Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition

X-linked mental retardation is a common disorder that accounts for 5–10% of cases of mental retardation in males. Fragile X syndrome is the most common form resulting from a loss of expression of the FMR1 gene. On the other hand, partial duplication of the long arm of the X chromosome is uncommon. It leads to functional disomy of the corresponding genes and has been reported in several cases of mental retardation in males. In this study, we report on the clinical and genetic characterization of a new X-linked mental retardation syndrome characterized by short stature, hypogonadism and facial dysmorphism, and show that this syndrome is caused by a small Xq27.3q28 interstitial duplication encompassing the FMR1 gene. This family broadens the phenotypic spectrum of FMR1 anomalies in an unexpected manner, and we suggest that this condition may represent the fragile X syndrome «contre-type».     

A novel polymorphism in the FMR1 gene: implications for clinical testing of fragile X syndrome

Fragile X syndrome is the most common cause of inherited mental retardation among males. In most cases, the molecular basis of fragile X syndrome is the expansion and subsequent methylation of a CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. Laboratory diagnosis usually relies on a combination of Southern blot and polymerase chain reaction analyses. In this case report we describe an unusual Southern blot result in a patient who presented with developmental delay and had a normal CGG repeat number by polymerase chain reaction analysis. Further investigation revealed a novel G3310C transversion in the FMR1 gene resulting in a new recognition site for the BssHII restriction enzyme. This novel restriction site could potentially mimic a partial deletion of the FMR1 gene on Southern blot analysis and thus represents a possible pitfall in the diagnosis of fragile X syndrome.     

Twin sisters, monozygotic with the fragile X mutation, but with a different phenotype

The absence of the fragile X mental retardation protein (FMRP) results in fragile X syndrome. All males with a full mutation in the FMR1 gene and an inactive FMR1 gene are mentally retarded while 60% of the females with a full mutation are affected. Here we describe monozygotic twin sisters who both have a full mutation in their FMR1 gene, one of whom is normal while the other is affected. Using molecular and protein studies it was shown that owing to preferential X inactivation in the affected female a minority of the cells expressed the normal FMR1 gene, while in her sister most cells expressed the normal FMR1 gene. This shows that X inactivation took place in the female twins after separation of the embryos and that for a normal phenotype FMR1 expression is necessary in the majority of cells.


Keywords: fragile X syndrome; mental retardation; monozygotic twins; Lyonisation     

甲基化特异性三重PCR检测FMR1基因突变的研究

目的探讨甲基化特异性三重PCR检测FMR1基因不同突变类型的价值。方法用甲基化特异性三重PCR方法检测了99例病人的FMR1基因,并用半巢式PCR和Southern印迹杂交方法进行比较。结果用甲基化特异性三重PCR检测出70例男性正常基因型、27例女性正常基因型,1例男性全突变基因型,1例女性前突变基因型,与半巢式PCR和Southern印迹杂交方法的检测结果相符。结论甲基化特异性三重PCR能准确检测FMR1突变的不同类型,适用于对脆性X综合征的临床筛查和诊断。     

应用PCR快速筛查脆性X综合征患儿

目的应用PCR快速筛查脆性X综合征患儿。方法采用PCR和聚丙烯酰胺凝胶电泳技术,对24例不明原因智力低下患儿的脆性X基因（CGG）n重复序列进行检测。结果在24例不明原因智力低下患儿中,筛查出1例脆性X综合征患者。结沦采用PCR技术扩增脆性X基因的（CGG）n重复序列,可对脆性X综合征患者进行快速筛查。     

The fragile X syndrome.

The fragile X syndrome is characterised by mental retardation, behavioural features, and physical features, such as a long face with large protruding ears and macro-orchidism. In 1991, after identification of the fragile X mental retardation (FMR1) gene, the cytogenetic marker (a fragile site at Xq27.3) became replaced by molecular diagnosis. The fragile X syndrome was one of the first examples of a "novel" class of disorders caused by a trinucleotide repeat expansion. In the normal population, the CGG repeat varies from six to 54 units. Affected subjects have expanded CGG repeats (>200) in the first exon of the FMR1 gene (the full mutation). Phenotypically normal carriers of the fragile X syndrome have a repeat in the 43 to 200 range (the premutation). The cloning of the FMR1 gene led to the characterisation of its protein product FMRP, encouraged further clinical studies, and opened up the possibility of more accurate family studies and fragile X screening programmes.     

Understanding the molecular basis of fragile X syndrome

Fragile X syndrome, a common form of inherited mental retardation, is mainly caused by massive expansion of CGG triplet repeats located in the 5'-untranslated region of the fragile X mental retardation-1 ( FMR1 ) gene. In patients with fragile X syndrome, the expanded CGG triplet repeats are hypermethylated and the expression of the FMR1 gene is repressed, which leads to the absence of FMR1 protein (FMRP) and subsequent mental retardation. FMRP is an RNA-binding protein that shuttles between the nucleus and cytoplasm. This protein has been implicated in protein translation as it is found associated with polyribosomes and the rough endoplasmic reticulum. We discuss here the recent progress made towards understanding the molecular mechanism of CGG repeat expansion and physiological function(s) of FMRP. These studies will not only help to illuminate the molecular basis of the general class of human diseases with trinucleotide repeat expansion but also provide an avenue to understand aspects of human cognition and intelligence.     

Four sisters compound heterozygotes for the pre- and full mutation in fragile X syndrome and a complete inactivation of X-functional chromosome: implications for genetic counseling

Fragile X syndrome (FXS) is a neurodevelopmental disorder and a leading monogenic form of cognitive impairment and autism. It is the most common form of inherited mental retardation in males and a significant cause of mental retardation in females. It is caused by the instability and subsequent expansion of the CGG repeat in the promoter region of the FMR1 (fragile X mental retardation 1) gene at Xq27.3. We describe a double consanguineous family with four sisters compound heterozygotes for the full and pre-mutation CGG repeat size. The index case shows clinical features of the affected males with profound mental retardation; the other three sisters also suffer from mental retardation, ranging from mild to severe. Molecular analysis reveals very similar ranges for the CGG expansions for both chromosomes in all four sisters. The phenotypic differences observed in the index case and her sisters are the total inactivation of X premutated chromosome and the total absence of FMRP (fragile X mental retardation protein). This family case raises important issues for genetic counseling in families with consanguinity and with cases of idiopathic mental retardation.     

Fragile X syndrome is less common than previously estimated.

In 1986, a population study of school children in the city of Coventry gave an overall prevalence in males and females for fragile X syndrome of 1/952. The 29 children diagnosed as having fragile X syndrome in this study have been re-evaluated with molecular diagnostic techniques. Eighteen of the original 29 children have been found not to have the expansion of the FMR1 gene associated with fragile X syndrome. Revised prevalence figures have been calculated giving rise to an overall prevalence figure of 1/2720 (range 1/2198-1/3089). If the four children lost to follow up are also assumed not to have the fragile X syndrome, the revised prevalence figure was 1/5714 (range 1/4762-1/6349). Clinical review of boys with severe mental retardation from this and a subsidiary study show that the clinical features of head circumference greater than the 50th centile, testicular volume greater than the 50th centile, and IQ between 35 and 70 remain helpful in distinguishing boys with fragile X syndrome from those who have non-specific mental retardation.     

Fragile X syndrome

Fragile X syndrome, the most common genetic disorder associated with mental retardation is caused by an expansion of the unstable CGG repeat within the FMR1 gene. Although overgrowth is not the main hallmark of this condition, the fragile X syndrome is usually included in the differential diagnosis of children with mental retardation and excess growth. This review highlights the most recent advances in the field of fragile X research.     

Rapid antibody test for prenatal diagnosis of fragile X syndrome on amniotic fluid cells: a new appraisal.

Fragile X syndrome is caused by mutations in the FMR1 gene and is one of the most frequent forms of inherited mental retardation in males. Postnatal and prenatal diagnosis of fragile X syndrome is feasible by direct DNA analysis. A new approach to prenatal diagnosis of fragile X syndrome in amniotic fluid cells is described, using a rapid and simple antibody test on uncultured amniotic fluid cells. The test requires 1 ml of amniotic fluid and the results of this antibody test are available on the same day as the amniocentesis.     

Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers.

The 5' untranslated CGG repeat in the fragile X mental retardation-1 (FMR1) gene is expanded in families with fragile X syndrome, with more than 200 CGGs resulting in mental retardation due to the absence of the encoded fragile X mental retardation protein (FMRP). Intermediate and premutation alleles, containing between approximately 40 and 200 repeats, express grossly normal FMRP levels and such carriers are widely believed to be non-penetrant, despite continued reports of subtle cognitive/psychosocial impairment and other phenotypes. Using a highly sensitive quantification assay, we demonstrate significantly diminished FMRP levels in carriers, negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpress FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate and premutation FMR1 alleles, found in approximately 4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.     

Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus.

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical phenotype. Here we describe a prenatal diagnosis performed in a female from a fragile X family carrying a large premutation. In chorionic villus DNA of the male fetus the normal maternal CGG allele and a normal pattern on Southern blot analysis were found in combination with the FRAXAC2 and DXS297 allele of the maternal at risk haplotype. A second chorionic villus sampling was performed giving identical results on DNA analysis and, in addition, expression of FMRP was shown by immunohistochemistry. We concluded that the male fetus was not affected with the fragile X syndrome. Subsequent detailed haplotype analysis showed a complex recombination pattern resembling either gene conversion or a double crossover within a 20 kb genomic region.