SpringerLink
Log in

Human Genetics of Semilunar Valve and Aortic Arch Anomalies

  • Chapter
  • First Online:
Congenital Heart Diseases: The Broken Heart

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1441))

  • 389 Accesses

Abstract

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt–Oram syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (Germany)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 234.33
Price includes VAT (Germany)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
EUR 299.59
Price includes VAT (Germany)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Armstrong EJ, Bischoff J. Heart valve development: endothelial cell signaling and differentiation. Circ Res. 2004;95(5):459–70. https://doi.org/10.1161/01.RES.0000141146.95728.da.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006;21(3):180–4. https://doi.org/10.1097/01.hco.0000221578.18254.70.

    Article  PubMed  Google Scholar 

  3. Bella JN, Tang W, Kraja A, Rao DC, Hunt SC, Miller MB, et al. Genome-wide linkage map** for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study. Hypertension. 2007;49(3):453–60. https://doi.org/10.1161/01.HYP.0000256957.10242.75.

    Article  CAS  PubMed  Google Scholar 

  4. Probst V, Le Scouarnec S, Legendre A, Jousseaume V, Jaafar P, Nguyen JM, et al. Familial aggregation of calcific aortic valve stenosis in the western part of France. Circulation. 2006;113(6):856–60. https://doi.org/10.1161/CIRCULATIONAHA.105.569467.

    Article  PubMed  Google Scholar 

  5. Chen HY, Small AM, Dina C, Cairns BJ, Whitmer RA, Lathrop M, et al. Genome-wide association meta-analysis in 652,134 participants identifies 9 novel susceptibility loci for aortic stenosis. Eur Heart J. 2020;41(Supplement_2):ehaa946-1862. https://doi.org/10.1093/ehjci/ehaa946.1862.

    Article  Google Scholar 

  6. Perrot N, Thériault S, Dina C, Chen HY, Boekholdt SM, Rigade S, et al. Genetic variation in LPA, calcific aortic valve stenosis in patients undergoing cardiac surgery, and familial risk of aortic valve microcalcification. JAMA Cardiol. 2019;4(7):620–7. https://doi.org/10.1001/jamacardio.2019.1581.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Viney NJ, van Capelleveen JC, Geary RS, **a S, Tami JA, Yu RZ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388(10057):2239–53. https://doi.org/10.1016/S0140-6736(16)31009-1.

    Article  CAS  PubMed  Google Scholar 

  8. Otto CM. Calcification of bicuspid aortic valves. Heart. 2002;88(4):321–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270–4. https://doi.org/10.1038/nature03940.

    Article  CAS  PubMed  Google Scholar 

  10. Niessen K, Karsan A. Notch signaling in cardiac development. Circ Res. 2008;102(10):1169–81. https://doi.org/10.1161/CIRCRESAHA.108.174318.

    Article  CAS  PubMed  Google Scholar 

  11. Wang Y, Fang Y, Lu P, Wu B, Zhou B. NOTCH signaling in aortic valve development and calcific aortic valve disease. Front Cardiovasc Med. 2021;8:682298. https://doi.org/10.3389/fcvm.2021.682298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mohamed SA, Aherrahrou Z, Liptau H, Erasmi AW, Hagemann C, Wrobel S, et al. Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun. 2006;345(4):1460–5. https://doi.org/10.1016/j.bbrc.2006.05.046.

    Article  CAS  PubMed  Google Scholar 

  13. Kerstjens-Frederikse WS, van de Laar IM, Vos YJ, Verhagen JM, Berger RM, Lichtenbelt KD, et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016;18(9):914–23. https://doi.org/10.1038/gim.2015.193.

    Article  CAS  PubMed  Google Scholar 

  14. Ducharme V, Guauque-Olarte S, Gaudreault N, Pibarot P, Mathieu P, Bosse Y. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis. 2013;22(2):142–9.

    PubMed  Google Scholar 

  15. Helle E, Cordova-Palomera A, Ojala T, Saha P, Potiny P, Gustafsson S, et al. Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts. Genet Epidemiol. 2019;43(2):215–26. https://doi.org/10.1002/gepi.22176.

    Article  PubMed  Google Scholar 

  16. Merla G, Brunetti-Pierri N, Piccolo P, Micale L, Loviglio MN. Supravalvular aortic stenosis: elastin arteriopathy. Circ Cardiovasc Genet. 2012;5(6):692–6. https://doi.org/10.1161/CIRCGENETICS.112.962860.

    Article  CAS  PubMed  Google Scholar 

  17. Pober BR, Johnson M, Urban Z. Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. J Clin Invest. 2008;118(5):1606–15. https://doi.org/10.1172/JCI35309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Urban Z, Zhang J, Davis EC, Maeda GK, Kumar A, Stalker H, et al. Supravalvular aortic stenosis: genetic and molecular dissection of a complex mutation in the elastin gene. Hum Genet. 2001;109(5):512–20. https://doi.org/10.1007/s00439-001-0608-z.

    Article  CAS  PubMed  Google Scholar 

  19. Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Incidence and natural history. Circulation. 1971;43(3):323–32.

    Article  CAS  PubMed  Google Scholar 

  20. Rosenthal E. Coarctation of the aorta from fetus to adult: curable condition or life long disease process? Heart. 2005;91(11):1495–502. https://doi.org/10.1136/hrt.2004.057182.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Braverman AC, Guven H, Beardslee MA, Makan M, Kates AM, Moon MR. The bicuspid aortic valve. Curr Probl Cardiol. 2005;30(9):470–522. https://doi.org/10.1016/j.cpcardiol.2005.06.002.

    Article  PubMed  Google Scholar 

  22. Prapa M, Ho SY. Risk stratification in bicuspid aortic valve disease: still more work to do. Eur J Cardiothorac Surg. 2012;41(2):327–8. https://doi.org/10.1016/j.ejcts.2011.06.023.

    Article  PubMed  Google Scholar 

  23. Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, et al. Major vascular anomalies in turner syndrome. Circulation. 2004;110(12):1694–700. https://doi.org/10.1161/01.CIR.0000142290.35842.B0.

    Article  PubMed  Google Scholar 

  24. Bondy C, Bakalov VK, Cheng C, Olivieri L, Rosing DR, Arai AE. Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome. J Med Genet. 2013;50(10):662–5. https://doi.org/10.1136/jmedgenet-2013-101720.

    Article  PubMed  Google Scholar 

  25. Loffredo CA, Chokkalingam A, Sill AM, Boughman JA, Clark EB, Scheel J, et al. Prevalence of congenital cardiovascular malformations among relatives of infants with hypoplastic left heart, coarctation of the aorta, and d-transposition of the great arteries. Am J Med Genet A. 2004;124A(3):225–30. https://doi.org/10.1002/ajmg.a.20366.

    Article  PubMed  Google Scholar 

  26. Loscalzo ML, Goh DL, Loeys B, Kent KC, Spevak PJ, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A. 2007;143A(17):1960–7. https://doi.org/10.1002/ajmg.a.31872.

    Article  CAS  PubMed  Google Scholar 

  27. Kappetein AP, Gittenberger-de Groot AC, Zwinderman AH, Rohmer J, Poelmann RE, Huysmans HA. The neural crest as a possible pathogenetic factor in coarctation of the aorta and bicuspid aortic valve. J Thorac Cardiovasc Surg. 1991;102(6):830–6.

    Article  CAS  PubMed  Google Scholar 

  28. Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40(12):2197–220. https://doi.org/10.1002/humu.23879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McElhinney DB, Krantz ID, Bason L, Piccoli DA, Emerick KM, Spinner NB, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation. 2002;106(20):2567–74.

    Article  PubMed  Google Scholar 

  30. Raas-Rothschild A, Shteyer E, Lerer I, Nir A, Granot E, Rein AJ. Jagged1 gene mutation for abdominal coarctation of the aorta in Alagille syndrome. Am J Med Genet. 2002;112(1):75–8. https://doi.org/10.1002/ajmg.10652.

    Article  PubMed  Google Scholar 

  31. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;109(11):1354–8. https://doi.org/10.1161/01.CIR.0000121361.01862.A4.

    Article  PubMed  Google Scholar 

  32. Zimrin AB, Pepper MS, McMahon GA, Nguyen F, Montesano R, Maciag T. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem. 1996;271(51):32499–502.

    Article  CAS  PubMed  Google Scholar 

  33. Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 1999;8(5):723–30.

    Article  CAS  PubMed  Google Scholar 

  34. Hallidie-Smith KA, Karas S. Cardiac anomalies in Williams-Beuren syndrome. Arch Dis Child. 1988;63(7):809–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sharma BK, Fujiwara H, Hallman GL, Ott DA, Reul GJ, Cooley DA. Supravalvar aortic stenosis: a 29-year review of surgical experience. Ann Thorac Surg. 1991;51(6):1031–9. https://doi.org/10.1016/0003-4975(91)91045-w.

    Article  CAS  PubMed  Google Scholar 

  36. McElhinney DB, Petrossian E, Tworetzky W, Silverman NH, Hanley FL. Issues and outcomes in the management of supravalvar aortic stenosis. Ann Thorac Surg. 2000;69(2):562–7. https://doi.org/10.1016/s0003-4975(99)01293-x.

    Article  CAS  PubMed  Google Scholar 

  37. Sugayama SM, Moises RL, Wagenfur J, Ikari NM, Abe KT, Leone C, et al. Williams-Beuren syndrome: cardiovascular abnormalities in 20 patients diagnosed with fluorescence in situ hybridization. Arq Bras Cardiol. 2003;81(5):462–73.

    Article  PubMed  Google Scholar 

  38. Bogershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M, et al. Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked Kabuki syndrome subtype 2. Hum Mutat. 2016;37(9):847–64. https://doi.org/10.1002/humu.23026.

    Article  CAS  PubMed  Google Scholar 

  39. Digilio MC, Gnazzo M, Lepri F, Dentici ML, Pisaneschi E, Baban A, et al. Congenital heart defects in molecularly proven Kabuki syndrome patients. Am J Med Genet A. 2017;173(11):2912–22. https://doi.org/10.1002/ajmg.a.38417.

    Article  CAS  PubMed  Google Scholar 

  40. Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, et al. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2007;27(5):1889–903. https://doi.org/10.1128/MCB.01506-06.

    Article  CAS  PubMed  Google Scholar 

  41. Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR, et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development. 2006;133(8):1423–32. https://doi.org/10.1242/dev.02302.

    Article  CAS  PubMed  Google Scholar 

  42. Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott DA, et al. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res. 2000;87(10):888–95.

    Article  CAS  PubMed  Google Scholar 

  43. Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998;281(5373):108–11.

    Article  CAS  PubMed  Google Scholar 

  44. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999;104(11):1567–73. https://doi.org/10.1172/JCI8154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol. 2003;42(9):1650–5.

    Article  CAS  PubMed  Google Scholar 

  46. Majumdar R, Yagubyan M, Sarkar G, Bolander ME, Sundt TM 3rd. Bicuspid aortic valve and ascending aortic aneurysm are not associated with germline or somatic homeobox NKX2-5 gene polymorphism in 19 patients. J Thorac Cardiovasc Surg. 2006;131(6):1301–5. https://doi.org/10.1016/j.jtcvs.2006.01.039.

    Article  CAS  PubMed  Google Scholar 

  47. Qu XK, Qiu XB, Yuan F, Wang J, Zhao CM, Liu XY, et al. A novel NKX2.5 loss-of-function mutation associated with congenital bicuspid aortic valve. Am J Cardiol. 2014;114(12):1891–5. https://doi.org/10.1016/j.amjcard.2014.09.028.

    Article  CAS  PubMed  Google Scholar 

  48. Proost D, Vandeweyer G, Meester JA, Salemink S, Kempers M, Ingram C, et al. Performant mutation identification using targeted next-generation sequencing of 14 thoracic aortic aneurysm genes. Hum Mutat. 2015;36(8):808–14. https://doi.org/10.1002/humu.22802.

    Article  CAS  PubMed  Google Scholar 

  49. McKellar SH, Tester DJ, Yagubyan M, Majumdar R, Ackerman MJ, Sundt TM 3rd. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2007;134(2):290–6. https://doi.org/10.1016/j.jtcvs.2007.02.041.

    Article  CAS  PubMed  Google Scholar 

  50. Laforest B, Andelfinger G, Nemer M. Loss of Gata5 in mice leads to bicuspid aortic valve. J Clin Invest. 2011;121(7):2876–87. https://doi.org/10.1172/JCI44555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bonachea EM, Chang SW, Zender G, LaHaye S, Fitzgerald-Butt S, McBride KL, et al. Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve. Pediatr Res. 2014;76(2):211–6. https://doi.org/10.1038/pr.2014.67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gaussin V, Van de Putte T, Mishina Y, Hanks MC, Zwijsen A, Huylebroeck D, et al. Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci U S A. 2002;99(5):2878–83. https://doi.org/10.1073/pnas.042390499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim RY, Robertson EJ, Solloway MJ. Bmp6 and Bmp7 are required for cushion formation and septation in the develo** mouse heart. Dev Biol. 2001;235(2):449–66. https://doi.org/10.1006/dbio.2001.0284.

    Article  CAS  PubMed  Google Scholar 

  54. Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, et al. A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet. 2000;24(2):171–4. https://doi.org/10.1038/72835.

    Article  CAS  PubMed  Google Scholar 

  55. Tan HL, Glen E, Topf A, Hall D, O’Sullivan JJ, Sneddon L, et al. Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Hum Mutat. 2012;33(4):720–7. https://doi.org/10.1002/humu.22030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Giusti B, Sticchi E, De Cario R, Magi A, Nistri S, Pepe G. Genetic bases of bicuspid aortic valve: the contribution of traditional and high-throughput sequencing approaches on research and diagnosis. Front Physiol. 2017;8:612. https://doi.org/10.3389/fphys.2017.00612.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44(8):922–7. https://doi.org/10.1038/ng.2349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pepe G, Nistri S, Giusti B, Sticchi E, Attanasio M, Porciani C, et al. Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome. BMC Med Genet. 2014;15:23. https://doi.org/10.1186/1471-2350-15-23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Freeze SL, Landis BJ, Ware SM, Helm BM. Bicuspid aortic valve: a review with recommendations for genetic counseling. J Genet Couns. 2016;25(6):1171–8. https://doi.org/10.1007/s10897-016-0002-6.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Powell CB, Stone FM, Atkins DL, Watson DG, Moller JH. Operative mortality and frequency of coexistent anomalies in interruption of the aortic arch. Am J Cardiol. 1997;79(8):1147–8.

    Article  CAS  PubMed  Google Scholar 

  61. Gruber PJ, Epstein JA. Development gone awry: congenital heart disease. Circ Res. 2004;94(3):273–83. https://doi.org/10.1161/01.RES.0000116144.43797.3B.

    Article  CAS  PubMed  Google Scholar 

  62. Corsten-Janssen N, Kerstjens-Frederikse WS, du Marchie Sarvaas GJ, Baardman ME, Bakker MK, Bergman JE, et al. The cardiac phenotype in patients with a CHD7 mutation. Circ Cardiovasc Genet. 2013;6(3):248–54. https://doi.org/10.1161/CIRCGENETICS.113.000054.

    Article  CAS  PubMed  Google Scholar 

  63. Goldmuntz E, Clark BJ, Mitchell LE, Jawad AF, Cuneo BF, Reed L, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998;32(2):492–8.

    Article  CAS  PubMed  Google Scholar 

  64. Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34(10):798–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marino B, Digilio MC, Toscano A, Anaclerio S, Giannotti A, Feltri C, et al. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med. 2001;3(1):45–8. https://doi.org/10.1097/00125817-200101000-00010.

    Article  CAS  PubMed  Google Scholar 

  66. Gao S, Li X, Amendt BA. Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome. Curr Allergy Asthma Rep. 2013;13(6):613–21. https://doi.org/10.1007/s11882-013-0384-6.

    Article  CAS  PubMed  Google Scholar 

  67. Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell. 2001;104(4):619–29.

    Article  CAS  PubMed  Google Scholar 

  68. Marino B, Digilio MC, Persiani M, Di Donato R, Toscano A, Giannotti A, et al. Deletion 22q11 in patients with interrupted aortic arch. Am J Cardiol. 1999;84(3):360–1. A9

    Article  CAS  PubMed  Google Scholar 

  69. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. 1999;135(6):703–6.

    Article  CAS  PubMed  Google Scholar 

  70. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333–42. https://doi.org/10.1016/S0140-6736(12)61023-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70(6):1555–63. https://doi.org/10.1086/340847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8. https://doi.org/10.1038/ng772.

    Article  CAS  PubMed  Google Scholar 

  73. Croonen EA, Nillesen W, Schrander C, Jongmans M, Scheffer H, Noordam C, et al. Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients. Mol Syndromol. 2013;4(5):227–34. https://doi.org/10.1159/000350686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, et al. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome. Am J Med Genet A. 2011;155A(3):486–507. https://doi.org/10.1002/ajmg.a.33857.

    Article  PubMed  Google Scholar 

  75. Ben-Shachar S, Constantini S, Hallevi H, Sach EK, Upadhyaya M, Evans GD, et al. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet. 2013;21(5):535–9. https://doi.org/10.1038/ejhg.2012.221.

    Article  CAS  PubMed  Google Scholar 

  76. Calcagni G, Limongelli G, D'Ambrosio A, Gesualdo F, Digilio MC, Baban A, et al. Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. Int J Cardiol. 2017;245:92–8. https://doi.org/10.1016/j.ijcard.2017.07.068.

    Article  PubMed  Google Scholar 

  77. Patel C, Silcock L, McMullan D, Brueton L, Cox H. TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype. Eur J Hum Genet. 2012;20(8):863–9. https://doi.org/10.1038/ejhg.2012.16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. **ang R, Fan LL, Huang H, Cao BB, Li XP, Peng DQ, et al. A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis. Gene. 2013;534:320. https://doi.org/10.1016/j.gene.2013.10.028.

    Article  CAS  Google Scholar 

  79. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424(6947):443–7. https://doi.org/10.1038/nature01827.

    Article  CAS  PubMed  Google Scholar 

  80. Okubo A, Miyoshi O, Baba K, Takagi M, Tsukamoto K, Kinoshita A, et al. A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family. J Med Genet. 2004;41(7):e97. 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, St George’s University Hospitals NHS Foundation Trust, London, UK

    Matina Prapa

  2. Cardiac Morphology, Royal Brompton & Harefield Hospitals, London, UK

    Siew Yen Ho

Authors
  1. Matina Prapa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siew Yen Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matina Prapa .

Editor information

Editors and Affiliations

  1. Cardiovascular Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Silke Rickert-Sperling

  2. Developmental Biology, Institut de Biologie du Dévelopment de Marseille, Aix Marseille Université, Marseille, France

    Robert G. Kelly

  3. LMU Ludwig Maximilian University, Klinikum der Universität München, München, Bayern, Germany

    Nikolaus Haas

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Prapa, M., Ho, S.Y. (2024). Human Genetics of Semilunar Valve and Aortic Arch Anomalies. In: Rickert-Sperling, S., Kelly, R.G., Haas, N. (eds) Congenital Heart Diseases: The Broken Heart. Advances in Experimental Medicine and Biology, vol 1441. Springer, Cham. https://doi.org/10.1007/978-3-031-44087-8_45

Download citation

Publish with us

Policies and ethics

Search

Navigation