Genetics of Marfan Syndrome and Loeys-Dietz Syndrome

  • Aline Verstraeten
  • Bart LoeysEmail author


Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are two clinically related aortic aneurysm conditions. LDS shows significant clinical overlap with MFS as regards its vascular and skeletal features, including aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity. In this chapter, we will review the current knowledge of the genetic basis of both disorders.


Aorta Marfan syndrome Loeys-Dietz syndrome Ghent nosology Mutations Molecular 


  1. 1.
    Marfan A. Un cas de déformation congénitale des quatres membres, plus prononcée aux extremités, caractérisée par l’allongement des os avec un certain degré d’amincissement. Bulletins et memoires de la Société medicale des Hôpitaux de Paris. 1896;13:220–8.Google Scholar
  2. 2.
    Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81.CrossRefGoogle Scholar
  3. 3.
    Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–85.CrossRefGoogle Scholar
  4. 4.
    Dietz HC. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337–9.CrossRefGoogle Scholar
  5. 5.
    Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007;81:229–40.CrossRefGoogle Scholar
  6. 6.
    Martinez-Quintana E, Caballero-Sanchez N, Rodriguez-Gonzalez F, Garay-Sanchez P, Tugores A. Novel Marfan syndrome-associated mutation in the FBN1 gene caused by parental mosaicism and leading to abnormal limb patterning. Mol Syndromol. 2017;8:148–54.CrossRefGoogle Scholar
  7. 7.
    Sipek A Jr, Grodecka L, Baxova A, Cibulkova P, Dvorakova M, Mazurova S, et al. Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome. Am J Med Genet A. 2014;164A:1559–64.CrossRefGoogle Scholar
  8. 8.
    Tekin M, Cengiz FB, Ayberkin E, Kendirli T, Fitoz S, Tutar E, et al. Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. Am J Med Genet A. 2007;143A:875–80.CrossRefGoogle Scholar
  9. 9.
    Collod-Beroud G, Lackmy-Port-Lys M, Jondeau G, Mathieu M, Maingourd Y, Coulon M, et al. Demonstration of the recurrence of Marfan-like skeletal and cardiovascular manifestations due to germline mosaicism for an FBN1 mutation. Am J Hum Genet. 1999;65:917–21.CrossRefGoogle Scholar
  10. 10.
    Rantamaki T, Kaitila I, Syvanen AC, Lukka M, Peltonen L. Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation. Am J Hum Genet. 1999;64:993–1001.CrossRefGoogle Scholar
  11. 11.
    Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, et al. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Eur J Hum Genet. 2001;9:13–21.CrossRefGoogle Scholar
  12. 12.
    Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet. 1999;65:1007–20.CrossRefGoogle Scholar
  13. 13.
    Baudhuin LM, Kotzer KE, Lagerstedt SA. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med. 2015;17:177–87.CrossRefGoogle Scholar
  14. 14.
    Hutchinson S, Furger A, Halliday D, Judge DP, Jefferson A, Dietz HC, et al. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum Mol Genet. 2003;12:2269–76.CrossRefGoogle Scholar
  15. 15.
    Aubart M, Gross MS, Hanna N, Zabot MT, Sznajder M, Detaint D, et al. The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele. Hum Mol Genet. 2015;24:2764–70.CrossRefGoogle Scholar
  16. 16.
    Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, et al. Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics. 1993;17:468–75.CrossRefGoogle Scholar
  17. 17.
    Tsipouras P, Del Mastro R, Sarfarazi M, Lee B, Vitale E, Child AH, et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The international Marfan syndrome collaborative study. N Engl J Med. 1992;326:905–9.CrossRefGoogle Scholar
  18. 18.
    Ades LC, Sreetharan D, Onikul E, Stockton V, Watson KC, Holman KJ. Segregation of a novel FBN1 gene mutation, G1796E, with kyphoscoliosis and radiographic evidence of vertebral dysplasia in three generations. Am J Med Genet. 2002;109:261–70.CrossRefGoogle Scholar
  19. 19.
    Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996;94:2708–11.CrossRefGoogle Scholar
  20. 20.
    Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010;2:23ra20.CrossRefGoogle Scholar
  21. 21.
    Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, et al. Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011;89:7–14.CrossRefGoogle Scholar
  22. 22.
    Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, et al. Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012;44:1249–54.CrossRefGoogle Scholar
  23. 23.
    Carmignac V, Thevenon J, Ades L, Callewaert B, Julia S, Thauvin-Robinet C, et al. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012;91:950–7.CrossRefGoogle Scholar
  24. 24.
    Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407–11.CrossRefGoogle Scholar
  25. 25.
    Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117–21.CrossRefGoogle Scholar
  26. 26.
    Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, et al. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med. 2014;371:2061–71.CrossRefGoogle Scholar
  27. 27.
    Micha D, Guo DC, Hilhorst-Hofstee Y, van Kooten F, Atmaja D, Overwater E, et al. SMAD2 mutations are associated with arterial aneurysms and dissections. Hum Mutat. 2015;36:1145–9.CrossRefGoogle Scholar
  28. 28.
    van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6.CrossRefGoogle Scholar
  29. 29.
    Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, et al. Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol. 2015;65:1324–36.CrossRefGoogle Scholar
  30. 30.
    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;44:922–7.CrossRefGoogle Scholar
  31. 31.
    Maccarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576–87.CrossRefGoogle Scholar
  32. 32.
    Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44:916–21.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Medical GeneticsAntwerp University Hospital and University of AntwerpAntwerpBelgium

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