Reverse mutation in fragile X syndrome

Journal of Medical Genetics, 1992

The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat. Two main types of mutation have been categorised. Clinical expression is associated with the presence of the full mutation, while subjects who carry only a premutation do not have mental retardation. Premutations have a high risk of transition to full mutation when transmitted by a female. We have used direct detection of the mutations to characterise large families who illustrate the wide variation in penetrance which has been observed in different sibships (a feature often called the Sherman paradox). A family originally found to show tight genetic linkage between the factor 9 gene and the fragile X locus was reanalysed, confirming the original genotype assignments and the observed linkage. The size of premutations was measured by Southern blotting and by using a PCR based test in 102 carrier mothers and this was correlated with the type of mutation found in their offspring. The risk of transition to full mutation was found to be very low for premutations with a size increase (A) of about 100 bp, increasing up to 100% when the size of premutation was larger than about 200 bp, even after taking into account (at least partially) ascertainment bias. These results confirm and extend those reported by Fu etal(1991) and Yu ct a) (1992) and explain the Sherman paradox. The low risk of transition to full mutation of small premutations leads to the prediction that carriers of such alleles may be more frequent in the population than was previously expected for fragile X carriers, and we have indeed observed a premutation in a man with no a priori risk. Possible mechanisms that could account for the sex biased expansion of the CGG repeat are discussed in relation to the absence of such bias in expansion at the myotonic dystrophy locus. (J Med Genet 1992;29:794-801) The fragile X syndrome is the most common inherited cause of mental retardation.' Segregation studies have previously shown the unique characteristics of its mode of inheritance.2 It was estimated that 20% of males carrying the mutation have no phenotypic expression; these were called normal transmitting males. Among carrier females, 55% were found to express the fragile site, and one third to have mental impairment in addition. However, daughters of normal transmitting males appeared to have little or no phenotypic expression. Even more curious was the observation that penetrance was low (-18%) in brothers of NTMs, and high (> 80%) in brothers of affected males, a phenomenon often called the Sherman paradox. This led to a clustering of NTMs in certain sibships and of affected patients in others, even within the same family. It has recently been shown that the fragile X mental retardation syndrome is caused by elongation of a small target DNA fragment, containing a repeat of the trinucleotide CGG -5 located in a 5' exon of the FMR-1 gene6 in Xq27.3. We have proposed that mutations can be classified as two main types, according to the size of the elongation (A), its stability in somatic cells, and the methylation status of nearby restriction sites.37 Premutations are characterised by an elongation of 70 to about 500 bp, show little or no somatic heterogeneity, and the nearby restriction sites are not methylated in males or on the active X chromosomes of females (but are methylated on the inactive X chromosome). Premutations do not appear to cause mental retardation, and their carriers show very low or absent expression of the fragile site.7 They are typically found in normal transmitting males and in their daughters (although some daughters of a carrier female may also have a premutation). The full fragile X mutation is characterised by an elongation (A) of more than 600 to 700 bp, often shows important somatic heterogeneity, and nearby sites are methylated on both active and inactive X chromosomes.

Human Molecular Genetics, 1997

In the fragile X syndrome, the transition from unmethylated moderate expansions of the CGG repeat (premutations) to methylated large expansions (full mutations) occurs only through maternal transmission. The risk of such transition is highly correlated with the size of the maternal premutation (PM), being very low for small PM alleles (∼60 repeats), to 100% for alleles above 100 repeats. The timing of this transition was the object of much speculation.

Journal of Medical Cases, 2015

Fragile X syndrome (FXS) is mainly caused by an expansion of a cytosine-guanine-guanine (CGG) trinucleotide repeat (greater than 200) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene resulting in gene silencing, methylation, and absence of FMRP. FXS involves a wide spectrum of phenotypes including intellectual disabilities, autism spectrum disorder (ASD), maladaptive behaviors or symptoms, social anxiety, mood disorders and physical features. Carriers of premutation alleles (55-200 CGG repeats) can manifest with neurodevelopmental phenotypes and are at risk for the neurodegenerative fragile X-associated tremor/ataxia syndrome (FX-TAS) and about 20% of women with a premutation develop fragile Xassociated primary ovarian insufficiency (FXPOI). These phenotypes are believed to be caused by a distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Premutation alleles are unstable and depending on the CGG length and the presence of AGG interruptions have the potential to expand to larger premutation or full mutation alleles during transmission from mothers to their children. The contraction of a CGG repeat allele, although rare, has been observed. Here, we report the case of a three-generation family, who was identified as part of a pilot study of newborn screening for FXS. Specifically, the maternal grandmother carried a premutation allele (109 CGG repeats), which contracted to an intermediate size allele (52 CGG repeats) in her son, the father of a newborn girl (proband). This allele expanded to a premutation allele of 59 CGG repeats in the proband newborn. A premutation allele of 61 CGG repeats was detected in the proband's sister who demonstrated social phobia but normal cognition. The proband newborn showed some fragile X associated physical stigmata but normal cognition. Intriguingly, all FMR1 CGG expanded allele showed no AGG interruptions. This case shows a remarkable instability of premutation alleles throughout the three generations likely arising from different mechanisms.

American Journal of Medical Genetics Part A, 2011

Individuals with alleles containing 55-200 CGG repeats in the fragile X mental retardation (FMR1) gene are premutation carriers. The premutation allele has been shown to lead to a number of types of clinical involvement, including shyness, anxiety, social deficits, attention deficit hyperactivity disorder (ADHD) and executive function deficits. Some of these problems could be due to mild deficits of the fragile X protein (FMRP) and a possible developmental effect of the elevated FMR1 mRNA observed in carriers. In addition, two abnormal phenotypes specific to the premutation have been described. Primary ovarian insufficiency (FXPOI), defined by cessation of menses prior to age 40, occurs in 20% of females with the premutation. The other phenotype, fragile X-associated tremor/ataxia syndrome (FXTAS), affects some older adult premutation carriers.

The American Journal of Human Genetics, 2003

The CGG repeat in the 5 untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (∼55-200 repeats) and intermediate (∼46-60 repeats) alleles. Our central findings were as follows:

Journal of Human Genetics, 2010

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.

Journal of Medical Genetics, 1993

Fragile X (fra(X)) syndrome, the most common form of familial mental retardation, is caused by heritable unstable DNA composed of CGG repeats. As reproductive fitness of fra(X) patients is severely compromised, a high mutation rate has been proposed to explain the high prevalence. However, we have been unable to show any new mutation for 84 probands referred to us to date. We show here the same fra(X) gene in five fra(X) probands with common ancestors married in 1747. The lack of new fra(X) mutations implies that there must be many more fra(X) gene carriers in the population than previously realised. As it is now possible to detect asymptomatic fra(X) gene carriers by DNA analysis, extended family studies for any new proband are recommended. A family illustrating the importance of fra(X) carriership determination is reported. (J Med Genet 1993;30:94-6)

American Journal of Medical Genetics, 1994

The mechanism responsible for the characteristic expansion of the trinucleotide repeat involved in the pathogenesis of the fragile X syndrome is still largely unclear. Slipped strand mispairing (SSM) and similar DNA replication errors could determine both increases and decreases of the unit number in simple repetitive sequences. Actually, there have been a few reports of size reduction of the (CGG), in parent-to-child transmission of the fragile X syndrome, which may help in understanding the mutational mechanism and may have practical implications for genetic counseling. We describe here 5 such cases from our series of fragile X patients and emphasize the possible role of SSM-like events in causing (CGG), expansions and reductions.

American journal of human genetics, 1994

The fragile X phenotype has been found, in the majority of cases, to be due to the expansion of a CGG repeat in the 5'-UTR region of the FMR-1 gene, accompanied by methylation of the adjacent CpG island and inactivation of the FMR-1 gene. Although several important aspects of the genetics of fragile X have been resolved, it remains to be elucidated at which stage in development the transition from the premutation to the full mutation occurs. We present two families in which discordance between two sets of MZ twins illustrates two important genetic points. In one family, two affected MZ brothers differed in the number of CGG repeats, demonstrating in vivo mitotic instability of this CGG repeat and suggesting that the transition to the full mutation occurred postzygotically. In the second family, two MZ sisters had the same number of repeats, but only one was mentally retarded. When the methylation status of the FMR-1 CpG island was studied, we found that the majority of normal ch...

Journal of Medical Genetics, 1997

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMRl 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.