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.
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