Original Article
A Molecular Approach to the Stratification of Cardiovascular Risk in Families with Marfan's Syndrome
N Engl J Med 1994; 331:148-153July 21, 1994
- Abstract
Background
The fibrillin gene encodes a protein in the extracellular matrix, and this protein is widely distributed in elastic tissues. The fibrillin gene is the site of mutations causing Marfan's syndrome. This disorder shows a high degree of clinical variability both between and within families. Each family appears to have a unique mutation in the fibrillin gene, which precludes the routine use of mutation screening for presymptomatic diagnosis of the disorder. The goal of this study was to develop a widely applicable method of molecular diagnosis.
Methods
We used three newly characterized intragenic sites of normal DNA repeat-sequence variation (i.e., polymorphisms) as markers to follow the inheritance pattern of specific copies (alleles) of the fibrillin gene in multiple kindreds with various clinical features of Marfan's syndrome.
Results
The polymorphic markers allowed identification of the particular copy of the fibrillin gene that cosegregated with Marfan's syndrome in 13 of the 14 families tested. In 11 families a definite presymptomatic diagnosis of Marfan's syndrome could be made in family members who had only equivocal manifestations of the disorder. In two other families, some family members demonstrated either classic Marfan's syndrome or a milder but closely related phenotype. The copy of the fibrillin gene that cosegregated with classic Marfan's syndrome was not inherited by 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 polymorphic DNA repeat sequences in the presymptomatic diagnosis of Marfan's syndrome. Our findings also demonstrate that the various clinical phenotypes seen in selected families may be due not to single fibrillin mutations, but rather to different genetic alterations. These findings underscore the need for a modification of the current diagnostic criteria for Marfan's syndrome in order to achieve accurate risk assessment.
Media in This Article
Figure 1
DNA Sequences Flanking the Microsatellite Polymorphisms in the FBN1 Gene.Figure 2
Haplotype-Segregation Analysis in Three Families.Article Activity
- Article
Marfan's syndrome is an autosomal dominant disorder of connective tissue that is characterized by ocular, skeletal, and cardiovascular manifestations. It is estimated to have a prevalence of 1 per 10,000 people, and at least 25 percent of the cases occur in the absence of a family history, suggesting parental germ-line defects1. The syndrome shows full penetrance, but there is considerable clinical variability both between and within families. Dissection of the ascending aorta is the leading cause of premature death2. The combination of careful follow-up of the cardiovascular status of patients with Marfan's syndrome, prophylactic aortic-root replacement, and the judicious use of β-adrenergic-blocking agents has led to a dramatic decrease in morbidity and mortality from cardiovascular causes over the past two decades3,4.
The effective treatment of patients with Marfan's syndrome relies heavily on early and accurate diagnosis. Until recently, such efforts were hampered by the lack of a sensitive and specific diagnostic test for the disorder. In 1991 a cause-and-effect relation was established between mutations in the gene on chromosome 15 encoding fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, and the Marfan's phenotype5. In addition, linkage between FBN1 and the classic phenotype of Marfan's syndrome has been observed in all families tested, suggesting that FBN1 defects are the predominant, if not the sole, cause of the disorder6-11. It therefore seemed likely that molecular genetic analysis would prove a valuable adjunct to clinical diagnosis for purposes of risk assessment. Unfortunately, the rate of detection of mutations in Marfan's syndrome has been extremely slow, and with one exception, all mutations identified to date have been unique to a single family5,12-18. These factors have precluded the widespread use of direct analysis of mutations for presymptomatic diagnosis.
As an alternative, we have explored the use of linkage analysis in family screening. Our intention was to devise a method that would allow discrimination between the many normal copies of the fibrillin gene and the single abnormal copy that is inherited by the affected members of a given family. To this end, we have identified a panel of highly informative intragenic microsatellite polymorphisms (genetic markers) that are widely interspersed in FBN1. Microsatellites consist of repeating sequences of a short block of nucleotides, and the number of repeats may vary from person to person. Typing each family member for these polymorphic markers (i.e., determining the number of repeats) and observing the inheritance pattern of these sequence variants allow the determination of haplotypes (combinations of polymorphic variants that are inherited as a unit and that therefore define single copies of the fibrillin gene). Haplotypes that carry disease-producing mutations vary from family to family. It is therefore necessary to determine which haplotype cosegregates with the disease in each kindred. In this article we demonstrate the usefulness of this method, called haplotype-segregation analysis, for a variety of clinical and diagnostic purposes in families affected by Marfan's syndrome.
Methods
Study Subjects
All the study subjects either were followed at the Medical Genetics Clinic of Johns Hopkins Hospital or were referred for presymptomatic diagnosis after evaluation by a medical geneticist. In addition, all the subjects were studied by echocardiography, angiography, or both and by slit-lamp examination, and those considered to be affected satisfied the international diagnostic criteria for Marfan's syndrome19.
Identification of Novel FBN1 Microsatellite Polymorphisms
A phage library was derived from a single yeast artificial-chromosome library clone (YAC-15) that contains the entire fibrillin gene, including the 5' and 3' untranslated regions. DNA isolated from overlapping phage clones was cleaved to completion with a panel of restriction enzymes, fractionated by electrophoresis through an agarose gel, and transferred to a nylon membrane. The resulting filters were hybridized to a labeled poly(dA-dC) • (dT-dG) probe (Pharmacia) as described elsewhere20. Hybridizing DNA fragments were purified from agarose gels, subcloned into the pUC19 plasmid vector, and sequenced by a modification of the dideoxy-chain-termination procedure21.
Typing of Family Members and Control Subjects
Polymerase-chain-reaction (PCR)22 primers were fashioned from the sequences flanking each of the short-sequence tandem-repeat regions, which were designated mts-1, mts-2, and mts-4. A fourth intragenic microsatellite polymorphism (mts-3) was evaluated with primers that have been previously described23. The sequence and relative position of each primer pair are shown in Figure 1Figure 1
DNA Sequences Flanking the Microsatellite Polymorphisms in the FBN1 Gene.. Each PCR was performed in a total volume of 25 microliters, including 500 ng of template genomic DNA, 1.25 units of Taq polymerase (Cetus), 2.5 microliters of 10 × PCR buffer (Cetus; final concentration of magnesium chloride, 1.5 micro M), 400 nM final concentration of unlabeled primer, 66 nM final concentration of end-labeled primer (one primer in each set), and deoxynucleotide triphosphates (Cetus; 400 micro M each). The primers were end-labeled in a reaction volume of 6.8 microliters containing 4.4 microliters of primer (10 micro M stock), 0.5 microliter of T4 polynucleotide kinase and 1.4 microliters of 5x kinase buffer (BRL), and 0.5 microliter of γ-32P-labeled ATP (0.15 micro Ci per microliter; NEN). The mixture was incubated at 37 °C for one hour and diluted with 20 microliters of distilled water, and 1 microliter was used per template for PCR amplification.The PCR thermal profile consisted of 8 minutes of denaturation at 94 °C, followed by 30 cycles of denaturation at 94 °C for 30 seconds, annealing at 58 °C for 30 seconds, and extension at 72 °C for 30 seconds. The products of each PCR varied in size according to the number of sequence repeats between the two primers with fixed positions. These products (marker alleles) were fractionated according to size by electrophoresis (60 W) through a 40-cm denaturing 8 percent polyacrylamide gel; they were visualized by autoradiography. Larger fragments contain more repeats than smaller ones and migrate more slowly through the gel. The size of the marker alleles was determined by observing their comigration with the extension products of a sequencing ladder.
Allele frequencies, marker heterozygosity, and haplotype heterozygosity were determined by analyzing genomic DNA from 50 unrelated and unaffected control subjects (100 chromosomes in all). The largest marker allele found in this test population for a given polymorphic locus was assigned the number 1. Successively smaller marker alleles were assigned successively larger numbers (Table 1Table 1
Allele Size and Frequency and Heterozygosity of Markers for FBN1 Intragenic Microsatellite Polymorphisms.). Genomic DNA was isolated from whole blood or immortalized lymphoblasts by methods that have been previously described24.Results
Four Novel FBN1 Microsatellite Polymorphisms
Southern blot analysis of overlapping phage DNA clones that spanned the entire fibrillin gene with a probe as described in the Methods section revealed four positively hybridizing genomic DNA fragments. One short sequence repeat (mts-3) had been previously identified. Subsequent mapping of the four repetitive sequences revealed that they were widely spaced throughout the 100-kb expanse of FBN1, with localization to introns 1, 5, 28, and 43. Direct sequencing of the tandem repeats and flanking regions revealed that mts-1, mts-2, and mts-4 are composed of (CA)n blocks (Figure 1). Mts-3 was previously known to be a pentanucleotide repeat -- (TAAAA)n.
To determine whether any of these repetitive sequences showed polymorphic variation in the general population, we generated fragments of DNA that spanned each repeat with flanking primers and fractionated them according to size. The number of distinct marker alleles for each microsatellite ranged from 4 (mts-3) to 15 (mts-2). The use of template genomic DNA from 50 unrelated and unaffected control subjects (100 chromosomes in all) allowed the determination of allele frequencies and marker heterozygosity in the population (Table 1). These data predict a minimum of 44 distinct haplotypes in the general population, with the haplotype 5/11/2/7 (ordered 5' to 3', from mts-1 to mts-4) being the most common and the only one seen in homozygous subjects. Genotyping for these four polymorphic markers identified two distinct haplotypes in 86 percent of those tested. Informativeness, a measure of the ability to determine which allele is passed from a parent to a child in haplotype-segregation analysis, is therefore predicted to be quite high.
Haplotype-Segregation Analysis
The parents of a four-month-old infant (Subject III-1, Family A) (Figure 2Figure 2
Haplotype-Segregation Analysis in Three Families.) requested presymptomatic diagnosis. The father (Subject II-1) and the paternal grandmother (Subject I-1) had classic features of Marfan's syndrome in the ocular, skeletal, and cardiovascular systems. The infant had mild pectus carinatum, but no specific signs of the disorder. Haplotype-segregation analysis suggested that the disease was passed from Subject I-1 to Subject II-1 on the 5/11/2/7 allele but that Subject III-1 inherited the 1/1/2/7 allele from her affected father. These data predict that this infant is unaffected.Families B and C in Figure 2 included family members who had a systemic disorder of connective tissue with a high degree of intrafamilial variability in organ-system involvement and clinical severity. In Family B, the proband (Subject II-6) had classic features of Marfan's syndrome, including pronounced skeletal features, striae atrophicae, ectopia lentis, mitral-valve prolapse, and mild dilatation of the ascending aorta. Both her daughters (Subjects III-1 and III-2) had severe skeletal features and aortic dilatation. In contrast, other family members had a connective-tissue disorder with variable skeletal features (arachnodactyly, joint laxity, highly arched palate, and scoliosis), myopia, and striae atrophicae but no evidence of heart involvement. The family members who showed this milder phenotype most clearly are indicated in the pedigree (Figure 2). As expected, the results of haplotype-segregation analysis showed that the proband passed the same fibrillin allele (4/15/3/1) to both of her affected daughters. Remarkably, two unaffected siblings of the proband also carried this allele, which originated with the proband's mother (Subject I-3), who was unaffected. The family members with the milder connective-tissue disorder did not carry this allele but shared the 5/11/2/8 haplotype. These data suggest that a new mutation causing classic Marfan's syndrome arose in the proband on the 4/15/3/1 allele, that she passed this allele to her affected daughters, and that this occurred against the genetic background of a milder connective-tissue disorder (not typical Marfan's) in the extended family.
Although the particular Marfan's mutation in Family B has not yet been identified, this hypothesis is strengthened by our analysis of another family (Family C) (Figure 2). The proband in this family was found to have a clinical variant that shows involvement of the mitral valve, aorta, skin, and skeleton (which we have termed the MASS phenotype), but no ectopia lentis or progression of aortic dilatation to dissection25. This patient had extreme dolichostenomelia (excessive growth of long bones), mitral-valve prolapse, early myopia, striae atrophicae, and an aortic root that was at the upper limit of the normal size when standardized with body-surface area. All the other family members were tall, but selected members also had early myopia, mitral-valve prolapse, scoliosis, or a combination of these. This milder connective-tissue phenotype segregates with the 9/3/4/9 haplotype, an allele that the proband did not carry. In fact, the occurrence of a novel frame-shift mutation in the fibrillin gene has been identified in the proband (Subject III-2)18.
Haplotype-segregation analysis cannot be used in diagnosis when there are not enough family members available for study to determine which allele is segregating with the disease. The specific number of family members required will vary with family structure and the informativeness of the marker alleles. Presymptomatic diagnosis by haplotype-segregation analysis was attempted successfully in 10 of 11 additional families tested (data not shown). Although we have not used linkage methods for prenatal diagnosis, such a use would not differ from presymptomatic diagnosis with regard to the theory, execution, or predicted informativeness of the technique.
Discussion
Fibrillin is a major glycoprotein component of the extracellular microfibril, a structure with wide distribution in elastic tissues26. Although its function remains to be fully elucidated, it is believed that fibrillin participates in determining the structural integrity of tissues, partly by guiding the organization of tropoelastin molecules into maturing elastic fibers. The identification of new polymorphic variants in the gene encoding fibrillin should facilitate the study of Marfan's syndrome and other disorders in which there is primary disruption of elastic tissues.
To date, 14 different FBN1 mutations causing Marfan's syndrome have been reported, thus limiting the use of direct mutation analysis for presymptomatic diagnosis12-18. In contrast, FBN1 haplotype-segregation analysis is applicable to all subjects with a positive family history and a sufficient number of participating family members to determine which allele is segregating with the disease. All families with classic Marfan's syndrome that have been studied with flanking markers, intragenic markers, or both have shown a consistent linkage between FBN1 and the disease phenotype6-11. This observation suggests that fibrillin-gene defects account for the vast majority of cases of classic Marfan's syndrome, if not all. It seems appropriate, therefore, to counsel small families on the basis of haplotype segregation even though statistically significant evidence of linkage may be unattainable. More caution is warranted when atypical phenotypes are considered.
Fibrillin is encoded by a large (approximately 110 kb) and highly fragmented (65 exon) gene27,28. Previous work identified a number of intragenic markers, including one microsatellite polymorphism (mts-3) and two single-nucleotide polymorphisms, which are all located in the central portion of the gene5,23,29. The combined informativeness of these markers is low, precluding their use for linkage analysis in many families5,11. To increase our ability to counsel families with Marfan's syndrome, we searched for additional highly informative intragenic microsatellite polymorphisms.
The data presented here clearly show that newly identified intragenic markers can be used to follow the segregation pattern of FBN1 alleles in most families with Marfan's syndrome. Although the 5/11/2/7 haplotype was observed in homozygosity in approximately 14 percent of unrelated persons in the general population, haplotype-segregation analysis was informative in 13 of the 14 families tested in this study. In addition, this type of analysis facilitates the detection of intragenic recombination, a potential confounding factor in any linkage study.
Recent work has demonstrated the usefulness of β-adrenergic blockade in slowing the rate of aortic-root dilatation in Marfan's syndrome4. It has also been suggested that the earlier this therapy is instituted in the course of the disease, the greater the benefit. This is one example of how presymptomatic diagnosis may have a direct effect on medical management. In addition, early exclusion of the diagnosis would avert the need for the routine use of expensive diagnostic testing in the follow-up of clinically equivocal cases.
Intrafamiliarol l clinical variability is a hallmark of Marfan's syndrome1. A previous study demonstrated that such variability can be seen among family members carrying an identical FBN1 mutation, predicting the existence of genetic or environmental modifiers (or both) to phenotypic expression12. This study offers a second molecular explanation. In two of the families shown in Figure 2, some family members have specific features of Marfan's syndrome, whereas others have nonspecific connective-tissue manifestations that are commonly seen as components of the Marfan's phenotype. Interestingly, all these family members satisfy the international diagnostic criteria for Marfan's syndrome and would therefore be assigned to affected status19. In the presence of an unequivocally affected first-degree relative, these guidelines do not require one of the major manifestations that are relatively specific for Marfan's syndrome (ectopia lentis, aortic-root dilatation, and dural ectasia), but only abnormalities of two organ systems that are consistent with the diagnosis. Haplotype-segregation analysis clearly demonstrates that not all affected members of Families B and C are segregating the same mutant fibrillin allele. It remains to be determined whether the milder disease phenotypes that indicate dominant mendelian inheritance in these families are caused by defects of the fibrillin gene or by mutations in other genes.
Many isolated features of Marfan's syndrome, including early myopia, mitral-valve prolapse, scoliosis, and joint hypermobility, have a high prevalence in the general population. Patients with mitral-valve-prolapse syndrome, the MASS phenotype, or variants of other common connective-tissue disorders (e.g., the Ehlers-Danlos syndrome) can have a clustering of these relatively mild features of Marfan's syndrome. It is not unexpected, but in fact predictable, that a subgroup of families with Marfan's syndrome will also segregate a clinically related but etiologically distinct connective-tissue disorder. This could explain why a large French kindred with incomplete, atypical, and variable manifestations of Marfan's syndrome, in which members with abnormal phenotypes were considered to be affected with the same disorder, did not have linkage to FBN130. Determining the precise prevalence of this phenomenon awaits molecular analysis of the majority of families with Marfan's syndrome that have wide variability in tissue involvement and severity of disease.
In the cases presented here, it is clear that not all family members who satisfy the diagnostic criteria for Marfan's syndrome are at equal risk for life-threatening cardiovascular manifestations. The implications include the need for individualized counseling and management and for appropriate caution when studies of natural history and therapeutic outcomes are interpreted. The requirement of a major manifestation of Marfan's syndrome for the clinical diagnosis, even when there is an unequivocal family history, complemented by the use of molecular analysis for those with atypical disease, should help optimize the assessment of cardiovascular risk in families segregating the Marfan phenotype.
Note added in proof: We have identified an additional family in which a person with atypically mild disease previously diagnosed as Marfan's syndrome did not inherit the FBN1 allele that cosegregates with the more severe Marfan's phenotype seen in the extended family. We have now identified the precise mutation, substitution of a cysteine residue in an epidermal growth factor-like domain, that is associated with classic Marfan's syndrome in this family. The person with milder manifestations, including skeletal features and mitral-valve prolapse, does not carry this mutation. This is consistent with the findings in this report.
Supported by grants (HL-02815 and HL-35877) from the National Institutes of Health, by a General Clinical Research Center grant (RR-00722), and by grants from the National Marfan Foundation, the American Heart Association (New York City affiliate), the Smilow Family Foundation, the Dr. Amy and James Elster Research Fund, and the British Heart Foundation.
We are indebted to Mrs. Evelyn Bull for expert technical assistance.
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.
- References
References
1
Pyeritz RE ,McKusick VA . The Marfan syndrome: diagnosis and management. N Engl J Med 1979;300:772-777
Full Text | Web of Science | Medline2
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;286:804-808
Full Text | Web of Science | Medline3
Gott VL ,Pyeritz RE ,Cameron DE ,Greene PS ,McKusick VA . Composite graft repair of Marfan aneurysm of the ascending aorta: results in 100 patients. Ann Thorac Surg 1991;52:38-45
CrossRef | Web of Science | Medline4
Shores J ,Berger KR ,Murphy EA ,Pyeritz RE . Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome. N Engl J Med 1994;330:1335-1341
Full Text | Web of Science | Medline5
Dietz HC ,Cutting GR ,Pyeritz RE , et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-339
CrossRef | Web of Science | Medline6
Kainulainen K ,Pulkkinen L ,Savolainen A ,Kaitila I ,Peltonen L . Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323:935-939
Full Text | Web of Science | Medline7
Dietz HC ,Pyeritz RE ,Hall BD , et al. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 1991;9:355-361
CrossRef | Web of Science | Medline8
Kainulainen K ,Steinmann B ,Collins F , et al. Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene. Am J Hum Genet 1991;49:662-667
Web of Science | Medline9
Tsipouras P ,Sarfarazi M ,Devi A ,Weiffenbach B ,Boxer M . Marfan syndrome is closely linked to a marker on chromosome 15q1.5-to-q2.1. Proc Natl Acad Sci U S A 1991;88:4486-4488
CrossRef | Web of Science | Medline10
Sarfarazi M ,Tsipouras P ,Del Mastro R , et al. A linkage map of 10 loci flanking the Marfan syndrome locus on 15q: results of an International Consortium study. J Med Genet 1992;29:75-80
CrossRef | Web of Science | Medline11
Tsipouras P ,Del Mastro R ,Sarfarazi M , et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. N Engl J Med 1992;326:905-909
Full Text | Web of Science | Medline12
Dietz HC ,Pyeritz RE ,Puffenberger EG , et al. Marfan phenotype variability in a family segregating a missense mutation in the epidermal growth factor-like motif of the fibrillin gene. J Clin Invest 1992;89:1674-1680
CrossRef | Web of Science | Medline13
Kainulainen K ,Sakai LY ,Child A , et al. Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides. Proc Natl Acad Sci U S A 1992;89:5917-5921
CrossRef | Web of Science | Medline14
Dietz HC ,Saraiva JM ,Pyeritz RE ,Cutting GR ,Francomano CA . Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum Mutat 1992;1:366-374
CrossRef | Medline15
Dietz HC ,Valle D ,Francomano CA ,Kendzior RJ Jr ,Pyeritz RE ,Cutting GR . The skipping of constitutive exons in vivo induced by nonsense mutations. Science 1993;259:680-683
CrossRef | Web of Science | Medline16
Hewett DR ,Lynch JR ,Smith R ,Sykes BC . A novel fibrillin mutation in the Marfan syndrome which could disrupt calcium binding of the epidermal growth factor-like module. Hum Mol Genet 1993;2:475-477
CrossRef | Web of Science | Medline17
Godfrey M ,Vandemark N ,Wang M , et al. Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome. Am J Hum Genet 1993;53:472-480
Web of Science | Medline18
Dietz HC ,McIntosh I ,Sakai LY , 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;17:468-475
CrossRef | Web of Science | Medline19
Beighton P ,de Paepe A ,Danks D , et al. International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am J Med Genet 1988;29:581-594
CrossRef | Web of Science | Medline20
Litt M. PCR of TG microsatellites. In: McPherson MJ, Quirke P, Taylor GR, eds. PCR: a practical approach. Oxford, England: IRL Press at Oxford University Press, 1991:85-99.
21
Zagursky RJ ,Berman ML ,Baumeister K ,Lomax N . Rapid and easy sequencing of linear double stranded DNA and supercoiled DNA. Gene Anal Technol 1986;2:89-94
CrossRef22
Saiki RK ,Scharf S ,Faloona F , et al. Enzymatic amplification of β-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 1985;230:1350-1354
CrossRef | Web of Science | Medline23
Lee B ,Godfrey M ,Vitale E , et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991;352:330-334
CrossRef | Web of Science | Medline24
Kunkel LM ,Smith KD ,Boyer SH , et al. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A 1977;74:1245-1249
CrossRef | Web of Science | Medline25
Glesby MJ ,Pyeritz RE . Association of mitral valve prolapse and systemic abnormalities of connective tissue: a phenotypic continuum. JAMA 1989;262:523-528
CrossRef | Web of Science | Medline26
Sakai LY ,Keene DR ,Engvall E . Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 1986;103:2499-2509
CrossRef | Web of Science | Medline27
Maslen CL ,Corson GM ,Maddox BK ,Glanville RW ,Sakai LY . Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991;352:334-337
CrossRef | Web of Science | Medline28
Pereira L ,D'Alessio M ,Ramirez F , et al. Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum Mol Genet 1993;2:961-968
CrossRef | Web of Science | Medline29
Clark BA ,Maslen CL ,Sakai LY ,Dhalimi MA ,Litt R ,Litt M . A BamHI polymorphism at the fibrillin (FBN) locus. Nucleic Acids Res 1991;19:4309-4309 abstract.
CrossRef | Web of Science | Medline30
Boileau C ,Jondeau G ,Babron M-C , et al. Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes. Am J Hum Genet 1993;53:46-54
Web of Science | Medline
- Citing Articles (42)
Citing Articles
1
L Faivre, G Collod-Beroud, L Adès, E Arbustini, A Child, BL Callewaert, B Loeys, C Binquet, E Gautier, K Mayer, M Arslan-Kirchner, M Grasso, C Beroud, D Hamroun, C Bonithon-Kopp, H Plauchu, PN Robinson, J De Backer, P Coucke, U Francke, O Bouchot, JE Wolf, C Stheneur, N Hanna, D Detaint, A De Paepe, C Boileau, G Jondeau. (2011) The new Ghent criteria for Marfan syndrome: what do they change?. Clinical Geneticsno-no
CrossRef2
Ivanete C. Sbruzzi, Alexandre C. Pereira, Beatriz Vasconcelos, Raquel S. Honjo, José E. Krieger, Chong A. Kim. (2010) Williams-Beuren Syndrome: Diagnosis by Polymorphic Markers. Genetic Testing and Molecular Biomarkers 14:2, 209-214
CrossRef3
Carlos Villamizar, Ellen S. Regalado, Van Tran Fadulu, Sumera N. Hasham, Prateek Gupta, Marcia C. Willing, Shao-Qing Kuang, Dongchuan Guo, Ann Muilenburg, Richard W. Yee, Yuxin Fan, Jeffrey Towbin, Joseph S. Coselli, Scott A. LeMaire, Dianna M. Milewicz. (2010) Paucity of skeletal manifestations in hispanic families with FBN1 mutations. European Journal of Medical Genetics 53:2, 80-84
CrossRef4
(2009) Yokosuka Science Festa 2009 Program and Proceedings June 4-June 7, 2009, Yokosuka, Japan. Connective Tissue Research 50:6, 349-420
CrossRef5
Rena Hirani, Barbara Koszyca, Roger W. Byard. (2008) Marfan syndrome and sudden death within a family – Aetiologic, molecular and diagnostic issues at autopsy. Journal of Forensic and Legal Medicine 15:4, 205-209
CrossRef6
Peter Boseman, Matthew Lewin, John Dillon, Sanjeev Sethi. (2008) Marfan Syndrome, MPGN, and Bacterial Endocarditis. American Journal of Kidney Diseases 51:4, 697-701
CrossRef7
Daniel P. Judge, Harry C. Dietz. (2008) Therapy of Marfan Syndrome. Annual Review of Medicine 59:1, 43-59
CrossRef8
J De Backer, B Loeys, B Leroy, P Coucke, H Dietz, A De Paepe. (2007) Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. Clinical Genetics 72:3, 188-198
CrossRef9
R. R. Valiev, R. I. Khusainova, I. A. Kutuev, E. K. Khusnutdinova. (2006) Analysis of the fibrillin-1 gene (FBN1) in patients with Marfan syndrome. Molecular Biology 40:6, 922-930
CrossRef10
Claudia Spits, Martine De Rycke, Willem Verpoest, Willy Lissens, Andre Van Steirteghem, Inge Liebaers, Karen Sermon. (2006) Preimplantation genetic diagnosis for Marfan syndrome. Fertility and Sterility 86:2, 310-320
CrossRef11
Gwenaëlle Collod‐Béroud, Catherine Boileau. 2004. Marfan Syndrome and Related Fibrillinopathies. , 761-765.
CrossRef12
Sakari Kakko, Tuija Räisänen, Minna Tamminen, Juhani Airaksinen, Kaj Groundstroem, Tatu Juvonen, Antti Ylitalo, Paavo Uusimaa, Markku J Savolainen. (2003) Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5q13-14 in Finnish families. The Journal of Thoracic and Cardiovascular Surgery 126:1, 106-113
CrossRef13
Stefanie Katzke, Patrick Booms, Frank Tiecke, Monika Palz, Angelika Pletschacher, Seval Türkmen, Luitgard M. Neumann, Reinhard Pregla, Christa Leitner, Cornelia Schramm, Peter Lorenz, Christian Hagemeier, Josefine Fuchs, Flemming Skovby, Thomas Rosenberg, Peter N. Robinson. (2002) TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Human Mutation 20:3, 197-208
CrossRef14
Gijs J. Nollen, Maarten Groenink, Ernst E. van der Wall, Barbara J. M. Mulder. (2002) Current insights in diagnosis and management of the cardiovascular complications of Marfan's syndrome. Cardiology in the Young 12:04, 320
CrossRef15
Philip F. Giampietro, Cathleen Raggio, Jessica G. Davis. (2002) Marfan syndrome: orthopedic and genetic review. Current Opinion in Pediatrics 14:1, 35-41
CrossRef16
B. Loeys, L. Nuytinck, P. Van Acker, S. Walraedt, M. Bonduelle, K. Sermon, B. Hamel, A. Sanchez, L. Messiaen, A. De Paepe. (2002) Strategies for prenatal and preimplantation genetic diagnosis in Marfan syndrome (MFS). Prenatal Diagnosis 22:1, 22-28
CrossRef17
Daniel P. Judge, Nancy J. Biery, Harry C. Dietz. (2001) Characterization of microsatellite markers flankingFBN1: Utility in the diagnostic evaluation for Marfan syndrome. American Journal of Medical Genetics 99:1, 39-47
CrossRef18
Peter S. Rose, Howard P. Levy, Nicholas U. Ahm, Paul D. Sponseller, Trish Magyari, Joie Davis, Clair A. Francomano. (2000) A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genetics in Medicine 2:5, 278-282
CrossRef19
Nick Hateboer, Maurice Buchalter, Sarah J. Davies, Lazarus P. Lazarou, David Ravine. (2000) Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred. American Journal of Kidney Diseases 35:4, 753-760
CrossRef20
Reed E. Pyeritz. (2000) The Marfan Syndrome. Annual Review of Medicine 51:1, 481-510
CrossRef21
Bo Yuan, Jeanne P. Thomas, Yskert von Kodolitsch, Reed E. Pyeritz. (1999) Comparison of heteroduplex analysis, direct sequencing, and enzyme mismatch cleavage for detecting mutations in a large gene,FBN1. Human Mutation 14:5, 440-446
CrossRef22
G Pepe, E Bertini, B Giusti, T Brunelli, P Comeglio, B Saitta, L Merlini, M.L Chu, G Federici, R Abbate. (1999) A novel de novo mutation in the triple helix of the COL6A3 gene in a two-generation Italian family affected by Bethlem myopathy. A diagnostic approach in the mutations' screening of type VI collagen. Neuromuscular Disorders 9:4, 264-271
CrossRef23
Gott, Vincent L., Greene, Peter S., Alejo, Diane E., Cameron, Duke E., Naftel, David C., Miller, D. Craig, Gillinov, A. Marc, Laschinger, John C., Borst, Hans G., Cabrol, Christian E.A., Cooley, Denton A., Coselli, Joseph S., David, Tirone E., Griepp, Randall B., Kouchoukos, Nicholas T., Turina, Marko I., Pyeritz, Reed E., . (1999) Replacement of the Aortic Root in Patients with Marfan's Syndrome. New England Journal of Medicine 340:17, 1307-1313
Full Text24
Terhi Rantamäki, Ilkka Kaitila, Ann-Christine Syvänen, Matti Lukka, Leena Peltonen. (1999) Recurrence of Marfan Syndrome as a Result of Parental Germ-Line Mosaicism for an FBN1 Mutation. The American Journal of Human Genetics 64:4, 993-1001
CrossRef25
Robert A. Montgomery, Michael T. Geraghty, Evelyn Bull, Bruce D. Gelb, Maureen Johnson, Iain McIntosh, Clair A. Francomano, Harry C. Dietz. (1998) Multiple Molecular Mechanisms Underlying Subdiagnostic Variants of Marfan Syndrome. The American Journal of Human Genetics 63:6, 1703-1711
CrossRef26
Filemon K. Tan, David N. Stivers, Morris W. Foster, Ranajit Chakraborty, Robert F. Howard, Dianna M. Milewicz, Frank C. Arnett. (1998) Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis & Rheumatism 41:10, 1729-1737
CrossRef27
Cheryl Black, Anne P. Withers, Jonathon R. Gray, Allan B. Bridges, Ashley Craig, David U. Baty, Maureen Boxer. (1998) Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial marfan syndrome phenotype. Human Mutation 11:S1, S198-S200
CrossRef28
Stephen Westaby, Takahiro Katsumata, Edward Freitas. (1997) Aortic Valve Conservation in Acute Type A Dissection. The Annals of Thoracic Surgery 64:4, 1108-1112
CrossRef29
Giuseppe Mercuro, Massimo Ruscazio, Sandra Zoncu, Roberta Montisci, Angelo Cherchi, Bernardo Carpiniello, Nereide Rudas. (1997) Association between psychiatric disorders and marfan's syndrome in a large sardinian family with a high prevalence of cardiac abnormalities. Clinical Cardiology 20:3, 243-245
CrossRef30
Caroline Hayward, David J. H. Brock. (1997) Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Human Mutation 10:6, 415-423
CrossRef31
Caroline Hayward, Mary E. Porteous, David J. H. Brock. (1997) Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: Report of 12 novel mutations. Human Mutation 10:4, 280-289
CrossRef32
J. T. POWELL, S. T. R. MacSWEENEY, R. M. GREENHALGH, R. J. TURNER, A. M. HENNEY. (1996) Interaction between Fibrillin Genotype and Blood Pressure and the Development of Aneurysmal Disease. Annals of the New York Academy of Sciences 800:1 The Abdominal, 198-207
CrossRef33
M.K. Wirtz, J.R. Samples, P.L. Kramer, K. Rust, J. Yount, T.S. Acott, R.D. Koler, J. Cisler, A. Jahed, R.J. Gorlin, M. Godfrey. (1996) Weill-Marchesani syndrome - possible linkage of the autosomal dominant form to 15q21.1. American Journal of Medical Genetics 65:1, 68-75
CrossRef34
Francesco Ramirez. (1996) Fibrillin mutations in Marfan syndrome and related phenotypes. Current Opinion in Genetics & Development 6:3, 309-315
CrossRef35
Anne De Paepe, Richard B. Devereux, Harry C. Dietz, Raoul C. M. Hennekam, Reed E. Pyeritz. (1996) Revised diagnostic criteria for the Marfan syndrome. American Journal of Medical Genetics 62:4, 417-426
CrossRef36
Kim M. Summers. (1996) Relationship between genotype and phenotype in monogenic diseases: Relevance to polygenic diseases. Human Mutation 7:4, 283-293
CrossRef37
Takeshi Aoyama, Uta Francke, Cheryll Gasner, Heinz Furthmayr. (1995) Fibrillin abnormalities and prognosis in marfan syndrome and related disorders. American Journal of Medical Genetics 58:2, 169-176
CrossRef38
Zayd A. Eldadah, Jamie A. Grifo, Harry C. Dietz. (1995) Marfan syndrome as a paradigm for transcript-targeted preimplantation diagnosis of heterozygous mutations. Nature Medicine 1:8, 798-803
CrossRef39
Mei Wang, John Mata, Christopher E. Price, Patrick L. Iversen, Maurice Godfrey. (1995) Prenatal and presymptomatic diagnosis of the marfan syndrome using fluorescence pcr and an automated sequencer. Prenatal Diagnosis 15:6, 499-507
CrossRef40
Harry Dietz, Uta Francke, Heinz Furthmayr, Clair Francomano, Anne De Paepe, Richard Devereux, Francesco Ramirez, Reed Pyeritz. (1995) The question of heterogeneity in Marfan syndrome. Nature Genetics 9:3, 228-229
CrossRef41
Catherine Boileau, Claudine Junien, Gwenaëlle Collod, Guillaume Jondeau, Olivier Dubourg, Jean-Pierre Bourdarias, Catherine Bonaïti-Pellié, Jean Frézal, Pierre Maroteaux. (1995) Reply to “The question of heterogeneity in Marfan syndrome”. Nature Genetics 9:3, 230-231
CrossRef42
Sutherland, Grant R., Richards, Robert I., . (1994) DNA Repeats -- A Treasury of Human Variation. New England Journal of Medicine 331:3, 191-193
Full Text
