Fragile X mental retardation is characterized by moderate to severe mental retardation, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw. In most cases, the disorder is caused by the unstable expansion of a ... Fragile X mental retardation is characterized by moderate to severe mental retardation, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw. In most cases, the disorder is caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain (Devys et al., 1993). - Reviews Fragile X syndrome accounts for about one-half of cases of X-linked mental retardation and is the second most common cause of mental impairment after trisomy 21 (190685) (Rousseau et al., 1995). McCabe et al. (1999) summarized the proceedings of a workshop on the fragile X syndrome held in December 1998. Jacquemont et al. (2007) provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder.
Jacky and Dill (1980) detected the fragile X chromosome in cultured lymphocytes and fibroblasts from affected patients. Glover (1981), Tommerup et al. (1981), and Jacobs et al. (1982) demonstrated that pharmacologic inhibition of thymidylate synthetase (TYMS; 188350) was ... Jacky and Dill (1980) detected the fragile X chromosome in cultured lymphocytes and fibroblasts from affected patients. Glover (1981), Tommerup et al. (1981), and Jacobs et al. (1982) demonstrated that pharmacologic inhibition of thymidylate synthetase (TYMS; 188350) was effective in inducing the fragile X marker in cell cultures. Snyder et al. (1984) showed that culture conditions that promote expression of the fragile X site do not affect expression of lymphocyte HPRT but do cause a marked reduction in G6PD activity. Sutherland (1989) indicated that there is a fragile site (FRAXD) located at Xq27.2, separate from the classic FRAXA site at Xq27.3 which is responsible for mental retardation. The FRAXD is inducible by high doses of aphidicolin. Ramos et al. (1992) concluded that the fragile site at Xq27.2 can be demonstrated in normal persons under the conditions of thymidylate stress routinely used for cytogenetic diagnosis of the fragile X syndrome. Furthermore, this fragile site is present at low levels (1-2%) in all persons who express it and, therefore, its expression is unlikely to cause false-positive diagnoses of the syndrome. Lesions at Xq26 are also seen at low levels in lymphocytes of persons without the syndrome. Griffiths and Strachan (1991) described a technique, based on a culture system reported by Wheater and Roberts (1987), that enabled the cytogeneticist to do fra(X) screening and prometaphase banding on the same specimen. Using restriction enzymes, Oberle et al. (1991) detected abnormally large-sized fragments and abnormal methylation around the fragile X site in affected males and carrier females. Some affected males appeared to be mosaics, with coexistence of a large methylated fragment and a smaller normal unmethylated fragment. Rare apparent false negatives were considered to be the result of genetic heterogeneity or misdiagnosis. Rousseau et al. (1991) concluded that direct DNA diagnosis of the fragile X syndrome is efficient and reliable. Southern analysis of EcoRI and EagI digests of DNA distinguished clearly in a single test between the normal genotype, the premutation, and the full mutation. All 103 affected males and 31 of 59 females with full mutations had mental retardation. Fifteen percent of those with full mutations had some cells carrying only the premutation. All of the mothers of affected children were carriers of either a premutation or a full mutation. Because of the certainty of DNA diagnosis, this method replaced cytogenetic detection of the fragile X chromosome, which carries a rate of misdiagnosis of about 5% for both false positives and the more frequent false negative conclusion, and diagnosis by the linkage principle, which gives a probabilistic result rather than an absolute one. Jacobs (1991), however, stated that the cytogenetic marker still had an honorable role to play in the diagnosis of fragile X syndrome. It was reliable for virtually all males and for the majority of affected females and was the most efficient and cost effective methodology at that time. Mandel et al. (1992) reported on the Fifth International Workshop on the Fragile X and X-Linked Mental Retardation held near Strasbourg, France, in August 1991. In addition to their summary, over 50 papers on the fragile X syndrome and 18 papers related to other X-linked mental retardation syndromes presented at the conference were published in the American Journal of Medical Genetics. Mandel et al. (1992) reviewed the hypothesis of Patricia Jacobs which postulated 3 mutations: a change from a normal insert (N) to a small insert that is at low risk of converting to a large insert (S); a change from that type of small insert to a small insert at high risk of converting to a large insert (S*); and a change from the high risk small insert to a large insert (L) which is associated with clinical abnormality. Cytogenetic screening of the mentally handicapped for the fra(X) was equivalent to testing for individuals with a large insert (L) as there was no evidence that a small insert (S) has a deleterious effect on the phenotype. The consensus was that in diagnostic laboratories cytogenetics is still the method of choice, with subsequent molecular investigation of those patients found or suspected of being fra(X) positive; no consensus was reached on the relative merits of cytogenetics and molecular techniques for screening. Mulley et al. (1992) reported a high success rate with the direct molecular diagnosis of fragile X using the pfxa3 probe which detects amplification of an unstable DNA element consisting of variable length CCG repeats. Snow et al. (1993) found that PCR followed by DNA sequencing of the FMR1 gene allowed the most accurate determination of CGG repeat numbers up to approximately 130 repeats. Turner et al. (1996) suggested that the clinical definition of fragile X syndrome be redefined in males as a mental handicap associated with absolute or relative deficiency of the FMR1 protein. In the absence of a readily available protein test, analysis of the trinucleotide repeat size has been used for diagnosis. An increase in the size of the trinucleotide repeat over a particular value initiates methylation of the FMR gene promoter site and suppression of FMR1 gene transcription. Testing can identify individuals who lack FMR1 protein as a consequence of deletion of the gene but will not identify those individuals whose FMR1 protein is defective through mutation. Willemsen et al. (1995, 1997) developed a diagnostic method using mouse monoclonal antibodies against the FMR1 protein that allowed for detection of the fragile X syndrome in a blood smear. This noninvasive test required only 1 or 2 drops of blood and could be used to screen large groups of mentally retarded persons and neonates. Willemsen et al. (1999) modified the antibody test for application to hair roots. Mentally retarded female patients with a full mutation showed FMR protein expression in only some of their hair roots (less than 55%), and no overlap with normal female controls was observed. Storm et al. (1998) noted that incomplete EcoRI digestion may lead to false diagnosis of fragile X syndrome and suggested that HindIII digest be used instead of EcoRI to identify premutation vs normal fragment length in genomic DNA. Abrams et al. (1999) examined olfactory neuroblasts from 2 mentally retarded, autistic brothers with fragile X expansion mutations in leukocytes. Olfactory neurons were chosen for study because they are accessible neurons that undergo regeneration and are closely linked to the brain. In both subjects, the genotype in neuroblasts was highly, but not perfectly, consistent with that observed in leukocytes. The results suggested that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain and demonstrated the feasibility of using olfactory neuron samples to evaluate FMR1 mutations in humans in vivo. Stoll (2001) presented 11 children under the age of 8 years and noted the difficulties in diagnosis of fragile X syndrome at this age. The author emphasized the importance of fragile X DNA testing in all children with mental retardation, autism, or significant developmental delay without a clear etiology. MacKenzie et al. (2006) reported a 46-year-old male patient with a typical fragile X syndrome phenotype who was found to be a somatic mosaic for the FMR1 repeat expansion. Analysis of peripheral blood detected a premutation allele of 58 CGG repeats, whereas skin fibroblasts yielded a full mutation allele of 500 CGG repeats. The authors suggested that the proband may have inherited a full mutation that has undergone selective contraction, given his age at molecular diagnosis. MacKenzie et al. (2006) concluded that testing of ectodermally derived tissues may provide improved diagnosis for fragile X syndrome. Coffee et al. (2009) reported the development of an assay for newborn screening of fragile X syndrome. The assay showed 100% specificity and 100% sensitivity for detecting FMR1 methylation on dried blood spots, thus successfully distinguishing normal males from those with the full mutation. The assay could also detect excess FMR1 methylation in 82% of females with full mutations, although the methylation status did not correlate with intellectual disability. With amelogenin PCR used for detecting the presence of a Y chromosome, this assay also detected males with Klinefelter syndrome (47,XXY). Among 64 males with FMR1 methylation, 7 were found to have full-mutation fragile X syndrome and 57 had Klinefelter syndrome. In their study of 36,124 newborn males, Coffee et al. (2009) estimated the incidence of fragile X syndrome to be 1 in 5,161 newborn males, and that of Klinefelter syndrome to be 1 in 633. - Carrier Females Toledano-Alhadef et al. (2001) tested 14,334 Israeli women of childbearing age for fragile X carrier status between 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. They identified 207 carriers of an allele with more than 50 repeats, representing a prevalence of 1:69. There were 127 carriers with more than 54 repeats, representing a prevalence of 1:113. Three asymptomatic women carried the full-mutation allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. The authors recommended wide-scale screening to identify female carriers. In 34 female full mutation carriers and unaffected female control relatives, Willemsen et al. (2003) found a correlation between cognitive function and the percentage of hair roots that expressed the FMRP protein. Cognitive function in the female carriers was much more strongly determined by the absence of FMRP than by genetic background. Angkustsiri et al. (2008) described a 23-year-old woman with the full fragile X mutation who had no dysmorphic features and above-average intelligence combined with significant impairments due to anxiety and learning disability. Her brother had fragile X syndrome, her mother was a premutation carrier, and her maternal grandfather was the first patient diagnosed with the fragile X tremor/ataxia syndrome (FXTAS; 300623 and Hagerman et al., 2001). Angkustsiri et al. (2008) concluded that women with fragile X syndrome can present primarily with learning and emotional problems and that clinicians should consider the diagnosis in these women regardless of their IQ, particularly if there are physical features or a family history consistent with fragile X syndrome. - Prenatal Diagnosis Jenkins et al. (1982) detected the fragile X marker in cultured amniocytes, enabling successful prenatal diagnosis. Jenkins et al. (1984) described prenatal diagnosis of 3 cases of fragile X syndrome based on cytogenetic analysis of cultured amniocytes. The testes of 2 positive fetuses appeared large for gestational age. Sutherland et al. (1991) reported prenatal diagnosis of fragile X syndrome in a male fetus using direct analysis of an unstable sequence in DNA obtained by chorionic villus sampling. They used a probe referred to as pfxa3 to detect an abnormal 2.3-kb band in the fetus. Normal carrier males usually have a fragile X band that is between 1.1 and 1.6 kb. Yamauchi et al. (1993) used the diagnostic DNA probe pPCRfx1 to confirm that an at-risk fetus was a heterozygous female carrier. Dreesen et al. (1995) approached preimplantation testing for the fragile X syndrome by genotyping the polymorphic DXS548 AC-repeat locus, which is closely linked to the FMR1 gene, in unfertilized oocytes and extruded polar bodies. They concluded that a PCR procedure could be performed within 16 hours after blastomere biopsy and that for carrier females heterozygous at the DXS548 locus, preimplantation testing with DXS548 is a possible alternative to prenatal testing.
Lubs (1969) reported a family in which 4 males spanning 3 generations had mental retardation. Cytogenetic studies showed an unusual constriction of the long arm of the X chromosome in 10 to 33% of cells. In a follow-up ... Lubs (1969) reported a family in which 4 males spanning 3 generations had mental retardation. Cytogenetic studies showed an unusual constriction of the long arm of the X chromosome in 10 to 33% of cells. In a follow-up report of the same family, Lubs et al. (1984) noted that affected individuals had large testes, low-set large ears, and asymmetric facial features with prominent angle of the jaw. Cantu et al. (1976) reported 4 male sibs with congenital bilateral macroorchidism and severe mental retardation. Detailed endocrinologic evaluation, including sperm analysis, indicated normal testicular function. Mattei et al. (1981) reported 20 patients from 15 unrelated families with fragile X syndrome. In all 19 affected male and 1 affected female proband, the fragile X site was detected in 10-61% of lymphocyte or fibroblast cells; there seemed to be no correlation between the frequency of the fragile site and clinical severity. Three sisters of probands were mildly affected, but carrier females were unaffected. Affected male individuals showed characteristic facies, including long face, high forehead, midface hypoplasia, large mouth with long upper middle incisors, thick lips, high-arched palate, large jaw with prominent chin, and large, poorly formed ears. None of 14 prepubertal males showed macroorchidism. Mental retardation was very variable, but language development was usually very delayed. Motor development was often delayed. Most showed unusual behavior, with alternating anxiety and hilarity, disordered hyperactivity, and aggressiveness. Lubs et al. (1984) reported a large African American kindred in which 10 males had mental retardation and macroorchidism associated with the abnormal X chromosome marker. Other variable clinical features included asymmetric facies and large hands. Six females were similarly affected. Meryash et al. (1984) studied 18 affected males, aged 18 to 69 years. Of 15 subjects, 13 had macroorchidism. Average height was less than published standards. Of the 18 subjects, 17 had absolute or relative macrocephaly and 12 were dolichocephalic. Jacobs (1982) encountered a man and Daker et al. (1981) reported 2 brothers with marXq28 and average intelligence. Similarly, Fryns and Van Den Berghe (1982) presented a kindred in which the fragile X chromosome was transmitted by at least 3 normal males. These men died at ages 68, 72, and 76 years and had a normal phenotype with normal intelligence; one was an administrator and 2 were officers. Voelckel et al. (1988) reported 3 brothers with the fragile X; only 2 were mentally retarded. Johnson et al. (1991) described a large kindred with 10 mentally retarded, fragile X-positive males, and 2 normal transmitting males. Pellissier et al. (1991) also described a kindred with 2 normal transmitter brothers. Loesch and Hay (1988) presented the clinical findings on 113 fragile X female heterozygotes from 44 families. In 85% of a subsample of 92 adult females, the nonverbal IQ score was 85 or less. Verbal ability deficits were much less common. Typical facial characteristics, irregular teeth, and hypermobility of finger joints occurred in approximately 40% of adult females, but facial abnormalities were less common in children. Although the frequency of miscarriages was increased, a moderate increase in the number of children was found in female carriers with borderline intellectual impairment. The question of whether ovarian size is increased in females with the fragile X was addressed by Goodman et al. (1987). A Prader-Willi-like subphenotype of the fragile X syndrome was described by de Vries et al. (1993). Clinical features included extreme obesity with a full, round face, small, broad hands and feet, and regional skin hyperpigmentation. Unlike the Prader-Willi syndrome (176270), the patients lacked the neonatal hypotonia and feeding problems during infancy followed by hyperphagia during toddlerhood. In a group of 26 patients with suspected Prader-Willi syndrome but without detectable molecular abnormalities of chromosome 15, one fragile X patient was found. General overgrowth was described in 4 fragile X patients, all of whom came from families with other affected relatives who showed the classic Martin-Bell phenotype (de Vries et al., 1995). Schrander-Stumpel et al. (1994) found the FMR1 mutation in a 3-year-old boy with unexplained extreme obesity and delayed motor and speech development. They compared the clinical features with those in 9 reported patients with the fragile X syndrome and extreme obesity. They suggested that behavioral characteristics such as hyperkinesis, autistic-like behavior, and apparent speech and language deficits may help point toward the diagnosis of the fragile X syndrome. Limprasert et al. (2000) described unilateral macroorchidism in a boy with fragile X syndrome and discussed the possible explanations. Backes et al. (2000) evaluated a group of boys with fragile X syndrome, ascertained by molecular genetic methods, to determine a cognitive and behavioral profile. The cognitive phenotype revealed a general intelligence corresponding to mild to moderately severe mental retardation. Psychiatric comorbidity was high, and attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, enuresis, and encopresis predominated. No significant correlation between the specific features of the phenotype and genotype were found.
The repeat involved in the fragile X syndrome is variously referred to here as (CGG)n or (CCG)n. The identical repeat found in the cloned FRAXE gene (309548) was referred to ... - Nomenclature of Expanded Trinucleotide Repeats The repeat involved in the fragile X syndrome is variously referred to here as (CGG)n or (CCG)n. The identical repeat found in the cloned FRAXE gene (309548) was referred to as (GCC)n by Knight et al. (1993). There are only 10 different trinucleotide repeats, but each can be written in a number of ways. Sutherland (1993) favored the convention that lists the motif in alphabetical order in the 5-prime to 3-prime direction. Consistent with this, he uses the (CCG)n designation. He preferred, furthermore, the designation (AGC)n for the other clinically significant dinucleotide repeat found in myotonic dystrophy (DM1; 160900), Huntington disease (143100), Kennedy disease (SMAX1; 313200), and SCA1 (164400); (CAG)n is the designation most often used. Sutherland (1993) suggested that the same convention can apply to dinucleotides. He wrote: 'It must be very confusing for newcomers to the literature to find (AC)n, (CA)n, (GT)n, and (TG)n repeats, when the cognoscenti know these are synonyms.' - Fragile X Syndrome Kremer et al. (1991) demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CGG)n (309550.0004), in the FMR1 gene is the basis of fragile X syndrome. The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. Pieretti et al. (1991) found absence of FMR1 mRNA in lymphoblastoid cell lines and leukocytes derived from patients with fragile X syndrome, whereas it was normally expressed in normal controls and carriers. Devys et al. (1992) noted that there are 2 main types of mutations involved in fragile X syndrome. Premutations, which do not cause mental retardation, are characterized by an elongation of 70 to 500 bp with little or no somatic heterogeneity and without abnormal methylation. Full mutations are associated with high risk of mental retardation and consist of a 600 bp or more amplification, often with extensive somatic heterogeneity and abnormal DNA methylation. De Boulle et al. (1993) identified a missense mutation in the FMR1 gene (I304N; 309550.0001) in a patient with a severe form of fragile X mental retardation, confirming that abnormality of the FMR1 gene underlies fragile X syndrome. Russo et al. (1998) described a female with borderline cognitive impairment who was compound heterozygous for a full FMR1 mutation and a premutation. The parents came from the same small village in Italy. The proband's mother and aunt reported that they had undergone premature ovarian failure at 35 years of age. Mila et al. (1996) reported a compound heterozygous Spanish female. Linden et al. (1999) reported a 15-year-old girl with fragile X syndrome who was compound heterozygous for a full expansion (363 repeats) and a premutation (103 repeats) in the FMR1 gene. Both parents carried premutations (98 repeats in the father, 146 repeats in the mother). Cognitively, this woman was functioning in the mid range of involvement for fragile X females. She attended regular classes and received supplemental assistance for her learning disabilities. She experienced behavioral characteristics typical of females with fragile X syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She responded well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attention problems, and educational therapy. Gronskov et al. (2011) identified a truncating mutation in the FMR1 gene (S27X; 309550.0005) in a man with classic features of fragile X syndrome. He had mental retardation, early-onset seizures, poor language development, and autistic tendencies. Dysmorphic features included an elongated face, high and broad forehead, low-set large ears, prognathia, and enlarged testes. Neurologic examination showed hypotonia and hypermobility, with hyperextensible joints. Western blot analysis of patient lymphoblastoid cells showed no FMRP protein expression. His mother, who also carried the mutation, had mild to moderate intellectual disability, hypermotor behavior, and automatisms. Gronskov et al. (2011) noted that the frequency of point mutations in the FMR1 gene is unknown, since most screening techniques look for the expanded repeat. - Reviews D'Hulst and Kooy (2009) provided a review of fragile X syndrome, with a focus on molecular genetics.
Jacobs (1982) indicated that a reasonable estimate of frequency of fragile X syndrome is 0.5 per 1,000 males. Although many of the cases first ascertained were of northern European descent, affected males have since been found in most ... Jacobs (1982) indicated that a reasonable estimate of frequency of fragile X syndrome is 0.5 per 1,000 males. Although many of the cases first ascertained were of northern European descent, affected males have since been found in most ethnic groups. In Sweden, Blomquist et al. (1982) found that 6 of 96 Swedish boys with IQ less than 50 born between 1959 and 1970 had fraXq28. Blomquist et al. (1985) found the fragile X in 13 (16%) of 83 boys but none of 129 girls with infantile autism. Webb et al. (1986) performed a population study of school children in the city of Coventry, England, and, using cytogenetic studies, gave an overall prevalence for fragile X syndrome in males and females of 1:952. Morton et al. (1997) reevaluated the 29 children diagnosed with fragile X syndrome by Webb et al. (1986) and confirmed the presence of the FMR1 gene expansion in only 7 of the children, giving a revised prevalence of 1:2,720 to 1:5,714, depending on whether the 4 children lost to follow-up are included. On the basis of molecular genetic analysis, Turner et al. (1996) reported that a prevalence of 1:4,000 or 2.4:10,000 was more realistic than the 1:1,000 reported by Webb et al. (1986). Filippi et al. (1991) reported findings in a very large Sardinian kindred spanning 6 generations and including 13 patients with Martin-Bell syndrome, several instances of normal transmitting males or females, and the G6PD Mediterranean (305900.0006) mutant segregating in some of its branches. All the fragile X patients and the 15 obligate heterozygous women could be traced through their X-chromosome lineage to a woman in the first generation who must have been heterozygous for a silent premutation at the fragile X locus. Filippi et al. (1991) concluded that this premutation had been converted into a full mutation at least 9 times during the gametogenesis of this ancestor's X-related descendants, of whom 4 were males. Morton and Macpherson (1992) proposed a model in which the fragile X mutation is postulated to occur as a multistep process. This attractive model provides a framework in which the seemingly contradictory observations of a mutation old enough to establish a founder effect and an apparently high new mutation rate are united. Morton and Macpherson (1992) suggested that 4 types of alleles occur in the fragile X syndrome (see table in the review by Chakravarti, 1992). The 4 types of alleles were as follows: N = normal, with a frequency of 0.9751; S = stable insert with a frequency of 0.0225 and a mean age of about 90 generations; Z = unstable insert with a frequency of 0.0014 and a mean age of 2 generations; and L = mutation with a frequency of 0.0010 and a mean age of 1.4 generations. Thus myotonic dystrophy (DM1; 160900) and fragile X appear to share both the phenomenon of anticipation and the phenomenon of founder effect. Richards and Sutherland (1992) referred to the amplification mutation involving (CCG)n in the fragile X syndrome and the trinucleotide repeats in myotonic dystrophy and Kennedy disease as 'dynamic mutations.' In studies using 2 polymorphic CA repeats located close to the 'mutation target' for the fragile X syndrome, Oudet et al. (1993) observed significant differences in allelic and haplotypic distributions between normal and fragile X chromosomes, indicating that a limited number of primary events may have been at the origin of most present-day fragile X chromosomes in Caucasian populations. They proposed a putative scheme with 6 founder chromosomes from which most of the observed fragile X-linked haplotypes can be derived directly or by a single event at one of the marker loci. Such founder chromosomes may have carried a number of CGG repeats in an upper-normal range, from which recurrent multistep expansion mutations have arisen. The diversity of haplotypes at the fragile X locus may reflect genetic heterogeneity but may also be explained by mutations in the markers themselves. Richards et al. (1992) presented haplotype evidence for a founder effect in the fragile X mutation. They found clear evidence of linkage disequilibrium between fragile X and 2 polymorphic microsatellite markers that flank FMR1 and are within 10 kb of the (CCG)n repeat. These markers have 5 to 7 alleles, show no recombination with each other, and define 15 haplotypes. In an analysis of 134 fragile X chromosomes from unrelated affected individuals in Australia and the United States, they found that 58% of the fragile X mutations occurred on the 3 backgrounds that account for 18% of normal chromosomes. Correspondingly, the single most common normal haplotype, which has a frequency of 50%, carries only 18% of fragile X mutations. The data argued for the expected occurrence of multiple, independent mutations, but also indicated the unexpectedly long history of some of these fragile X mutations. Using the FRAXAC1 polymorphic marker in the study of a large number of patients, Hirst et al. (1993) found its allele distribution to be strikingly different on fragile X chromosomes, confirming earlier observations and giving further support to the suggestion of a fragile X founder effect (Richards et al., 1992). Haataja et al. (1994) presented evidence for a founder effect of fragile X syndrome in Finland arising from a common ancestor in the 16th century. In a study of 122 Israeli families affected with the fragile X syndrome diagnosed in 7 genetic centers, Dar et al. (1995) found that Tunisian Jews, who comprise only 4% of the general population, accounted for 21% of the fragile X families, suggesting founder effect. Rousseau et al. (1995) reported a population frequency of 1 in 259 for female carriers of an allele of more than 54 repeats. The CGG repeat, which is normally polymorphic in length, is frequently interrupted by AGG triplets, which are believed to stabilize the repeat. The absence of AGG triplets, leading to long tracts of perfect CGG repeats, may give rise to predisposed alleles. Kunst et al. (1996) determined the repeat length of 345 chromosomes from 9 populations from various parts of the world and used automated DNA sequencing to assess 14 of them. They found that the FMR1 alleles were very heterogeneous, although the level of variation correlated with the age and/or genetic history of a particular population. Native American alleles, interrupted by 3 AGG repeats, exhibited marked stability over 7,000 years. However, in older African populations, parsimony analysis predicted the occasional loss of an AGG, leading to more perfect CGG repeats. Studies of (CGG)n repeat structures of selected human populations showed a high degree of conservation of the canonical (CGG)9AGG interruption pattern in different populations and confirmed the proposed stabilizing effect of AGG interruptions (Eichler and Nelson, 1996). In the native population of Greenland, Larsen et al. (1999) found a narrow distribution of (CGG)n allele sizes, similar to that reported for Asian populations. DNA sequencing of alleles with 36 CGG repeats revealed an AGG(CGG)6 insertion previously reported exclusively in Asian populations and a high frequency of 2 other sequence patterns. The data confirmed the Asian origin of the Greenlandic (Eskimo) population and indicated that some (CGG)n alleles have remained stable for 15,000 to 30,000 years, since the population of the New World arrived from Asia via the Bering Strait. The findings added new evidence for the 'out of Asia' theory of the colonization of the New World (Cavalli-Sforza et al., 1994). Studies in Native Americans (Amerinds) had not shown the (CGG)6AGG insertion. This may be due to the relatively small sample sizes in these studies, but may also be caused either by a later migration of the Eskimo population compared with the Amerind and the Na-dene populations (as proposed in the '3 migrations theory' Greenberg et al., 1986 or by genetic bottlenecks during the population of the New World (Wallace and Torroni, 1992)). Goldman et al. (1997) reported that the prevalence of FRAXA syndrome among institutionalized South African blacks was similar to that reported in the literature for institutionalized white populations. Crawford et al. (1999) found that the prevalence of the FRAXA full mutation in African American males was approximately the same as that in Caucasian American males. Beresford et al. (2000) reported molecular analysis of 177 males with mental handicap and 1,226 random alleles from Guthrie newborn screening samples in Nova Scotia. No FMR1 premutations or mutations were found. Beresford et al. (2000) also noted that only 1 case of fragile X had been reported in this region since 1980, in an individual who had moved from elsewhere in Canada. Beresford et al. (2000) concluded that the fragile X syndrome was rare in Nova Scotia, a phenomenon they found remarkable given the high prevalence of other rare heritable disorders in the region and that the population has tens of thousands of founders from multiple founding groups. Larsen et al. (2001) analyzed the AGG interspersion pattern of the (CGG)n repeat and the haplotype distribution of 2 closely located microsatellite markers in 3 circumarctic populations: Norwegians, Saami, and Nenets. The data indicated the existence of chromosomes of Asian origin in the Saami and Nenets populations. Haplotype analysis of Norwegian fragile X males compared to other populations showed that the fragile X founder haplotypes may vary between populations and that the CGG expansion associated with fragile X syndrome may originate from subpopulations of unstable alleles within the normal population. Several population-based studies in Caucasians of mostly northern European descent established that the prevalence of the fragile X syndrome is probably between 1 in 6,000 and 1 in 4,000 males. Crawford et al. (2002) presented the final results of a 4-year study in the metropolitan area of Atlanta, Georgia, establishing the prevalence of the fragile X syndrome and the frequency of CGG repeat variants in a large Caucasian and African American population. They found that one-quarter to one-third of the children identified with the fragile X syndrome attending Atlanta public schools were not diagnosed before the age of 10 years. Also, a revised prevalence for the syndrome revealed a higher point estimate for African American males (1/2,545; 95% CI 1/5,208-1/1,289) than reported previously, although confidence intervals included the prevalence estimated for Caucasians from this and other studies (1/3,717; 95% CI 1/7,692-1/1,869). Mingroni-Netto et al. (2002) studied the distribution of CGG repeats and DXS548/FRAXAC1 haplotypes in normal South American populations of different ethnic backgrounds. They found that some rare alleles that seem nearly absent in Europe occurred in higher frequencies among African Brazilians, which suggested a general trend for higher genetic diversity among Africans. Thus, the rarer alleles could be African in origin and would have been lost or possibly not present in the groups that gave rise to Europeans. Dombrowski et al. (2002) screened 10,572 independent French Canadian males for premutation-size FMR1 alleles and identified 13 who carried alleles of more than 54 repeats, which corresponded to a population frequency of 1 in 813. Haplotype analysis of the 13 identified male carriers revealed that the prevalence of the major fragile X mutation-associated haplotype was increased among FMR1 alleles of 40 to 54 repeats. Although sequencing of highly unstable premutation alleles from fragile X families revealed only pure CGG tracts, 48 of 49 males from the general population with 40 or more triplets had 1 to 2 AGG interruptions. This suggests that the loss of an AGG interruption in the triplet repeat array may not be necessary for expansion of normal alleles of 29 to 30 triplets to intermediate size. The authors concluded that loss of AGG interruptions appears to be a late event that may lead to greatly increased instability and may be related to the haplotype background of specific FMR1 alleles. Biancalana et al. (2004) reported the molecular diagnosis of fragile X syndrome in France during the 5-year period from 1997 to 2001: 477 families were diagnosed with fragile X syndrome, representing 2.8% of tested male probands and 1% of tested female probands.