Abstract
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.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
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.
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.
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.
Dietz HC. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337–9.
Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007;81:229–40.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer-Verlag GmbH Austria, part of Springer Nature
About this chapter
Cite this chapter
Verstraeten, A., Loeys, B. (2019). Genetics of Marfan Syndrome and Loeys-Dietz Syndrome. In: Stanger, O., Pepper, J., Svensson, L. (eds) Surgical Management of Aortic Pathology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-4874-7_38
Download citation
DOI: https://doi.org/10.1007/978-3-7091-4874-7_38
Published:
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-4872-3
Online ISBN: 978-3-7091-4874-7
eBook Packages: MedicineMedicine (R0)