Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effec...Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.展开更多
Background:Mayer-Rokitansky-Küster-Hauser(MRKH)syndrome is a rare congenital disorder characterized by agenesis or hypoplasia of the uterus and upper vagina due to Müllerian duct anomalies.Fragile X syndrome...Background:Mayer-Rokitansky-Küster-Hauser(MRKH)syndrome is a rare congenital disorder characterized by agenesis or hypoplasia of the uterus and upper vagina due to Müllerian duct anomalies.Fragile X syndrome(FXS),a leading cause of inherited intellectual disability,is caused by CGG repeat ex pansions in the FMR1 gene and has been associated with premature ovarian insufficiency(FXPOI).Objective:We report a unique case of co-occurrence of MRKH syndrome and a premutation in the FMR1 gene,raising the ques-tion of a possible link between FMR1-related genomic instability and Müller-ian developmental anomalies.Case Presentation:A 25-year-old woman with a history of delayed psychomotor development and familial intellectual disa bility presented with primary amenorrhea.Clinical evaluation revealed hyper-gonadotropic hypogonadism,absent pubertal development,neuropsychiatric symptoms,and bilateral sensorineural hearing loss.Pelvic MRI confirmed the diagnosis of MRKH syndrome.Molecular testing revealed a premutation in the FMR1 gene.Conclusion:This rare association between MRKH syndrome and FMR1 premutation highlights the potential role of FMR1 or related loci in embryonic morphogenesis beyond its known neurological and ovarian func-tions.Further studies are needed to explore the possible pathogenic link be-tween genomic instability and Müllerian tract development.展开更多
Fragile X syndrome(FXS)is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome,leading to a range of developmental and intellectual disabilities.FXS is characterized by intellectual disability,...Fragile X syndrome(FXS)is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome,leading to a range of developmental and intellectual disabilities.FXS is characterized by intellectual disability,behavior challenges,and distinct physical features such as an elongated face,large ears,and hyperflexible joints;FXS remains the most common inherited cause of intellectual disability.Behavioral manifestations often include attention deficits,hyperactivity,anxiety,and features of autism spectrum disorder.The prevalence of FXS in the South Asian population is not well-documented,but existing studies suggest it may be comparable to global prevalence rates,which are approximately 1 in 4,000 males and 1 in 8,000 females.Accurate diagnosis of FXS in South Asians is crucial due to the implications for early intervention and treatment,which can significantly improve the quality of life and developmental outcomes for affected individuals.Early diagnosis also facilitates genetic counselling and family planning,helping to reduce the risk of recurrence in families.Increased awareness and screening in South Asian communities are essential to address the diagnostic gap and ensure timely support for individuals with FXS or disorders associated with the premutation of FMR1.展开更多
Lack of the fragile X mental retardation protein leads to Fragile X syndrome(FXS)while increased levels of FMR1 mRNA,as those observed in premutation carriers can lead to Fragile X-associated tremor ataxia syndrome(FX...Lack of the fragile X mental retardation protein leads to Fragile X syndrome(FXS)while increased levels of FMR1 mRNA,as those observed in premutation carriers can lead to Fragile X-associated tremor ataxia syndrome(FXTAS).Until recently,FXTAS had been observed only in carriers of an FMR1 premutation(55–200 CGG repeats);however the disorder has now been described in individuals carriers of an intermediate allele(45–54 CGG repeats)as well as in a subject with a full mutation with mosaicism.Here,we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles.Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype.We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis.In addition,a dramatic 90%depletion of both FMR1 mRNA and FMRP levels was observed in the blood,as normally observed in FXS cases,and an even greater depletion in the brain.A clinical report of this patient,at age 71,described neurodegenerative signs of parkinsonism that were likely,in retrospect,part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions,the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles.In addition,based on symptoms and pathological and molecular evidence,this report suggests the need to redefine the diagnostic criteria of FXTAS.展开更多
基金supported by the National Key Research and Development Program of China(2016YFC0905100)the National Natural Science Foundation of China(31625015,31521003,and 31571297).
文摘Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.
文摘Background:Mayer-Rokitansky-Küster-Hauser(MRKH)syndrome is a rare congenital disorder characterized by agenesis or hypoplasia of the uterus and upper vagina due to Müllerian duct anomalies.Fragile X syndrome(FXS),a leading cause of inherited intellectual disability,is caused by CGG repeat ex pansions in the FMR1 gene and has been associated with premature ovarian insufficiency(FXPOI).Objective:We report a unique case of co-occurrence of MRKH syndrome and a premutation in the FMR1 gene,raising the ques-tion of a possible link between FMR1-related genomic instability and Müller-ian developmental anomalies.Case Presentation:A 25-year-old woman with a history of delayed psychomotor development and familial intellectual disa bility presented with primary amenorrhea.Clinical evaluation revealed hyper-gonadotropic hypogonadism,absent pubertal development,neuropsychiatric symptoms,and bilateral sensorineural hearing loss.Pelvic MRI confirmed the diagnosis of MRKH syndrome.Molecular testing revealed a premutation in the FMR1 gene.Conclusion:This rare association between MRKH syndrome and FMR1 premutation highlights the potential role of FMR1 or related loci in embryonic morphogenesis beyond its known neurological and ovarian func-tions.Further studies are needed to explore the possible pathogenic link be-tween genomic instability and Müllerian tract development.
基金supported by the ITPND program at the MIND Institute,the Victor LaFave III fund and the Tides Foundation.
文摘Fragile X syndrome(FXS)is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome,leading to a range of developmental and intellectual disabilities.FXS is characterized by intellectual disability,behavior challenges,and distinct physical features such as an elongated face,large ears,and hyperflexible joints;FXS remains the most common inherited cause of intellectual disability.Behavioral manifestations often include attention deficits,hyperactivity,anxiety,and features of autism spectrum disorder.The prevalence of FXS in the South Asian population is not well-documented,but existing studies suggest it may be comparable to global prevalence rates,which are approximately 1 in 4,000 males and 1 in 8,000 females.Accurate diagnosis of FXS in South Asians is crucial due to the implications for early intervention and treatment,which can significantly improve the quality of life and developmental outcomes for affected individuals.Early diagnosis also facilitates genetic counselling and family planning,helping to reduce the risk of recurrence in families.Increased awareness and screening in South Asian communities are essential to address the diagnostic gap and ensure timely support for individuals with FXS or disorders associated with the premutation of FMR1.
基金This work was supported by NICH through individual research awards HD02274 and HD36071Brain tissue for this study was obtained from the UC Davis brain repository(NIH HD040661)Control tissues were obtained from the Brain Endowment Bank,Dept.Neurology University of Miami Miller School of Medicine.
文摘Lack of the fragile X mental retardation protein leads to Fragile X syndrome(FXS)while increased levels of FMR1 mRNA,as those observed in premutation carriers can lead to Fragile X-associated tremor ataxia syndrome(FXTAS).Until recently,FXTAS had been observed only in carriers of an FMR1 premutation(55–200 CGG repeats);however the disorder has now been described in individuals carriers of an intermediate allele(45–54 CGG repeats)as well as in a subject with a full mutation with mosaicism.Here,we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles.Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype.We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis.In addition,a dramatic 90%depletion of both FMR1 mRNA and FMRP levels was observed in the blood,as normally observed in FXS cases,and an even greater depletion in the brain.A clinical report of this patient,at age 71,described neurodegenerative signs of parkinsonism that were likely,in retrospect,part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions,the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles.In addition,based on symptoms and pathological and molecular evidence,this report suggests the need to redefine the diagnostic criteria of FXTAS.
