Application of genetic testing in the diagnosis and individualized treatment of heritable aortic disease_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHEN Tao ^1,2 ,  HU Kui ¹ , LU Wang ^1,2 , XIANG Daokang ¹

1. Department of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, 550002, P. R. China;
2. Graduate School, Zunyi Medical University, Zunyi, 563000, Guizhou, P. R. China;

Corresponding author：

HU Kui, Email: cardiahukui@126.com

Keywords：

Heritable aortic disease; genetic testing; diagnosis; treatment; review

DOI：

10.7507/1007-4848.202310008

Video：

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Heritable aortic disease (HAD) is characterized by thoracic aortic aneurysm/dissection with strong genetic predisposition and high clinical phenotypic heterogeneity. HAD is one of the main causes of sudden death. Early diagnosis of this disease is difficult because of atypical clinical symptoms, leading to the deterioration of disease with the development of aortic aneurysm, aortic dissection or sudden death. Genetic testing plays an important role in the early diagnosis, standardized follow-up, screening of family members, genetic counseling and individualized treatment of HAD. This review focused on the application of genetic testing in the standardized diagnosis and treatment of HAD.

Citation： CHEN Tao, HU Kui, LU Wang, XIANG Daokang. Application of genetic testing in the diagnosis and individualized treatment of heritable aortic disease. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2025, 32(10): 1504-1509. doi: 10.7507/1007-4848.202310008 Copy

1.	Kwartler CS, Gong L, Chen J, et al. Variants of unknown significance in genes associated with heritable thoracic aortic disease can be low penetrant "Risk Variants". Am J Hum Genet, 2018, 103(1): 138-143.
2.	Milewicz DM, Braverman AC, De Backer J, et al. Marfan syndrome. Nat Rev Dis Primers, 2021, 7(1): 64.
3.	胡馗. Loeys-Dietz综合征的诊断及治疗进展. 复旦学报(医学版), 2022, 49(1): 138-143.Hu K. Progress on the diagnosis and treatment of Loeys-Dietz syndrome. Fudan Univ J Med Sci, 2022, 49(1): 138-143.
4.	MacCarrick G, Black JH, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med, 2014, 16(8): 576-587.
5.	Bowen JM, Sobey GJ, Burrows NP, et al. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet, 2017, 175(1): 27-39.
6.	Shalhub S, Byers PH, Hicks KL, et al. A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis. J Vasc Surg, 2020, 71(1): 149-157.
7.	Doyle AJ, Doyle JJ, Bessling SL, et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet, 2012, 44(11): 1249-1254.
8.	Pinard A, Jones GT, Milewicz DM. Genetics of thoracic and abdominal aortic diseases. Circ Res, 2019, 124(4): 588-606.
9.	Thakker PD, Braverman AC. Cardiogenetics: genetic testing in the diagnosis and management of patients with aortic disease. Heart, 2021, 107(8): 619-626.
10.	Bowdin SC, Laberge AM, Verstraeten A, et al. Genetic testing in thoracic aortic disease: when, why, and how? Can J Cardiol, 2016, 32(1): 131-134.
11.	国家心血管病专家委员会血管外科专业委员会. 遗传性胸主动脉瘤/夹层基因检测及临床诊疗专家共识. 中国循环杂志, 2019, 34(4): 319-325.National Society of Vascular Surgery. Chinese expert consensus on the genetic testing and clinical management of heritable thoracic aortic aneurysm/dissection. Chin Circ J, 2019, 34(4): 319-325.
12.	Mariscalco G, Debiec R, Elefteriades JA, et al. Systematic review of studies that have evaluated screening tests in relatives of patients affected by nonsyndromic thoracic aortic disease. J Am Heart Assoc, 2018, 7(15): e009302.
13.	Campens L, Callewaert B, Muiño Mosquera L, et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis, 2015, 10: 9.
14.	杨航, 罗明尧, 殷昆仑, 等. 遗传性主动脉疾病基因检测的应用. 中国循环杂志, 2016, 31(3): 304-306.Yang H, Luo MY, Yin KL, et al. Application of genetic testing in hereditary aortic diseases. Chin Circ J, 2016, 31(3): 304-306.
15.	Sheick-Yousif B, Sheinfield A, Tager S, et al. Aortic root surgery in Marfan syndrome. Isr Med Assoc J, 2008, 10(3): 189-193.
16.	Martín C, Evangelista A, Serrano-Fiz S, et al. Aortic complications in Marfan syndrome: should we anticipate preventive aortic root surgery? Ann Thorac Surg, 2020, 109(6): 1850-1857.
17.	Izgi C, Newsome S, Alpendurada F, et al. External aortic root support to prevent aortic dilatation in patients with Marfan syndrome. J Am Coll Cardiol, 2018, 72(10): 1095-1105.
18.	Tognato E, Perona A, Aronica A, et al. Neonatal Marfan syndrome. Am J Perinatol, 2019, 36(S2): S74-S76.
19.	Schrijver I, Liu W, Odom R, et al. Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. Am J Hum Genet, 2002, 71(2): 223-237.
20.	Faivre L, Collod-Beroud G, Loeys BL, et al. Effect of mutation type and location on clinical outcome in 1, 013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet, 2007, 81(3): 454-466.
21.	Rommel K, Karck M, Haverich A, et al. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat, 2005, 26(6): 529-539.
22.	Franken R, den Hartog AW, Radonic T, et al. Beneficial outcome of losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circ Cardiovasc Genet, 2015, 8(2): 383-388.
23.	Franken R, Groenink M, de Waard V, et al. Genotype impacts survival in Marfan syndrome. Eur Heart J, 2016, 37(43): 3285-3290.
24.	Malhotra A, Westesson PL. Loeys-Dietz syndrome. Pediatr Radiol, 2009, 39(9): 1015.
25.	van de Laar IM, van der Linde D, Oei EH, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet, 2012, 49(1): 47-57.
26.	Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet, 2017, 175(1): 8-26.
27.	Wang S, Niu Z, Wang H, et al. De novo paternal FBN1 mutation detected in embryos before implantation. Med Sci Monit, 2017, 23: 3136-3146.
28.	Isselbacher EM, Preventza O, Hamilton Black J, 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, 2022, 146(24): e334-e482.
29.	Goldstein SA, Evangelista A, Abbara S, et al. Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr, 2015, 28(2): 119-182.
30.	Verhagen JMA, Kempers M, Cozijnsen L, et al. Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Int J Cardiol, 2018, 258: 243-248.
31.	Brooke BS, Arnaoutakis G, McDonnell NB, et al. Contemporary management of vascular complications associated with Ehlers-Danlos syndrome. J Vasc Surg, 2010, 51(1): 131-138.
32.	Shalhub S, Byers PH, Hicks KL, et al. A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome. J Vasc Surg, 2019, 70(5): 1543-1554.
33.	Schepers D, Tortora G, Morisaki H, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat, 2018, 39(5): 621-634.
34.	Hou JW, Hwu WL, Tsai WY, et al. Cardiovascular disorders in Turner's syndrome and its correlation to karyotype. J Formos Med Assoc, 1993, 92(2): 188-189.
35.	Kim HK, Gottliebson W, Hor K, et al. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. AJR Am J Roentgenol, 2011, 196(2): 454-460.
36.	Silberbach M, Roos-Hesselink JW, Andersen NH, et al. Cardiovascular health in Turner syndrome: a scientific statement from the American Heart Association. Circ Genom Precis Med, 2018, 11(10): e000048.
37.	Harris SL, Lindsay ME. Role of clinical genetic testing in the management of aortopathies. Curr Cardiol Rep, 2021, 23(2): 10.
38.	Kocyigit D, Griffin BP, Xu B. Medical therapies for Marfan syndrome and other thoracic aortic dilatation in adults: a contemporary review. Am J Cardiovasc Drugs, 2021, 21(6): 609-617.
39.	Shores J, Berger KR, Murphy EA, et al. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med, 1994, 330(19): 1335-1341.
40.	Brooke BS, Habashi JP, Judge DP, et al. Angiotensin Ⅱ blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med, 2008, 358(26): 2787-2795.
41.	Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J, 2013, 34(45): 3491-3500.
42.	Mullen M, Jin XY, Child A, et al. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet, 2019, 394(10216): 2263-2270.
43.	Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation, 2010, 121(13): e266-e369.
44.	Engelfriet PM, Boersma E, Tijssen JG, et al. Beyond the root: dilatation of the distal aorta in Marfan's syndrome. Heart, 2006, 92(9): 1238-1243.
45.	Benrashid E, Ohman JW. Current management of the vascular subtype of Ehlers-Danlos syndrome. Curr Opin Cardiol, 2020, 35(6): 603-609.
46.	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.
47.	Michelena HI, Della Corte A, Evangelista A, et al. International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes. J Thorac Cardiovasc Surg, 2021, 162(3): e383-e414.
48.	Masri A, Kalahasti V, Svensson LG, et al. Aortic cross-sectional area/height ratio and outcomes in patients with bicuspid aortic valve and a dilated ascending aorta. Circ Cardiovasc Imaging, 2017, 10(6): e006249.

1. Kwartler CS, Gong L, Chen J, et al. Variants of unknown significance in genes associated with heritable thoracic aortic disease can be low penetrant "Risk Variants". Am J Hum Genet, 2018, 103(1): 138-143.
2. Milewicz DM, Braverman AC, De Backer J, et al. Marfan syndrome. Nat Rev Dis Primers, 2021, 7(1): 64.
3. 胡馗. Loeys-Dietz综合征的诊断及治疗进展. 复旦学报(医学版), 2022, 49(1): 138-143.Hu K. Progress on the diagnosis and treatment of Loeys-Dietz syndrome. Fudan Univ J Med Sci, 2022, 49(1): 138-143.
4. MacCarrick G, Black JH, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med, 2014, 16(8): 576-587.
5. Bowen JM, Sobey GJ, Burrows NP, et al. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet, 2017, 175(1): 27-39.
6. Shalhub S, Byers PH, Hicks KL, et al. A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis. J Vasc Surg, 2020, 71(1): 149-157.
7. Doyle AJ, Doyle JJ, Bessling SL, et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet, 2012, 44(11): 1249-1254.
8. Pinard A, Jones GT, Milewicz DM. Genetics of thoracic and abdominal aortic diseases. Circ Res, 2019, 124(4): 588-606.
9. Thakker PD, Braverman AC. Cardiogenetics: genetic testing in the diagnosis and management of patients with aortic disease. Heart, 2021, 107(8): 619-626.
10. Bowdin SC, Laberge AM, Verstraeten A, et al. Genetic testing in thoracic aortic disease: when, why, and how? Can J Cardiol, 2016, 32(1): 131-134.
11. 国家心血管病专家委员会血管外科专业委员会. 遗传性胸主动脉瘤/夹层基因检测及临床诊疗专家共识. 中国循环杂志, 2019, 34(4): 319-325.National Society of Vascular Surgery. Chinese expert consensus on the genetic testing and clinical management of heritable thoracic aortic aneurysm/dissection. Chin Circ J, 2019, 34(4): 319-325.
12. Mariscalco G, Debiec R, Elefteriades JA, et al. Systematic review of studies that have evaluated screening tests in relatives of patients affected by nonsyndromic thoracic aortic disease. J Am Heart Assoc, 2018, 7(15): e009302.
13. Campens L, Callewaert B, Muiño Mosquera L, et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis, 2015, 10: 9.
14. 杨航, 罗明尧, 殷昆仑, 等. 遗传性主动脉疾病基因检测的应用. 中国循环杂志, 2016, 31(3): 304-306.Yang H, Luo MY, Yin KL, et al. Application of genetic testing in hereditary aortic diseases. Chin Circ J, 2016, 31(3): 304-306.
15. Sheick-Yousif B, Sheinfield A, Tager S, et al. Aortic root surgery in Marfan syndrome. Isr Med Assoc J, 2008, 10(3): 189-193.
16. Martín C, Evangelista A, Serrano-Fiz S, et al. Aortic complications in Marfan syndrome: should we anticipate preventive aortic root surgery? Ann Thorac Surg, 2020, 109(6): 1850-1857.
17. Izgi C, Newsome S, Alpendurada F, et al. External aortic root support to prevent aortic dilatation in patients with Marfan syndrome. J Am Coll Cardiol, 2018, 72(10): 1095-1105.
18. Tognato E, Perona A, Aronica A, et al. Neonatal Marfan syndrome. Am J Perinatol, 2019, 36(S2): S74-S76.
19. Schrijver I, Liu W, Odom R, et al. Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. Am J Hum Genet, 2002, 71(2): 223-237.
20. Faivre L, Collod-Beroud G, Loeys BL, et al. Effect of mutation type and location on clinical outcome in 1, 013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet, 2007, 81(3): 454-466.
21. Rommel K, Karck M, Haverich A, et al. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat, 2005, 26(6): 529-539.
22. Franken R, den Hartog AW, Radonic T, et al. Beneficial outcome of losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circ Cardiovasc Genet, 2015, 8(2): 383-388.
23. Franken R, Groenink M, de Waard V, et al. Genotype impacts survival in Marfan syndrome. Eur Heart J, 2016, 37(43): 3285-3290.
24. Malhotra A, Westesson PL. Loeys-Dietz syndrome. Pediatr Radiol, 2009, 39(9): 1015.
25. van de Laar IM, van der Linde D, Oei EH, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet, 2012, 49(1): 47-57.
26. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet, 2017, 175(1): 8-26.
27. Wang S, Niu Z, Wang H, et al. De novo paternal FBN1 mutation detected in embryos before implantation. Med Sci Monit, 2017, 23: 3136-3146.
28. Isselbacher EM, Preventza O, Hamilton Black J, 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, 2022, 146(24): e334-e482.
29. Goldstein SA, Evangelista A, Abbara S, et al. Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr, 2015, 28(2): 119-182.
30. Verhagen JMA, Kempers M, Cozijnsen L, et al. Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Int J Cardiol, 2018, 258: 243-248.
31. Brooke BS, Arnaoutakis G, McDonnell NB, et al. Contemporary management of vascular complications associated with Ehlers-Danlos syndrome. J Vasc Surg, 2010, 51(1): 131-138.
32. Shalhub S, Byers PH, Hicks KL, et al. A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome. J Vasc Surg, 2019, 70(5): 1543-1554.
33. Schepers D, Tortora G, Morisaki H, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat, 2018, 39(5): 621-634.
34. Hou JW, Hwu WL, Tsai WY, et al. Cardiovascular disorders in Turner's syndrome and its correlation to karyotype. J Formos Med Assoc, 1993, 92(2): 188-189.
35. Kim HK, Gottliebson W, Hor K, et al. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. AJR Am J Roentgenol, 2011, 196(2): 454-460.
36. Silberbach M, Roos-Hesselink JW, Andersen NH, et al. Cardiovascular health in Turner syndrome: a scientific statement from the American Heart Association. Circ Genom Precis Med, 2018, 11(10): e000048.
37. Harris SL, Lindsay ME. Role of clinical genetic testing in the management of aortopathies. Curr Cardiol Rep, 2021, 23(2): 10.
38. Kocyigit D, Griffin BP, Xu B. Medical therapies for Marfan syndrome and other thoracic aortic dilatation in adults: a contemporary review. Am J Cardiovasc Drugs, 2021, 21(6): 609-617.
39. Shores J, Berger KR, Murphy EA, et al. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med, 1994, 330(19): 1335-1341.
40. Brooke BS, Habashi JP, Judge DP, et al. Angiotensin Ⅱ blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med, 2008, 358(26): 2787-2795.
41. Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J, 2013, 34(45): 3491-3500.
42. Mullen M, Jin XY, Child A, et al. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet, 2019, 394(10216): 2263-2270.
43. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation, 2010, 121(13): e266-e369.
44. Engelfriet PM, Boersma E, Tijssen JG, et al. Beyond the root: dilatation of the distal aorta in Marfan's syndrome. Heart, 2006, 92(9): 1238-1243.
45. Benrashid E, Ohman JW. Current management of the vascular subtype of Ehlers-Danlos syndrome. Curr Opin Cardiol, 2020, 35(6): 603-609.
46. 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.
47. Michelena HI, Della Corte A, Evangelista A, et al. International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes. J Thorac Cardiovasc Surg, 2021, 162(3): e383-e414.
48. Masri A, Kalahasti V, Svensson LG, et al. Aortic cross-sectional area/height ratio and outcomes in patients with bicuspid aortic valve and a dilated ascending aorta. Circ Cardiovasc Imaging, 2017, 10(6): e006249.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Application of genetic testing in the diagnosis and individualized treatment of heritable aortic disease

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