methodist DeBakey Cardiovascular Journal. 2023 Mar 7;19(2)doi:10.14797/mdcvj.1218
9. Mills AC, Sandhu HK, Ikeno Y, et al. Heritable thoracic aortic disease: a literature review on genetic aortopathies and current surgical management. General Thoracic and Cardiovascular Surgery 2024 72:5. 2024-03-14;72(5)doi:10.1007/s11748-024-02017-x
10. Renard M, Francis C, Ghosh R, et al. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. Journal of the American College of Cardiology. 2018 Aug 7;72(6)doi:10.1016/j.jacc.2018.04.089
11. The Marfan Foundation. Familial Thoracic Aortic Aneurysm and Dissection. 2025. Updated April 2021. https://marfan.org/conditions/familial-aortic-aneurysm/ Accessed Sept 8, 2025.
12. Dietz H. FBN1-Related Marfan Syndrome. 2001 Apr 18 [Updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1335/ Accessed Sept 8, 2025.
13. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2024 Sep 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1133/ Accessed Sept 8, 2025.
14. Byers PH. Vascular Ehlers-Danlos Syndrome. 1999 Sep 2 [Updated 2025 Apr 10]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1494/ Accessed Sept 8, 2025.
15. Albornoz G, Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and dissections—incidence, modes of inheritance, and phenotypic patterns. The Annals of thoracic surgery. 2006;82(4):1400-1405. doi:10.1016/j.athoracsur.2006.04.098
16. Isselbacher EM, Preventza O, Hamilton Black J, 3rd, et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. Dec 13 2022;146(24):e334-e482. doi:10.1161/cir.0000000000001106
17. Shalhub S, Rah JY, Campbell R, Sweet MP, Quiroga E, Starnes BW. Characterization of syndromic, nonsyndromic familial, and sporadic type B aortic dissection. J Vasc Surg. Jun 2021;73(6):1906-1914.e2. doi:10.1016/j.jvs.2020.10.080
18. Holmes KW, Markwardt S, Eagle KA, et al. Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions. J Am Coll Cardiol. May 31 2022;79(21):2069-2081. doi:10.1016/j.jacc.2022.03.367
19. Czerny M, Grabenwöger M, Berger T, et al. EACTS/STS Guidelines for Diagnosing and Treating Acute and Chronic Syndromes of the Aortic Organ. Ann Thorac Surg. Jul 2024;118(1):5-115. doi:10.1016/j.athoracsur.2024.01.021
20. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. Aug 24 2006;355(8):788-98. doi:10.1056/NEJMoa055695
21. Guo D-c, Regalado ES, Pinard A, et al. LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections. The American Journal of Human Genetics. 2018;102(4):706-712. doi:10.1016/j.ajhg.2018.03.002
22. De Bakey ME, Crawford ES. Surgical considerations of acquired diseases of the aorta and major peripheral arteries. I. Aortic aneurysms. Mod Concepts Cardiovasc Dis. Oct 1959;28:557-61.
23. DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of the aorta: twenty-year follow-up of five hundred twenty-seven patients treated surgically. Surgery. Dec 1982;92(6):1118-34.
24. Guo DC, Regalado ES, Gong L, et al. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res. 2016;118(6):928-934. doi:10.1161/CIRCRESAHA.115.307130
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/Please complete this form to access the requested resource.
