Original Article
Direct Diagnosis by DNA Analysis of the Fragile X Syndrome of Mental Retardation
N Engl J Med 1991; 325:1673-1681December 12, 1991
- Abstract
- Abstract
Background.
The fragile X syndrome, the most common form of inherited mental retardation, is caused by mutations that increase the size of a specific DNA fragment of the X chromosome (in Xq27.3). Affected persons have both a full mutation and abnormal DNA methylation. Persons with a smaller increase in the size of this DNA fragment (a premutation) have little or no risk of retardation but are at high risk of having affected children or grandchildren. The passage from premutation to full-mutation status occurs only with transmission from the mother. We have devised a method of identifying carriers of these mutations by direct DNA analysis.
Method.
We studied 511 persons from 63 families with the fragile X syndrome. Mutations and abnormal methylation were detected by Southern blotting with a probe adjacent to the mutation target. Analysis of EcoRI and EagI digests of DNA distinguished clearly in a single test between the normal genotype, the premutation, and the full mutation.
Results.
DNA analysis unambiguously established the genetic status at the fragile X locus for all samples tested. This method was much more powerful and reliable than cytogenetic testing or segregation studies with closely linked polymorphic markers. The frequency of mental retardation in persons with premutations was similar to that in the general population, whereas all 103 males and 31 of 59 females with full mutations had mental retardation. About 15 percent of those with full mutations had some cells carrying only the premutation. All the mothers of affected children were carriers of either a premutation or a full mutation.
Conclusions.
Direct diagnosis by DNA analysis is now an efficient and reliable primary test for the diagnosis of the fragile X syndrome after birth, as well as for prenatal diagnosis and genetic counseling. (N Engl J Med 1991; 325:1673–81.)
Article Activity
- Article
THE fragile X syndrome is the most common cause of inherited mental retardation and one of the most frequent genetic diseases. It is estimated to cause one case of mental retardation in every 1000 to 1500 males and one case of generally milder mental handicap in every 2000 to 2500 females.1 , 2 It was initially described in 1969 by Lubs,3 and a reproducible cytogenetic test was proposed by Sutherland in 1977.4 In affected males, the syndrome is characterized by moderate-to-severe mental retardation, facial dysmorphic features, macroorchidism, and a folate-sensitive fragile site on the X chromosome, at band Xq27.3. The physical signs are neither specific nor constant and are generally more apparent after childhood.5 Thus, no early diagnosis can be made on clinical grounds alone, and cytogenetic analysis is often undertaken only after more than one boy in a family is found to be retarded. The inheritance of this syndrome is peculiar and unlike that of any other X-linked disease.6 At least 20 percent of males who are known on the basis of genealogic data to carry a fragile X mutation have no clinical or cytogenetic evidence of it; these phenotypically normal, transmitting males are here called male carriers. A high proportion of females who are carriers (35 percent) have some mental impairment, but mental retardation is very rare among the daughters of male carriers, who are obligate carriers. To account for these unique features, it has been proposed that two different types or states of mutation may exist. The first type, which has little or no clinical expression, could change to the second, disease-causing type with high frequency when it is transmitted by a woman.7 8 9 As with other severe X-linked diseases, the mutation rate was expected to be high, given the very low reproductive fitness of affected males.10 , 11
Until now, the diagnosis of the fragile X syndrome has been based on the detection of the fragile site at Xq27.3 by cytogenetic analysis, which is delicate, tedious, and not completely reliable for prenatal diagnosis.12 , 13 The cytogenetic test is least reliable in the detection of clinically normal carriers (male or female), a fact that severely limits its value in genetic counseling. Only 55 percent of females who are obligate carriers have a detectable fragile X site,10 often in a small proportion of cells. On the other hand, a false positive diagnosis is also possible, especially in females, because of a background level of fragile X positivity. Thus, persons in whom 1 to 4 percent of cells show a fragile X site posed a difficult diagnostic problem. More recently, linkage analysis with DNA markers very close to the fragile X locus has been used in conjunction with cytogenetic analysis for prenatal diagnosis and genetic counseling in families with the fragile X syndrome. But such analysis depends on the presence of a proper family structure and the availability of key family members, and it necessitates testing for many markers.14
We recently reported that a small DNA region in Xq27.3 is abnormally methylated in affected persons.15 16 17 This region is characterized by a high density of cytidine phosphate guanosine (CpG) dinucleotides and belongs to the class of regulatory sequences called CpG "islands." DNA methylation in such regions generally shuts off the expression of adjacent genes.18 Cloning of this region yielded probes that detect, in genomic DNA, both the abnormal methylation in persons expressing the mutation and the mutations in all carriers.17 The fragile X mutations consist of an increase in the size of a 200-base-pair (bp) target fragment in the CpG island.17 , 19 , 20 This increase in size, measured by the number of base pairs, is generally larger than 600 bp in persons expressing the phenotype (the full mutation) and between 100 and 500 bp in carriers. We call the latter increase a "premutation," since it precedes the appearance of the full mutation in succeeding generations. The transition from the premutation to the full mutation was found to occur frequently, but only when the mutated gene was transmitted by the mother. From the study of restriction sites that are inhibited by DNA methylation, we concluded that fragments corresponding to the full mutation are abnormally methylated in affected males and on the active X chromosome of females, whereas fragments corresponding to the premutation or the normal sequence are methylated only on the inactive X chromosome in women. We describe the use of a DNA probe that permits easy, reliable, and direct diagnosis in the carriers of fragile X mutations, regardless of sex or clinical status, and that is applicable to early prenatal diagnosis. We also evaluate the predictability of mental status on the basis of the DNA analysis.
Methods
We analyzed genomic DNA from 530 subjects: 511 members of 63 families with the fragile X syndrome (including 28 prenatal samples) and 19 unrelated normal subjects. Cytogenetic analysis of the fragile X site was performed according to standard procedures.13 The subjects' mental status was considered to be that reported by the contributing clinicians. DNA was extracted from leukocytes in most cases. Digestion of DNA by EcoRI and EagI was performed in a buffer containing 20 mM solution of magnesium chloride. Electrophoresis was performed on 0.8 percent agarose gels, with a 20-cm migration of bromophenol blue. The DNA samples were blotted onto Hybond N+ (Amersham) and hybridized in 40 percent formamide as described elsewhere.17 The blots were washed in 0.5× saline sodium citrate (SSC; 1× SSC contains 150 mM sodium chloride and 15 mM sodium citrate) and 0.1 percent sodium dodecyl sulfate at 60°C.
Artifacts such as contamination of the digested DNA samples by plasmids or incomplete digestion may generate spurious bands and lead to false conclusions. Extensive heterogeneity caused by further somatic mutation in some carriers of the full mutation may cause the fragments to appear as a smear. A high signal-to-background ratio is thus necessary and is favored by the size of probe StB12.3 and the lack of repetitive sequences in the probe. Most of these problems can be assessed by rehybridization of the blot to a control human probe (containing a plasmid vector), such as probe F33,16 which detects a clear sex-related difference in the pattern of EcoRI and EagI digests.
Results
Patterns Detected by Probe StB12.3
The mutations associated with the fragile X syndrome affect a 200-bp fragment very rich in CpG dinucleotides that are susceptible to methylation (a CpG island) (Fig. 1Figure 1
Schematic Representation of Normal and Mutated Restriction Fragments Detected by Probe StB12.3.). Probes that hybridized to DNA adjacent to this island, such as StB12.3, allow the mutations to be detected by Southern blot analysis of genomic DNA digested with a variety of restriction enzymes.17 , 19 As a compromise among these, we chose EcoRI for reliable detection of the various types of mutations described below. For optimal analysis, however, we propose the use of a double digest with both EcoRI and EagI, which allows mutations to be detected and methylation status to be determined in a single test. This method has been tested on leukocyte DNA, biopsy specimens of chorionic villi, and amniocytes.Digestion by EcoRI
The results of the digestion of DNA with EcoRI are shown in Figure 2Figure 2
Detection of Fragile X Mutations in EcoRI Digests of DNA.. StB12.3 detected a 5.2-kb EcoRI fragment in normal persons (Fig. 2, lanes 11 and 20). In mentally retarded males with the fragile X syndrome, the normal fragment was missing, and one or more bands were detected in a range from 5.7 to 8 kb or more (an increase in size of 500 to >3000 bp), corresponding to the full mutation (lanes 14 and 15). Multiple bands are often seen, because the full mutation is unstable in somatic cells. Different cells may carry fragments of different sizes. If the heterogeneity is extensive, the mutated fragments can appear as a smear17 , 19 (lane 17). In male carriers, the 5.2-kb band was replaced by a generally homogeneous fragment with an increase in size of 100 to 500 bp (a premutation; lane 5). In female carriers, the 5.2-kb fragment derived from the normal X chromosome was present together with the fragment or fragments specific for the premutation (lanes 2, 12, and 21) or the full mutation (lanes 1, 9, and 13). In about 15 percent of persons carrying a full mutation, an additional band characteristic of a premutation was detected in variable proportion (lanes 19 and 22). We have called this pattern a "mosaic," because persons bearing it have two populations of cells that differ with regard to the type of mutation.17 Double Digestion by EcoRI and EagI
We have analyzed the families with the fragile X syndrome by double DNA digestion with EcoRI and EagI, a process that reveals both the presence of the mutation and the methylation status (EagI is unable to cut the DNA if its CpG-rich restriction site is methylated). The results are shown in Figure 3Figure 3
Detection of Fragile X Mutations and Methylation Patterns in DNA Digested by EcoRI and EagI.. In the double digest, StB12.3 hybridized in all normal persons to a 2.8-kb EcoRI—EagI fragment corresponding to the active X chromosome (Fig. 3, lanes 2, 4, 5, and 14); in the females it also hybridized to an additional 5.2-kb EcoRI fragment corresponding to the inactive (methylated) X chromosome (lanes 1, 7, 18, and 27). The 2.8-kb fragment was absent in males with a fragile X mutation, whereas female carriers had both the normal fragments (2.8 and 5.2 kb) and mutated ones. Premutations were detected as EcoRI—EagI fragments of 2.9 to about 3.3 kb in males (lane 3) and were found on the active X chromosome in females (lanes 8, 24, 26, and the like), whereas the 5.3-to-5.7-kb EcoRI fragments corresponded to the premutation on the inactive X chromosome. The fragments corresponding to full mutations were not digested by EagI and thus appeared as single or heterogeneous bands above 5.7 kb (lanes 10, 12, 15, and the like). The cases of mosaicism appeared as a mixture of a full (methylated) mutation and an unmethylated premutation (lanes 20 and 21). These accounted for most cases of incomplete methylation previously reported in males with the fragile X syndrome.17 A few persons had a partly unmethylated, rather homogeneous band with an increase in size in the 600-to-1000-bp range. This pattern was described as "methylation mosaicism."New Insights in the Analysis of Fragile X Pedigrees
The following examples illustrate familial transmission of the mutations and show how previously ambiguous or undetermined cases were resolved with the new test (Fig. 4Figure 4
Transmission of Fragile X Mutations in Three Families.).Family A was one of several families in which cytogenetic and segregation analysis with linked DNA polymorphisms failed to determine either the parental origin of the fragile X mutation in a sporadic case or the generation in which the mutation appeared. Segregation of very close polymorphic markers revealed that the one affected boy (Subject 7) and his normal cousin had both inherited their grandfather's chromosome in the fragile X region, and the carrier Status of the aunt (Subject 5) was uncertain. Direct DNA analysis revealed that the grandmother was normal and that the grandfather was a carrier. Their two daughters were unaffected carriers of the premutation, as was the normal cousin (Subject 8), with a 400-bp increase in the size of the target fragment —much smaller than the 1800-bp increase observed in the affected boy, but larger than that in his mother (Subject 5).
Family B had been thoroughly and unsuccessfully investigated with linked restriction-fragmentlength polymorphisms (RFLPs) in order to establish the status of a woman with a low level of fragile-site expression (Subject 10) and that of her cousin (Subject 7), who had a mildly retarded son with no fragile site (Subject 11). A mentally retarded uncle (Subject 4) had expression of fragile X in 10 percent of cells. The direct DNA analysis confirmed that the affected uncle and the grandmother had typical fragile X mutations but established definitely that no one else in the family had inherited a mutated X chromosome. Hence, the mental retardation in Subject 11 was not related to the fragile X syndrome. Previously, the finding of even low levels of cells bearing the fragile X mutation in a female relative of a patient with the syndrome would have indicated a high probability that she was a carrier.
The case of Family C demonstrates how various patterns of mutation can be found in the same generation and can account for different clinical expressions. The premutation was brought into the family by a male carrier (Subject 1, with a 200-bp increase in the size of the target fragment) who transmitted it with little change to his four daughters, who did not express the mutation clinically. In the third generation, the two proband brothers (Subjects 5 and 7) each had an increase in the size of the target fragment of 1300 to 1400 bp. Their two cousin sibships were also analyzed. Among the children of Subject 9 we found one normal male (Subject 18) and a two-year-old boy carrying a premutation (Subject 19), and prenatal diagnosis revealed a normal pattern in a female fetus (designated as Subject 20). In the other sibship, all three boys (Subjects 14, 15, and 16) carried an abnormal X chromosome, but no abnormal band was found in the cytogenetically normal male fetus (designated as Subject 17). The oldest boy (Subject 14, eight years old), who had borderline mental retardation, had difficulty in following second-grade studies. He had a very low percentage of cells with the fragile X site (3 percent) and had facial morphologic features analogous to those of his affected cousins. DNA analysis revealed that he had methylation mosaicism, because we observed heterogeneous mutated fragments with an increase in size of 700 to 900 bp; 90 percent of them were unmethylated. The boy's two mentally normal younger brothers had unmethylated premutations with increases in fragment size of 200 and 500 bp.
Retrospective Studies
Correlation of Direct DNA Diagnosis with Cytogenetic and Segregation Data
We determined the mutation and methylation status of the fragile X locus in 530 DNA samples digested with either EcoRI or EcoRI and EagI, as described above, or with BanI, as reported elsewhere17 (Table 1Table 1
Relation of the Mutation Patterns Identified by Direct DNA Analysis at the Fragile X Locus to the Results of Cytogenetic Analysis and the Occurrence of Mental Retardation.). Persons with an abnormal fragment could be classified as carrying a premutation (a small increase in size without methylation), a methylated full mutation, or a mosaic pattern. Among carriers of a mutation, 64 percent of the females but only 16 percent of the males were found to carry a premutation. This difference may be attributed to the ascertainment bias for affected males in our sample and to the large proportion of families with transmission from a male carrier (see below) whose daughters are obligate carriers of the premutation. Among carriers with a full mutation, the mosaic pattern appeared in 10 percent of females and 19 percent of males.Four hundred thirty-nine persons had already been classified as normal carriers not expressing the mutation or as mutation-expressing carriers on the basis of clinical data, cytogenetic data, or the segregation of linked RFLPs. In families in which StB12.3 detected a fragile X mutation in the index subject, we found no false positive or false negative results among the 439 persons whose status was unambiguously known (on the basis of a high level of expression of a fragile site, linkage analysis, or both).
Previous cytogenetic and linkage analysis of DNA samples from 91 subjects (including 10 samples of chorionic villi) was inconclusive. Of these 91 samples, 54 were found to be normal, 29 (including 11 from phenotypically normal males) had a small increase in fragment size, 6 had a large increase in fragment size, and 2 had a mosaic pattern. Three phenotypically normal males who had inherited the same haplotype of markers as an affected relative were found to carry the premutation. Most important, 10 females with low levels of expression of fragile sites (less than 4 percent) were in fact found to be normal (in 5 of them, linkage analysis was informative, and a normal haplotype had been found). One putative premutation (increase in fragment size, 150 bp) was found in a man with no known relative with the fragile X syndrome and in his daughter.
We analyzed retrospectively 28 samples of chorionic villi obtained during pregnancies considered to be at risk. Either a premutation or a full mutation was readily detected in all 10 samples involving fetuses previously concluded to be affected. One fragile X—negative female fetus for which segregation analysis had been inconclusive had a full mutation. It has been reported that DNA methylation of X-linked sequences in chorionic villi may differ from that of the fetus,22 and we have indeed observed incomplete methylation of the fragile X—related CpG island in chorionic villi from a normal female. However, chorionic-villus sampling showed that DNA from all normal male fetuses was unmethylated, whereas that from eight male fetuses carrying full mutations had at least partial methylation. The finding of fragments with an increase in size in the range of 500 to 700 bp could pose a problem in terms of the prediction of mental status, because the methylation pattern of the full mutation might not be completely established in these cells.
Correlation of DNA Pattern and Mental Status
Information on mental status was available for 478 subjects (Table 1). Either the remaining subjects could not be evaluated (fetuses or children less than six years old), or information on mental status was not reported. Of 198 subjects with no abnormal pattern, 1.5 percent were described as mentally retarded (although they were fragile X—negative). Some mental impairment was found in 3 percent of carriers of the premutation. This risk was comparable to that in the general population.5 , 23 In contrast, 53 percent of the female subjects carrying the full mutation had mental retardation. All the male subjects with a full mutation had at least moderate mental retardation. All three fragile X—positive male subjects with only mild mental retardation had a mosaic pattern. One of these had methylation mosaicism, with an increase in fragment size that was at the lower end of the range for a full mutation (700 to 900 bp). His mutated DNA fragments were 90 percent unmethylated (Subject 14 in Family C; Fig. 4). Within sibships, our preliminary observations suggest that male subjects with mosaicism could perform better than their siblings who had a full mutation only.
Transmission of Mutations
We studied the change in mutation patterns after transmission from different types of carrier parents (Table 2Table 2
Influence of Parental Sex and Pattern of Fragile X Mutation on the Transmission of the Mutation to Children.) and deduced general rules. Full mutation or mosaicism was not detected in 54 daughters of male carriers. Small variations in the increase in size of the fragment could be observed in those daughters, however.17 In mutation-bearing offspring of women with a premutation, we found that 83 percent of the children had a full mutation (including those with mosaicism), and 17 percent a premutation. We did not observe passage in one generation from the presence of a normal fragment to that of a full mutation or to mosaicism. Children of women with full mutations can have smaller full mutations than their mothers, but we observed only one case of regression from a full mutation to a premutation.The type of mutation (premutation or full mutation) often appeared to be homogeneous within a sibship. This clustering accords with the observation that phenotypic penetrance appears low in sibships with carrier males and high in sibships with affected males.6
For the pedigrees in which we analyzed the grandparents of the index subject, we examined whether the premutation originated in a male or a female carrier. We found 15 pedigrees in which the initial carrier was a male, and 22 in which the initial carrier was a female. In 13 of the latter pedigrees there were affected uncles, excluding the possibility that there had been a male carrier in the preceding generation.
In one family, the mother of an affected male (with an increase in fragment size of 700 bp, associated with the grandpaternal haplotype) carried a small 90-bp premutation (lanes 24 and 25 in Fig. 3). Her sister had a fragment at the upper limit of the normal range20 (increase in size, 50 bp). It is thus possible that the deceased grandfather also carried a fragment of nearly normal size; if so, it could represent the occurrence of a new mutation.
Potential Diagnostic Problems
Although our experience suggests that this direct diagnostic approach is accurate, some artifacts or difficulties of interpretation are possible. They can be overcome with the proper use of controls (see the Methods section). The existence of a polymorphism of the fragile X locus in normal subjects20 raises the problem of determining the lower cutoff point in the diagnosis of a premutation. More studies are needed to evaluate the risk for persons with an increase in fragment size of 50 to 100 bp of having children with full mutations.
Persons with a mosaic pattern (who are at high risk for mental retardation) may sometimes be mistaken for carriers of a premutation when their fully mutated fragments are very heterogeneous and the resulting smear widely spread (as in Fig. 2, lane 22). This would strongly affect the prediction of mental status in prenatal diagnosis. The use of restriction enzymes (such as BglII) that yield larger fragments than those produced by EcoRI can condense the smear and resolve the diagnosis in these rare cases (Fig. 2). Also, there is a "gray area" for increases in fragment size of 500 to 700 bp, in which the methylation pattern is compatible with a premutation in some persons and with full mutation in others. Further studies should determine whether impairment is correlated with abnormal methylation in such cases.
Absence of Abnormal Fragments in Families Thought to Have the Fragile X Syndrome
An apparent contradiction between the results of direct DNA diagnosis and the status as previously determined was found for five families excluded from the retrospective study summarized in Table 1. In these pedigrees, the presence of fragile X syndrome had been suggested on the basis of cytogenetic analysis, but we failed to find a mutation or methylation abnormality in any family member. We classified these families in two groups. One family included a mentally retarded boy once found to have a low percentage of cells with fragile sites (3 percent). When he was retested, no fragile sites were detected. Such cases may be accounted for by diagnostic overinterpretation of a background level in the cytogenetic test. A more interesting case was encountered in other families with one mentally impaired person; in these families, high levels of Xq27 fragile sites were found to be expressed in the proband and in other relatives. In one such family, a boy had fragile X expressed on 40 percent of his cells; he had mild mental retardation but no other phenotypic features typical of the fragile X syndrome. His mother and two sisters, all mentally normal, also had high levels of expression of the fragile X site (14 percent to 40 percent). Retesting of the cells from the male patient revealed that his fragile site was expressed even in folate-rich culture medium; hence, this may have been a folate-insensitive fragile site. Three similar families are under study.
These findings suggest that a different fragile site is located in the same Xq27 region that may not necessarily be linked to mental retardation. The apparent association with mental retardation in the probands could be due to the ascertainment bias resulting from testing for the fragile X site in mentally retarded persons. Thus, before DNA analysis is used in genetic counseling, an index case should always be analyzed to confirm that a typical fragile X mutation is segregating in the pedigree. This will ensure the validity of a diagnosis of noncarrier status.
Discussion
We have described a new and simple diagnostic test for the fragile X syndrome that detects with very high sensitivity and specificity the DNA anomalies associated with the disease. When no abnormality is detected in a family, we believe that this results from previous misdiagnosis or from the existence of a different neighboring fragile site that does not have the same clinical expression.
Direct DNA diagnosis may be helpful in two clinical situations: in the differential diagnosis of mental retardation and in the genetic counseling of families with the fragile X syndrome. We propose the use of a single EcoRI digestion to test systematically for a fragile X mutation in boys or girls with unexplained mental retardation, late onset of speech, or autistic or hyperactive behavior, even if there is no family history of mental retardation. This should permit the early identification of families at risk and proper genetic counseling about this disease, which is often underdiagnosed.2
When a fragile X mutation has been detected in a family, one can identify all the females who are carriers with double DNA digestion by EcoRI and EagI, the process that distinguishes best between a premutation and a full mutation. Although the testing of mentally normal boys to detect asymptomatic carriers of the defect has great scientific interest for better understanding the mode of transmission of the disease, it is not clear whether and how the results should be communicated to the parents, since only the grandchildren of those boys are at risk of being clinically affected. The ethical implications of such a diagnosis should be examined further.
This DNA test should make prenatal diagnosis reliable and widely available. The ability to discriminate between a premutation and a full mutation provides a much improved prediction of the risk of mental retardation. Our present figures indicate that among persons with a full mutation, 100 percent of males and about 50 percent of females will be mentally impaired, whereas that risk is very low (about 3 percent) in carriers of a premutation. The figure of 50 percent is in agreement with the risk of mental retardation estimated in females who have a substantial level of fragile X site expression by cytogenetic analysis.24
A more accurate prediction of mental retardation in females would probably require analyzing the proportion of cells that carry the mutation on the active X chromosome in tissues involved in the phenotype. It is unlikely that this proportion could be deduced accurately from the analysis of peripheral-blood leukocytes.25
A gene (FMR-1) was recently cloned26 that includes the (CGG)n repeat that is likely to be the target of the fragile X mutations.17 , 20 It will be interesting to test the expression of this gene in relation to the various DNA patterns observed (full mutation, premutation, and mosaicism) and to the appearance of clinical phenotypes. Complete methylation of the region would be expected to shut off the expression of this gene and could account for the great difference in mental status between persons with an unmethylated 400-bp gene fragment and those with a 600-bp methylated one. We have observed, however, that a certain number of male carriers have dysmorphic features similar to those of their affected relatives. Since the premutation is probably located in a sequence coding for protein, it may cause changes in the protein product that are quantitative, qualitative, or both. Alternatively, the complexity of the fragile X phenotype and the possibility of dissociation between mental retardation and physical signs could suggest that more than one gene is implicated. A putative diagnostic test based on analysis of the expression of the FMR-1 protein product would be unlikely to detect unaffected carriers.
The use of this test to identify all carriers of the fragile X mutation (including those not clinically affected) revealed a high proportion of phenotypically normal persons who carry a premutation (Table 2) and a large proportion of pedigrees (15 of 37) in which a premutation was introduced by a male carrier. Laird has proposed that the phenotypic expression of the fragile X syndrome depends on the transmission of the causal mutation on a previously inactive X chromosome.9 If this hypothesis is true, there should be as many carrier males as affected males among the offspring of a woman carrying a premutation.27 This can be tested by DNA analysis of complete families, including sibships that include only mentally normal persons.
In severe X-linked diseases, up to one third of the cases are due to new mutations. Even when the partial penetrance of the fragile X syndrome in males is considered, a very high mutation rate would be expected in order to account for the high frequency of the disease.10 We have not observed new mutations, however, and all the mothers of affected children were carriers of a premutation or a full mutation, a fact that has important consequences for genetic counseling. It suggests that the transition from a normal sequence to a full mutation cannot be made in one generation. Evidence for new mutations should thus be sought among the parents of persons with a premutation. This is impractical in families with the fragile X syndrome who are selected on the basis of having an affected family member, since one would have to analyze that person's grandparents and even preceding generations. One should thus search systematically for carriers of a premutation in the general population and then analyze their parents. Our finding of a probable premutation in a man with no known relative with the fragile X syndrome indicates that this approach is feasible. Such a prospective study would also allow the real prevalence of fragile X premutations to be estimated. In addition, it would be important to determine the cutoff in size between normal variations of the target fragment20 and a true premutation. Perhaps the presence of the largest among normal alleles could predispose the DNA fragment to further changes leading to premutation and full mutation.
In conclusion, the fragile X syndrome is one genetic disease for which the primary diagnosis will be based on the direct detection of mutation at the DNA level. The role of cytogenetic analysis in the diagnosis must now be reevaluated.
Supported by a grant from the Association Française contre les Myopathies, by a grant (88.C.0178) from the Ministère de la Recherche et de la Technologie, by a grant to Dr. Mandel from the Caisse Nationale de l'Assurance Maladie des Travailleurs Salariés, and by grants to Dr. Tommerup from the Danish Center for Human Genome Research and the Sigurd K. Thoresens Foundation.
We are indebted to Drs. M.F. Bertheas, E. Engel, E. Flori, P.A. Jacobs, and J.F. Mattei for contributing blood or DNA samples from families with the fragile X syndrome and information on the results of cytogenetic analysis and clinical phenotypes.
Source Information
From the Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 184, and the Laboratoire de Génétique Moléculaire des Eucaryotes of the Centre National de la Recherche Scientifique, Faculté de Médecine, Strasbourg, France (F.R., D.H., V.B., S.B., C.K., I.O., J.-L.M.); INSERM Unité 73, Paris (J.B.); the Department of Medical Genetics, Ulleval Hospital, Oslo, Norway (N.T., C.V.D.H.); the J.F. Kennedy Institute, Glostrup, Denmark (N.T.); Institut Universitaire de Génétique Médicale, Geneva, Switzerland (C.D.-B.); Hôpital St.-Antoine, Lille, France (M.-F.C.); Centre de Transfusion, Vandoeuvre-les-Nancy, France (S.G.); Centre Hospitalier Régional et Universitaire de Grenoble, Grenoble, France (P.J.); and INSERM Unité 242, Marseilles, France (M.-A.V.). Address reprint requests to Dr. Mandel at INSERM-U.184/CNRS-LGME, 11 rue Humann, 67085 Strasbourg CEDEX, France.
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