From vascular biology to vascular medicine

Open access


Cardiovascular disorders include various conditions characterized by morphological and functional defects of the heart and vascular system. Molecular biology techniques (in particular DNA sequencing) have recently offered new insights into the etiology of cardiovascular defects, revealing their association with germline as well as somatic mutations.

Genetic tests are evaluated on the basis of their analytical and clinical validity, clinical utility, and ethical, legal and social implications. Next generation sequencing is so far the best approach for molecular diagnosis of congenital heart defects and vascular anomalies, the genetic and phenotypic heterogeneity of which makes them difficult to diagnose. Understanding the molecular causes of congenital heart defects and vascular anomalies has permitted clinical trials of drugs targeting affected genes and pathways.

The articles in this Special Issue aim to provide guidance for those concerned with diagnosis and research in the field of cardiovascular defects. The approach to genetic testing is discussed.

1. Khodyuchenko T, Zlotina A, Pervunina T, Zverev D, Malashicheva A, Kostareva A. Congenital heart defects are rarely caused by mutations in cardiac and smooth muscle actin genes. Biomed Res Int. 2015;2015:127807.

2. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. Sturge–Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368:1971–1979.

3. Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, Le J, Wallenstein MB, Milla C, Teng JM, Bernstein JA, Stevenson DA. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet Part A 2016; 170(6):1450–54.

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7. Burke W, Zimmern RL, Kroese M. Defining purpose: a key step in genetic test evaluation. Genet Med 2007; 9:675–81.

8. Burke W, Atkins D, Gwinn M, Guttmacher A, Haddow J, Lau J, Palomaki G, Press N, Richards CS, Wideroff L, Wiesner GL. Genetic test evaluation: Information needs of clinicians, policy makers, and the public. Am J Epidemiol 2002; 156(4): 311–18.

9. Kohler JN, Turbitt E, Biesecker BB. Personal utility in genomic testing: a systematic literature review. Eur J Hum Genet 2017; 25(6):662-68.

10. Khoury MJ, Jones K, Grosse SD (2006) Quantifying the health benefits of genetic tests: the importance of a population perspective. Genet Med 8:191–95.

11. Biesecker L, Julie S. Proteus syndrome. GeneReviews. (3rdedn) 2012; University of Washington, Seattle.

12. Mansour S, Brice GW, Jeffery S, Mortimer P. Lymphedema-distichiasis syndrome. GeneReviews. (7thedn) 2005; University of Washington, Seattle.

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14. Bayrak-Toydemir P, Stevenson D. RASA1-related disorders. GeneReviews. (4thedn) 2011; University of Washington, Seattle.

15. Mirzaa G, Conway R, Graham JM, Dobyns WB. PIK3CA-related segmental overgrowth. GeneReviews. (2ndedn) 2013; University of Washington, Seattle.

16. Allanson JE, Roberts AE. Noonan syndrome. GeneReviews. (12thedn) 2016; University of Washington, Seattle.

17. Boon L, Vikkula M. Multiple cutaneous and mucosal venous malformations. GeneReviews. (4thedn) 2008; University of Washington, Seattle.

18. McDonald J, Pyeritz RE (2000) Hereditary hemorrhagic telangiectasia. GeneReviews. (11thedn), University of Washington, Seattle.

19. Morrison L, Akers A. Cerebral cavernous malformation, familial. GeneReviews. (8thedn) 2003; University of Washington, Seattle.

20. Loeys BL. Loeys-Dietz syndrome. GeneReviews. (4thedn) 2001; University of Washington, Seattle.

21. Dietz HC. Marfan Syndrome. GeneReviews. (8thedn) 2001; University of Washington, Seattle.

22. Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, et al. GeneReviews. University of Washington, Seattle.

23. Brett GR, Wilkins EJ, Creed ET, West K, Jarmolowicz A, Valente GM, Prawer Y, Lynch E, Macciocca I. Genetic counseling in the era of genomics: what’s all the fuss about? J Genet Couns 2018; (Epub ahead of print).

24. Skirton H, Eiser C. Discovering and addressing the client’s lay construct of genetic disease: an important aspect of genetic healthcare? Res Theory Nurs Pract An Int J 2003; 17:339–52.

25. Rew L, Mackert M, Bonevac D. Cool, but is it credible? Adolescents’ and parents’ approaches to genetic testing. West J Nurs Res 2010; 32:610–627.

26. Rose AL, Peters N, Shea JA, Armstrong K. Attitudes and misconceptions about predictive genetic testing for cancer risk. A focus group study. Community Genet 2005; 8:145–51.

27. Frazier L, Calvin AO, Mudd GT, Cohen MZ (2006) Understanding of genetics among older adults. J Nurs Scholarsh 38:126–132.

28. Houfek JF, Soltis-Vaughan BS, Atwood JR, Reiser GM, Schaefer GB. Adults’ perceptions of genetic counseling and genetic testing. Appl Nurs Res 2015; 28: 25–30.

30. Burke W, Pinsky LE, Press NA. Categorizing genetic tests to identify their ethical, legal, and social implications. Am J Med Genet 2001; 106(3):233-240.

31. Blue GM, Kirk EP, Giannoulatou E, Dunwoodie SL, Ho JW, Hilton DC, White SM, Sholler GF, Harvey RP, Winlaw DS. Targeted next-generation sequencing identifies pathogenic variants in familial congenital heart disease. J Am Coll Cardiol 2014; 64(23): 2498–06.

32. Mattassi R, Manara E, Colombo PG, Manara S, Porcella A, Bruno G, Bruson A, Bertelli M. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg 2018; 67(3):922-932.e11.

33. Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, Gaynor JW, Deanfield J, Giardini A, Porter GA Jr, Srivastava D, Lo CW, Shen Y, Watkins WS, Yandell M, Yost HJ, Tristani-Firouzi M, Newburger JW, Roberts AE, Kim R, Zhao H, Kaltman JR, Goldmuntz E, Chung WK, Seidman JG, Gelb BD, Seidman CE, Lifton RP, Brueckner M. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 2017; 49(11):1593–1601.

34. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, Chung W, Dubois J, Lacour JP, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks D, Dupont J, González-Enseñat MA, Frieden I, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quere I, Salhi A, Turner A, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation–arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation 2017; 136(11):1037-1048.

35. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363(9412): 852-9.

36. Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, Ganguly A, Castells A, Ploos van Amstel JK, Westermann CJ, Pyeritz RE, Marchuk DA. SMAD4 mutations found in unselected HHT patients. J Med Genet 2006; 43(10): 793–797.

37. Akhurst RJ. Taking thalidomide out of rehab. Nat Med 2010; 16: 370–372.

38. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Bréant C, Mathivet T, Larrivée B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16(4):420–428.

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