Marfan Syndrome

C. Baumgartner; G. Mátyás; B. Steinmann; D. Baumgartner

doi:10.1055/s-0038-1633999

Methods of Information in Medicine, Table of Contents

Methods Inf Med 2005; 44(04): 487-497
DOI: 10.1055/s-0038-1633999

Original Article

Schattauer GmbH

Marfan Syndrome

A Diagnostic Challenge Caused by Phenotypic and Genetic Heterogeneity

C. Baumgartner

¹Research Group for Biomedical Data Mining, University for Health Sciences, Medical Informatics and Technology, Hall i. T., Austria

,

G. Mátyás

²Division of Metabolism and Molecular Pediatrics, University Children´s Hospital, Zurich, Switzerland

³Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland

,

B. Steinmann

²Division of Metabolism and Molecular Pediatrics, University Children´s Hospital, Zurich, Switzerland

,

D. Baumgartner

⁴Clinical Division of Pediatric Cardiology, Innsbruck Medical University, Innsbruck, Austria

› Author Affiliations

Abstract

Summary

Objectives: Marfan syndrome (MFS) is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene with variable clinical manifestations in the cardiovascular, musculoskeletal and ocular systems.

Methods: Data of molecular genetic analysis and a catalogue of clinical manifestations including aortic elastic parameters were mined in order to (i) assess aortic abnormality before and during medical treatment, and to (ii) identify novel correlations between the genotype and phenotype of the disease using hierarchical cluster analysis and logistic regression analysis. A score measure describing the similarity between a patient’s clinical symptoms and a characteristic phenotype class was introduced.

Results: A probabilistic model for monitoring the loss of aortic elasticity was built on merely aortic parameters of 34 patients with classic MFS and 43 control subjects showing a sensitivity of 82% and a specificity of 96%. The clinical phenotypes of 100 individuals with classical or suspected MFS were clustered yielding four different phenotypic expressions. The highest correlation was found between FBN1 missense mutations, which manifested as ectopia lentis, skeletal major and skin minor criteria, and two out of four clustered phenotypes. The probability of the presence of a missense mutation in both phenotype classes is approximately 70%.

Conclusions: Monitoring of aortic elastic properties during medical treatment may serve as additional criterion to indicate elective surgical interventions. Genotype-phenotype correlation may contribute to anticipate the clinical consequences of specific FBN1 mutations more comprehensively and may be helpful to identify MFS patients at risk at an early stage of disease.

Keywords

Marfan syndrome - fibrillin-1 (FBN1) - aortic elasticity - phenotype-genotype correlation - data mining

Full Text

References

References
1 Pyeritz RE, Dietz HC. Marfan syndrome and other microfibrillar disorders. In Royce PM, Steinmann B. editors Connective tissue and its heritable disorders: molecular. genetic and medical aspects. 2nd ed. New York: Wiley-Liss; 2002: 585-626.
2 Nijbroek G, Sood S, McIntosh I, Francomano CA, Bull E, Pereira L, Ramirez F, Pyeritz RE, Dietz HC. Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Am J Hum Genet 1995; 5: 8-21.
3 Collod-Beroud G, Le Bourdelles S, Ades L, Ala- Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Beroud C, Boileau C. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003; 22: 199-208.
4 De Paepe A, Devereux RB, Dietz HC, Hennekam RCM, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996; 62: 417-26.
5 Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 1972; 286: 804-8.
6 Stefanadis C, Stratos C, Boudoulas H, Kourouklis C, Toutouzas P. Distensibility of the ascending aorta: comparison of invasive and non-invasive techniques in healthy men and in men with coronary artery disease. Eur Heart J 1990; 11: 990-6.
7 Hirata K, Triposkiadis F, Sparks E, Bowen J, Wooley CF, Boudoulas H. The Marfan syndrome: abnormal aortic elastic properties. J Am Coll Cardiol 1991; 18: 57-63.
8 Savolainen A, Keto P, Hekali P, Nisula L, Kaitila I, Vitasalo M, Poutanen VP, Standertskjold-Nordenstam CG, Kupari M. Aortic distensibility in children with the Marfan syndrome. Am J Cardiol 1992; 70: 691-3.
9 Baumgartner D, Baumgartner C, Matyas G, Steinmann B, Löffler J, Schermer E, Schweigmann U, Baldissera I, Frischhut B, Hess J, Hammerer I. Diagnostic power of aortic elastic properties in young patients with Marfan syndrome. J Thorac Cardiovasc Surg 2005; 129: 730-9.
10 Biggin A, Holman K, Brett M, Bennetts B, Ades L. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat 2004; 23: 99
11 Pereira L, D’Alessio M, Ramirez F, Lynch JR, Sykes B, Pangilinan T, Bonadio J. Genomic organization of the sequence coding for fibrillin. The defective gene product in Marfan syndrome. Hum Mol Genet 1993; 2: 961-8.
12 Mátyás G, De Paepe A, Halliday D, Boileau C, Pals G, Steinmann B. Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. Hum Mutat 2002; 19: 443-56.
13 Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Turkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat 2002; 20: 197-208.
14 Hosmer DW, Lemeshow S. Applied logistic regression. 2nd edition. New York: Wiley; 2000
15 Witten IH, Frank E. Data Mining – Practical machine learning tools and techniques with java implementations. San Francisco: Morgan Kaufmann; 2000
16 Kaufman L, Rousseeuw PJ. Finding groups in data: an introduction to cluster analysis. John Wiley & Sons; 1990
17 Everitt BS. Cluster Analysis. London: Edward Arnold; 1993
18 Peters KF, Kong F, Horne R, Francomano CA, Biesecker BB. Living with Marfan syndrome I. Perceptions of the condition. Clin Genet 2001; 60: 273-82.
19 Roman MJ, Rosen SE, Kramer-Fox R, Devereux RB. Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J Am Coll Cardiol 1993; 22: 1470-6.
20 Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin- 1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 2001; 161: 2447-54.
21 Lipscomb KJ, Clayton-Smith J, Harris R. Evolving phenotype of Marfan’s syndrome. Arch Dis Child 1997; 76: 41-6.
22 Groenink M, Rozendaal L, Naeff MSJ, Hennekam RCM, Hart AAM, van der Wall EE, Mulder BJ. Marfan syndrome in children and adolescents: predictive and prognostic value of aortic root growth for screening for aortic complications. Heart 1998; 80: 163-9.
23 Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, Mathews KR, Scheuner M, Hinkel GK, Brenner RE, Hovels-Gurich HH, Hagemeier C, Fuchs J, Skovby F, Rosenberg T. 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.
24 Pepe G, Giusti B, Evangelisti L, Porcini MC, Brunelli T, Giurlani L, Attanasio M, Fattori R, Bagni C, Comeglio P, Abbate R, Genuini GF. Fibrillin-1 (FBN1) gene frameshift mutations in Marfan patients: genotype-phenotype correlation. Clin Genet 2001; 59: 444-50.
25 Robinson PN, Booms P, Katzke S, Ladewig M, Neumann L, Palz M, Pregla R, Tiecke F, Rosenberg T. Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 2002; 20: 153-61.