Original Article
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; 326:905-909April 2, 1992
- Abstract
- Abstract
Background.
The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5.
Methods.
Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders — congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1).
Results.
Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 1025.6:1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the fibrillin gene on chromosome 5. There was no linkage of mitral-valve prolapse to the fibrillin gene on chromosome 5; studies of chromosome 15 were not informative. Annuloaortic ectasia was not linked to either fibrillin gene.
Conclusions.
The Marfan syndrome appears to be caused by mutations in a single fibrillin gene on chromosome 15. Diagnosis of the Marfan syndrome by genetic linkage and analysis is now feasible in many families. (N Engl J Med 1992;326:905–9.)
Article Activity
- Article
THE Marfan syndrome is a common genetic disorder of connective tissue, with characteristic manifestations in the musculoskeletal, cardiovascular, and ocular systems.1 Recently, two independent studies2 , 3 linked the syndrome to a fibrillin gene localized on chromosome 15.2 This finding agreed with those of previous immunohistochemical and genetic-linkage studies, which implicated fibrillin in the pathogenesis of the condition4 and established chromosome 15 as the location of the gene for the Marfan syndrome.5 6 7 More important, one of these reports described the same missense mutation in two sporadic cases of the syndrome.3 Lee et al.2 further substantiated this causal relation, by showing genetic linkage between another fibrillin gene mapped to chromosome 5 and congenital contractural arachnodactyly, a disorder presenting with marfanoid habitus, flexion contractures, abnormal pinnae, muscular hypoplasia, and rarely, aortic-root dilatation.8 , 9 Fibrillin, a large glycoprotein (350 kd), is one of the structural components of the elastin-associated microfibrils. These microfibrils have been detected in a wide variety of tissues, including the suspensory ligament, periosteum, and the aortic media.10 , 11
These previous findings led to two important questions: Is more than one fibrillin gene implicated in causing the Marfan syndrome? And are the fibrillin genes genetically linked to other phenotypically related disorders, such as the mitral-valve prolapse syndrome, annuloaortic ectasia, and autosomal-dominant ectopia lentis? To address these two questions, we performed genetic-linkage analysis in a large number of families with the Marfan syndrome and other phenotypically related disorders.
Methods
Clinical Studies
Members of 36 mutigenerational families underwent genotyping for markers specific for the fibrillin genes on chromosomes 15 and 5. The Marfan syndrome had been diagnosed clinically in 28 families, ectopia lentis in 2, congenital contractural arachnodactyly in 3, mitral-valve prolapse syndrome in 2, and annuloaortic ectasia in 1. The families were identified by and evaluated in several centers in North America, Europe, and South Africa. The clinical diagnosis was established according to widely accepted criteria.12
DNA Markers
Two informative markers have been identified — a (TAAAA)n for the fibrillin gene on chromosome 15 (fibrillin 15) and a (GT)n for the fibrillin gene on chromosome 5 (fibrillin 5)2 (n denotes the number of repeats). Genomic DNA (0.5 μg) was amplified with the use of primers specific for fibrillin 15 and fibrillin 5. These primers have been described previously2; those for fibrillin 15 are 5′-CCTGGCTACCATTCAACTCCC-3′ and 5′-GAGTACATAGAGTGTTTTAGGG-3′, and those for fibrillin 5 are 5′-AAGGTGTTCTTTGCATGTTCACC-3′ and 5′-GTAATGTGTTCTATCTAGTTCAACG-3′. Amplification was carried out under the following conditions: denaturing at 94°C for 90 seconds, annealing at 50°C (55°C for fibrillin 5) for 150 seconds, and elongation at 72°C for 60 seconds. One primer was phosphorylated in each reaction, with gamma[32P]ATP (activity, 6000 Ci per millimole) (New England Nuclear) and T4 polynucleotide kinase (Promega). One microliter of the denatured product of the polymerase chain reaction was subjected to electrophoresis in a 7 M urea—5 percent polyacrylamide gel. The gel was exposed on x-ray film at -70°C for autoradiography.
In addition, 5-μg samples of genomic DNA obtained from affected family members and their relatives were digested with the restriction endonuclease TaqI. The DNA fragments were separated by agarose gel electrophoresis, transferred onto a nylon filter (Zeta-bind; Kuno), and hybridized overnight to a 32P-labeled 1-kb fragment of fibrillin 15 complementary DNA derived from the MF-13 clone.2 After washing, the filters were exposed on x-ray film at -70°C for autoradiography. A constant band (8 kb) and two variable bands (6 kb and 5 kb) were observed.
All genotypes were interpreted from the autoradiograms by two independent observers and recorded in a dedicated data-entry computer program (LARMAS).13
Genetic Analysis
Linkage analysis of each disorder and its fibrillin gene marker was performed with the LIPED and LINKAGE programs.14 , 15 The programs calculate the odds of the observed pattern of inheritance for markers linked at hypothetical distances on the chromosome map and for unlinked, randomly assorting markers. An odds ratio of more than 1000:1 in favor of linkage (expressed on a logarithmic scale as a lod score of more than 3) is considered a statistically significant demonstration of linkage in humans. On the other hand, an odds ratio of less than 1:100 (or a lod score of less than -2) is agreed to exclude linkage. Confidence intervals were obtained in the usual manner (by subtracting 1 from the maximal lod score).
A total of 439 genotypes were obtained for fibrillin 15—(TAAAA)n, 224 for fibrillin 15—TaqI, and 402 for fibrillin 5—(GT)n. The Marfan syndrome and the other disorders were defined as having full penetrance and a gene frequency of 0.0001. Family members less than five years old were excluded from the analysis. The lod scores for linkage between the Marfan syndrome and each of the two fibrillin genes were used to estimate the proportion of families whose disorders were linked to either gene or both genes, and 95 percent confidence intervals were subsequently obtained. These calculations were made with the HOMOG program (version 3.0).16
Results
Linkage Analysis for the Marfan Syndrome
A maximal lod score of 25.6 (the Z value when the recombination fraction [θ] was 0.00) was derived from the genotyping of the 28 families with the Marfan syndrome by means of the fibrillin 15 markers (Table 1Table 1
Two-Point Lod Scores for Linkage between the Disease Loci and Fibrillin Genes on Chromosomes 15 and 5 (Fibrillin 15 and Fibrillin 5).). We did not observe any recombinants between the fibrillin 15 gene and the syndrome. Ten families were not informative for either marker (Table 2Table 2
Phenotypic Features and Individual Lod Scores of 28 Families with the Marfan Syndrome.*). The lod scores obtained for each family when θ was 0.00 are shown in Table 2. Pairwise linkage between the Marfan syndrome and the fibrillin 5 gene gave consistently negative lod scores. Four families were not informative for the fibrillin 5 gene marker.The clinical phenotype of each family with the Marfan syndrome (Table 2) reflected the presence of a particular manifestation in several affected members of the family. The clinical presentation ranged from the classic involvement of three systems in most families to primarily skeletal and cardiovascular manifestations in a group of four families (Families 24 through 27, Table 2) and musculoskeletal and ocular manifestations in one family (Family 28). It should be noted that the degree of severity of aortic disease varied greatly; aortic dissection was found in 60 percent of the families.
The Test of Admixture
Analysis of two-point lod scores for linkage between the Marfan syndrome and fibrillin 15 showed that all the families were linked with this gene (100 percent; lower 95 percent confidence limit, 80 percent). A similar type of analysis for fibrillin 5 showed that there was no linkage between this gene and the syndrome (estimated upper 95 percent confidence limit, 5 percent). These estimates reflect the small positive lod score obtained from analysis for fibrillin 5 in four families linked with fibrillin 15.
Linkage Analysis for Ectopia Lentis
Two families with ectopia lentis underwent genotyping for fibrillin 15 and fibrillin 5. The results in one family are shown in Figure 1Figure 1
Results of Genotyping for Two Fibrillin Gene Markers on Chromosome 15 in a Family with Ectopia Lentis.. The phenotype of both families was characterized by the presence of bilateral ectopia lentis and iridodonesis in all affected members without any skeletal or aortic manifestations characteristic of the Marfan syndrome. Genotyping was performed in 17 members, and a maximal lod score of 3.0 (θ = 0.00; 95 percent confidence interval, 0.00 to >0.18) was obtained with the use of fibrillin 15 (Table 1). Discordant segregation with fibrillin 5 markers was observed in one family; analysis in the other family was not informative.Linkage Analysis for Congenital Contractural Arachnodactyly
Three families with congenital contractural arachnodactyly underwent genotyping. The clinical phenotype of each family is shown in Table 3Table 3
Phenotypic Features and Individual Lod Scores in Three Families with Congenital Contractural Arachnodactyly.; Family 2 has been described previously.9 Affected members of all three families had the characteristic abnormalities of the pinnae. The flexion contractures of the small joints tended to improve with age. There was no evidence of cardiovascular involvement in any of the three families. The results of the ophthalmologic examination of the affected members of two families were normal. Sixty-three members underwent genotyping. Pairwise linkage between congenital contractural arachnodactyly and fibrillin 5 gave a maximum lod score of 6.2 (θ = 0.00; 95 percent confidence interval, 0.00 to >0.10), and no linkage with fibrillin 15 was observed in any of the three families (Table 1).Linkage Analysis for Mitral-Valve Prolapse Syndrome
The clinical phenotype of one of the two families with mitral-valve prolapse syndrome was characterized by normal height and a decreased ratio (<2 SD) of the upper to the lower body segment, echocardiographic and clinical evidence of mitral-valve prolapse, myopia, pectus deformity, and scoliosis. The phenotype of the other family was very similar, and in addition arachnodactyly was present in all affected members. Twenty-two members underwent genotyping. Analysis of both families was uninformative for the fibrillin 15 markers, and both had no evidence of linkage with the fibrillin 5 markers (Table 1).
Linkage Analysis for Annuloaortic Ectasia
The phenotype of the family with annuloaortic ectasia was characterized by aortic-root dilatation, dissecting aneurysms, and mild generalized hypermobility of the joints. Eight members from three generations underwent genotyping. No linkage was found with either the fibrillin 15 or the fibrillin 5 gene (Table 1).
Discussion
Our data show that the Marfan syndrome is genetically linked to the fibrillin gene on chromosome 15, since the maximal lod score for the families we studied (Z = 25.6 when θ = 0.00) indicates that the odds of linkage are 1025.6:1. In the same group of families we found no linkage with the fibrillin gene on chromosome 5. These data indicate that the Marfan syndrome is probably caused by mutations within or very close to the chromosome 15 fibrillin gene. Genetic-linkage analysis could therefore be used for diagnosis at the molecular level both prenatally and postnatally.
We observed marked clinical variation within and between the families we studied. It is appropriate to speculate that a variety of fibrillin 15 gene mutations will be detected among patients with the Marfan syndrome. Given the severe morbidity associated with this condition and the frequently encountered difficulty of establishing the diagnosis at an early age, a correlation between its clinical and molecular features, if established, would make the detection of a particular mutation early in life a meaningful prognostic tool.
Our findings suggest a genetic linkage between ectopia lentis and fibrillin 15. This observation suggests the cause of a rare genetic trait and also sheds light on the pleiotropy associated with the Marfan syndrome. Little is known about the folding of the fibrillin protein and its interactions with other molecules in the extracellular matrix of different tissues.10 , 11 , 17 It appears that a specific qualitative or quantitative change in fibrillin may affect primarily the morphology of the suspensory ligament of the lens but produce no other systemic manifestations characteristic of the Marfan syndrome. This situation may be similar to that involving another structural protein, Type I collagen, in which defects in two domains of the molecule have been found in patients with osteogenesis imperfecta18 and Ehlers—Danlos syndrome Type VII.19
The results of the present study expand our previous findings of genetic linkage between congenital contractural arachnodactyly and fibrillin 5, indicated by a maximal lod score of 6.2 (θ = 0.00). Congenital contractural arachnodactyly is a mild disorder whose clinical phenotype overlaps with that of the Marfan syndrome, of which it has been considered an allelic form. Our findings demonstrate that the two conditions are caused by mutations in two different but structurally related genes located on different chromosomes.
The identification of different fibrillin genes coding for at least two distinct proteins2 , 20 raises questions about the relation between the structure and function of these proteins and others found in microfibrils. Furthermore, the described causal association of two distinct, albeit phenotypically overlapping disorders with two related proteins gives credence to the concept of a family of disorders in which each is associated with a distinct gene from a gene family. With this concept in mind, we studied two other phenotypically related disorders, mitral-valve prolapse syndrome21 and annuloaortic ectasia.21 , 22 We found that the latter was not linked with either the fibrillin 15 or the fibrillin 5 gene in the family we studied and that mitral-valve prolapse was not linked with fibrillin 5. In addition to the fibrillins, a number of structural proteins have been identified in microfibrils.10 , 11 The genes coding for these proteins are appropriate candidates for the causes of some forms of mitral-valve prolapse and annuloaortic ectasia.
Supported in part by grants from the National Marfan Foundation, the Coles Family Foundation, the Wellcome Trust, the National Institutes of Health (AR-38648), the March of Dimes (1–1196), the Dr. Amy and James Elster Research Fund, and the British Heart Foundation. (This is publication no. 79 from the Brookdale Center.)
We are indebted to the families studied and their affected members for their cooperation.
Source Information
From the Department of Pediatrics, University of Connecticut Health Center, Farmington (P.T., R.D.M., M.S.); the Department of Clinical Genetics, Birmingham University, Birmingham, United Kingdom (R.D.M., M.K.); the Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York(B.L., E.V., F.R.); the Department of Cardiological Sciences, St. George's Medical School, University of London, United Kingdom (A.H.C.); Hollister Research Laboratories, University of Nebraska, Omaha (M.G.); the Department of Medicine, Cornell University Medical Center, New York (R.B.D.); the Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom (D.H., B.C.S.); the Department of Pediatrics, University of Zurich, Zurich, Switzerland (B.S.); and the Department of Human Genetics. University of Cape Town, Cape Town, South Africa (D.V.). Address reprint requests to Dr. Tsipouras at the Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06030.
* The following participants in the International Marfan Syndrome Collaborative Study contributed the information about the families studied: Peter A. Farndon, Birmingham Maternity Hospital, Birmingham, United Kingdom; Maureen Boxer, Ninewells Medical School, Dundee, United Kingdom; David J.H. Brock, Caroline Hayward, and Marion Keston, University of Edinburgh, Edinburgh, United Kingdom; Dianna M. Milewicz, University of Texas, Houston; Peter H. Byers, University of Washington, Seattle; Andrea Superti-Furga, University of Zurich, Zurich, Switzerland; Rajkumar S. Ramesar, University of Cape Town Medical School, Cape Town, South Africa; Margaret Anne Davee and David D. Weaver, Indiana University, Indianapolis; Stephen Wainer, University of Witwatersrand, Johannesburg, South Africa; and Randi Kramer-Fox, Cornell Medical Center, New York.
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