Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and autism spectrum disorder (ASD). More than 99% of individuals with FXS are caused by the unstable expansion of CGG repeats located within the 5'-untranslated region of the FMR1 gene. The clinical features of FXS include various degrees of cognitive deficit, physical, behavioral and psychiatric problems. Early treatment and prevention from having further affected children can be guided by molecular genetic testing of the FMR1 gene. The following guideline has combined the relevant research, guidelines and consensus worldwide, and summarized the genetic knowledge and clinical treatment for FXS in order to achieve a standardized diagnosis, treatment and prevention for patients and families affected by this disease.
Child ; Humans ; Autism Spectrum Disorder/therapy* ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Syndrome/therapy* ; Intellectual Disability/genetics*

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1^KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1^KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABA_A receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1^KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.
Animals ; Disease Models, Animal ; Fragile X Mental Retardation Protein/metabolism* ; Fragile X Syndrome/metabolism* ; Humans ; Mice ; Mice, Knockout ; Neurons/metabolism*

OBJECTIVE: To explore the correlation between Fragile X mental retardation gene-1 (FMR1) gene CGG repeats with diminished ovarian reserve (DOR). METHODS: For 214 females diagnosed with DOR, DNA was extracted from peripheral blood samples. FMR1 gene CGG repeats were determined by PCR and capillary electrophoresis. RESULTS: Three DOR patients were found to carry FMR1 premutations, and one patient was found to carry gray zone FMR1 repeats. After genetic counseling, one patient and the sister of another patient, both carrying FMR1 permutations, conceived naturally. Prenatal diagnosis showed that both fetuses have carried FMR1 permutations. CONCLUSION FMR1 gene permutation may be associated with DOR. Determination of FMR1 gene CGG repeats in DOR patients can provide a basis for genetic counseling and guidance for reproduction.
Female ; Fragile X Mental Retardation Protein/metabolism* ; Fragile X Syndrome/genetics* ; Humans ; Ovarian Diseases ; Ovarian Reserve/genetics* ; Primary Ovarian Insufficiency/genetics* ; Trinucleotide Repeats/genetics*

OBJECTIVE: To analyze the (CGG)n repeats of FMR1 gene among patients with unexplained mental retardation. METHODS: For 201 patients with unexplained mental retardation, the (CGG)n repeats of the FMR1 gene were analyzed by PCR and FragilEase RESULTS: For the 201 patients with unexplained mental retardation, 15 were identified with full mutations of the FMR1 gene. The prevalence of fragile X syndrome (FXS) in patients with unexplained mental retardation was determined as 7.5% (15/201). Prenatal diagnosis was provided for 6 pregnant women with pre- or full mutations. Analysis revealed that women with mental retardation and full FMR1 mutations exhibited a skewed XCI pattern with primary expression of the X chromosome carrying the mutant allele. CONCLUSION FXS has a high incidence among patients with unexplained mental retardation. Analysis of FMR1 gene (CGG)n repeats in patients with unexplained mental retardation can facilitate genetic counseling and prenatal diagnosis for their families. FMR1 gene (CGG)n repeats screening should be recommended for patients with unexplained mental retardation.
Female ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Syndrome/genetics* ; Humans ; Intellectual Disability/genetics* ; Mutation ; Pregnancy ; Prenatal Diagnosis

OBJECTIVE: To screen for mutations of fragile X mental retardation 1 (FMR1) gene during early and middle pregnancy and provide prenatal diagnosis for those carrying high-risk CGG trinucleotide expansions. METHODS: Peripheral blood samples of 2316 pregnant women at 12 to 21(+6) gestational weeks were collected for the extraction of genomic DNA. CGG repeats of the FMR1 gene were detected by fluorescence PCR and capillary electrophoresis. Genetic counseling and prenatal diagnosis were provided for 3 women carrying the premutations. RESULTS: The carrier rate of CGG repeats of the FMR1 gene was 1 in 178 for the intermediate type and 1 in 772 for the premutation types. The highest frequency allele of CGG was 29 repeats, which accounted for 49.29%, followed by 30 repeats (28.56%) and 36 repeats (8.83%). In case 1, the fetus had a karyotype of 45,X, in addition with premutation type of CGG expansion of the FMR1 gene. Following genetic counseling, the couple chose to terminate the pregnancy through induced labor. The numbers of CGG repeats were respectively 70/- and 29/30 for the husband and wife. In case 2, amniocentesis was performed at 20 weeks of gestation. The number of CGG repeats of the FMR1 gene was 29/-. No abnormality was found in the fetal karyotype and chromosomal copy number variations. The couple chose to continue with the pregnancy. Case 3 refused prenatal diagnosis after genetic counseling and gave birth to a girl at full term, who had a birth weight of 2440 g and no obvious abnormality found during follow-up. CONCLUSION Pregnant women should be screened for FMR1 gene mutations during early and middle pregnancy, and those with high-risk CGG expansions should undergo prenatal diagnosis, genetic counseling and family study.
DNA Copy Number Variations ; Female ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Syndrome/genetics* ; Genetic Counseling ; Humans ; Mutation ; Pregnancy ; Trinucleotide Repeat Expansion ; Trinucleotide Repeats

OBJECTIVE: To explore the genetic basis for a child with febrile seizures. METHODS: Peripheral venous blood samples were taken from the child and his parents for the analysis of chromosomal karyotype and dynamic variant of the FMR1 gene. The family trio was also subjected to target capture and next generation sequencing (NGS) with a gene panel related to developmental retardation, mental retardation, language retardation, epilepsy and special facial features. RESULTS: The child was found to have a normal karyotype by conventional cytogenetic analysis (400 bands). No abnormal expansion was found with the CGG repeats of the FMR1 gene. NGS revealed that the child has carried a heterozygous c.864+1 delG variant of the MEF2C gene, which may lead to abnormal splicing and affect its protein function. The same variant was found in neither parent, suggesting that it has a de novo origin. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.864+1delG variant of MEF2C gene was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION MEF2C, as the key gene for chromosome 5q14.3 deletion syndrome which was speculated as a cause for febrile seizures, has an autosomal dominant effect. The c.864+1delG variant of the MEF2C gene may account for the febrile seizures in this patient.
Child ; Chromosome Deletion ; Chromosome Disorders ; Epilepsy ; Fragile X Mental Retardation Protein ; Humans ; Intellectual Disability/genetics* ; Karyotyping ; MEF2 Transcription Factors/genetics*

OBJECTIVE: To explore the genetic basis for a pedigree affected with X-linked mental retardation. METHODS: The proband was subjected to chromosomal karyotyping, FMR1 mutation testing and copy number variation analysis with a single nucleotide polymorphism microarray (SNP array). His family members were subjected to multiplex ligation-dependent probe amplification (MLPA) assaying. Expression of genes within the repeated region were analyzed. RESULTS: The proband had a normal chromosomal karyotype and normal number of CGG repeats within the FMR1 gene. SNP array identified a 370 kb duplication in Xq28 (ChrX: 153 027 633-153 398 515), which encompassed 14 genes including MECP2. The patient was diagnosed as Lubs X-linked mental retardation syndrome (MRXSL). MLPA confirmed the presence of copy number variation, its co-segregation with the disease, in addition with the carrier status of females. Genes from the duplicated region showed higher levels of expression (1.79 to 5.38 folds) within peripheral blood nucleated cells of the proband. CONCLUSION The patients were diagnosed with MRXSL. The expression of affected genes was up-regulated due to the duplication. Genetic counseling and prenatal diagnosis may be provided based on the results.
DNA Copy Number Variations ; Female ; Fragile X Mental Retardation Protein ; Humans ; Mental Retardation, X-Linked ; Methyl-CpG-Binding Protein 2 ; Pedigree ; Pregnancy

OBJECTIVE: To determine the CGG repeat number and methylation status of FMR1 gene for fetuses whose mothers have carried a FMR1 mutation. METHODS: For 30 pregnant women, the fetal CGG repeat number was determined with a GC-rich PCR system by using chorionic villus, amniotic fluid or umbilical blood samples. The methylation status of the FMR1 gene was confirmed with Southern blotting. RESULTS: In total 30 prenatal diagnoses were performed for 29 carriers of FMR1 gene mutations and 1 with FMR1 gene deletion mosaicism. Three fetuses were found to carry premutations, 9 were with full mutations and 1 with mosaicism of premutation and full mutations. Eighteen fetuses were normal. CONCLUSION Considering the genetic complexity of Fragile X syndrome (FXS), single method may not suffice accurate determination of their genetic status. The pitfalls and technical limitations of protocols requires adoption of personalized strategy for its prenatal diagnosis.
Female ; Fragile X Mental Retardation Protein ; genetics ; Fragile X Syndrome ; diagnosis ; Heterozygote ; Humans ; Mutation ; Pregnancy ; Prenatal Diagnosis

Animals ; Fragile X Mental Retardation Protein ; metabolism ; Fragile X Syndrome ; metabolism ; Humans ; Neurons ; metabolism ; RNA-Binding Proteins ; metabolism ; Receptor, Metabotropic Glutamate 5 ; metabolism ; Sumoylation ; physiology

Myelin is a specialized structure of the nervous system that both enhances electrical conductance and insulates neurons from external risk factors. In the central nervous system, polarized oligodendrocytes form myelin by wrapping processes in a spiral pattern around neuronal axons through myelin-related gene regulation. Since these events occur at a distance from the cell body, post-transcriptional control of gene expression has strategic advantage to fine-tune the overall regulation of protein contents in situ. Therefore, many research interests have been focused to identify RNA binding proteins and their regulatory mechanism in myelinating compartments. Fragile X mental retardation protein (FMRP) is one such RNA binding protein, regulating its target expression by translational control. Although the majority of works on FMRP have been performed in neurons, it is also found in the developing or mature glial cells including oligodendrocytes, where its function is not well understood. Here, we will review evidences suggesting abnormal translational regulation of myelin proteins with accompanying white matter problem and neurological deficits in fragile X syndrome, which can have wider mechanistic and pathological implication in many other neurological and psychiatric disorders.
Axons ; Cell Body ; Central Nervous System ; Fragile X Mental Retardation Protein* ; Fragile X Syndrome ; Gene Expression ; Myelin Proteins* ; Myelin Sheath* ; Nervous System ; Neuroglia ; Neurons ; Oligodendroglia ; Risk Factors ; RNA-Binding Proteins ; White Matter