Background The fibrillin gene encodes a protein in the extracellularmatrix, and this protein is widely distributed in elastic tissues.The fibrillin gene is the site of mutations causing Marfan'ssyndrome. This disorder shows a high degree of clinical variabilityboth between and within families. Each family appears to havea unique mutation in the fibrillin gene, which precludes theroutine use of mutation screening for presymptomatic diagnosisof the disorder. The goal of this study was to develop a widelyapplicable method of molecular diagnosis.
Methods We used three newly characterized intragenic sites ofnormal DNA repeat-sequence variation (i.e., polymorphisms) asmarkers to follow the inheritance pattern of specific copies(alleles) of the fibrillin gene in multiple kindreds with variousclinical features of Marfan's syndrome.
Results The polymorphic markers allowed identification of theparticular copy of the fibrillin gene that cosegregated withMarfan's syndrome in 13 of the 14 families tested. In 11 familiesa definite presymptomatic diagnosis of Marfan's syndrome couldbe made in family members who had only equivocal manifestationsof the disorder. In two other families, some family membersdemonstrated either classic Marfan's syndrome or a milder butclosely related phenotype. The copy of the fibrillin gene thatcosegregated with classic Marfan's syndrome was not inheritedby family members with the latter, atypical, form of the disease.These milder phenotypes, previously diagnosed as Marfan's syndrome,were not associated with aortic involvement.
Conclusions These results document the usefulness of novel polymorphicDNA repeat sequences in the presymptomatic diagnosis of Marfan'ssyndrome. Our findings also demonstrate that the various clinicalphenotypes seen in selected families may be due not to singlefibrillin mutations, but rather to different genetic alterations.These findings underscore the need for a modification of thecurrent diagnostic criteria for Marfan's syndrome in order toachieve accurate risk assessment.
Source Information
From the Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York (L.P., O.L., F.R.); the Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, United Kingdom (J.R.L., B.S.); the Department of Human Genetics, Allegheny-Singer Research Institute, Pittsburgh (R.E.P.); and the Division of Pediatric Cardiology and the Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore (H.C.D.).
Address reprint requests to Dr. Dietz at the Division of Pediatric Cardiology, Ross 1170, Johns Hopkins Hospital, 720 Rutland Ave., Baltimore, MD 21205.
Faivre, L, Collod-Beroud, G, Child, A, Callewaert, B, Loeys, B L, Binquet, C, Gautier, E, Arbustini, E, Mayer, K, Arslan-Kirchner, M, Stheneur, C, Kiotsekoglou, A, Comeglio, P, Marziliano, N, Halliday, D, Beroud, C, Bonithon-Kopp, C, Claustres, M, Plauchu, H, Robinson, P N, Ades, L, De Backer, J, Coucke, P, Francke, U, De Paepe, A, Boileau, C, Jondeau, G
(2008). Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands. J. Med. Genet.
45: 384-390
[Abstract][Full Text]
Robinson, P N, Arteaga-Solis, E, Baldock, C, Collod-Beroud, G, Booms, P, De Paepe, A, Dietz, H C, Guo, G, Handford, P A, Judge, D P, Kielty, C M, Loeys, B, Milewicz, D M, Ney, A, Ramirez, F, Reinhardt, D P, Tiedemann, K, Whiteman, P, Godfrey, M
(2006). The molecular genetics of Marfan syndrome and related disorders. J. Med. Genet.
43: 769-787
[Abstract][Full Text]
Cardy, C. M., Maskell, N. A., Handford, P. A., Arnold, A. G., Davies, R. J. O., Morrison, P. J., Thornley, P. E.
(2004). Familial Spontaneous Pneumothorax and FBN1 Mutations. Am. J. Respir. Crit. Care Med.
169: 1260-1262
[Full Text]
Nienaber, C. A., Eagle, K. A.
(2003). Aortic Dissection: New Frontiers in Diagnosis and Management: Part II: Therapeutic Management and Follow-Up. Circulation
108: 772-778
[Full Text]
Kakko, S., Raisanen, T., Tamminen, M., Airaksinen, J., Groundstroem, K., Juvonen, T., Ylitalo, A., Uusimaa, P., Savolainen, M. J.
(2003). Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5q13-14 in Finnish families. J. Thorac. Cardiovasc. Surg.
126: 106-113
[Abstract][Full Text]
Behan, W M H, Longman, C, Petty, R K H, Comeglio, P, Child, A H, Boxer, M, Foskett, P, Harriman, D G F
(2003). Muscle fibrillin deficiency in Marfan's syndrome myopathy. J. Neurol. Neurosurg. Psychiatry
74: 633-638
[Abstract][Full Text]
Halliday, D J, Hutchinson, S, Lonie, L, Hurst, J A, Firth, H, Handford, P A, Wordsworth, P
(2002). Twelve novel FBN1 mutations in Marfan syndrome and Marfan related phenotypes test the feasibility of FBN1 mutation testing in clinical practice. J. Med. Genet.
39: 589-593
[Full Text]
Wityk, R. J., Zanferrari, C., Oppenheimer, S.
(2002). Neurovascular Complications of Marfan Syndrome: A Retrospective, Hospital-Based Study. Stroke
33: 680-684
[Abstract][Full Text]
Loeys, B., Nuytinck, L., Delvaux, I., De Bie, S., De Paepe, A.
(2001). 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
161: 2447-2454
[Abstract][Full Text]
Erbel, R., Alfonso, F., Boileau, C., Dirsch, O., Eber, B., Haverich, A., Rakowski, H., Struyven, J., Radegran, K., Sechtem, U., Taylor, J., Zollikofer, Ch., Klein, W.W., Mulder, B., Providencia, L.A.
(2001). Diagnosis and management of aortic dissection: Task Force on Aortic Dissection, European Society of Cardiology. Eur Heart J
22: 1642-1681
Guo, D., Hasham, S., Kuang, S.-Q., Vaughan, C. J., Boerwinkle, E., Chen, H., Abuelo, D., Dietz, H. C., Basson, C. T., Shete, S. S., Milewicz, D. M.
(2001). Familial Thoracic Aortic Aneurysms and Dissections : Genetic Heterogeneity With a Major Locus Mapping to 5q13-14. Circulation
103: 2461-2468
[Abstract][Full Text]
Vaughan, C. J., Casey, M., He, J., Veugelers, M., Henderson, K., Guo, D., Campagna, R., Roman, M. J., Milewicz, D. M., Devereux, R. B., Basson, C. T.
(2001). Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder. Circulation
103: 2469-2475
[Abstract][Full Text]
Gott, V. L., Greene, P. S., Alejo, D. E., Cameron, D. E., Naftel, D. C., Miller, D. C., Gillinov, A. M., Laschinger, J. C., Pyeritz, R. E.
(1999). Replacement of the Aortic Root in Patients with Marfan's Syndrome. NEJM
340: 1307-1313
[Abstract][Full Text]
Maron, B. J., Moller, J. H., Seidman, C. E., Vincent, G. M., Dietz, H. C., Moss, A. J., Towbin, J. A., Sondheimer, H. M., Pyeritz, R. E., McGee, G., Epstein, A. E.
(1998). Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome : A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association. Circulation
98: 1460-1471
[Full Text]
Westaby, S., Katsumata, T., Freitas, E.
(1997). Aortic Valve Conservation in Acute Type A Dissection. Ann. Thorac. Surg.
64: 1108-1112
[Abstract][Full Text]
Powell, J T, Turner, R J, Henney, A M, Miller, G J, Humphries, S E
(1997). An association between arterial pulse pressure and variation in the fibrillin-1 gene. Heart
78: 396-398
[Abstract][Full Text]
Lipscomb, K. J, Clayton-Smith, J., Harris, R.
(1997). Evolving phenotype of Marfan's syndrome. Arch. Dis. Child.
76: 41-46
[Abstract][Full Text]
Milewicz, D. M.
(1995). Ultrasonic Characterization of the Aortic Architecture in Marfan Patients. Circulation
91: 1272-1274
[Full Text]
Sutherland, G. R., Richards, R. I.
(1994). DNA Repeats -- A Treasury of Human Variation. NEJM
331: 191-193
[Full Text]
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