Primary hyperoxaluria type 1(PH1)is a rare but devastating autosomal recessive inherited disease caused by mutations in gene AGXT.Pathogenic mutations of AGXT were mostly reported in Caucasian but infrequently in Asia...Primary hyperoxaluria type 1(PH1)is a rare but devastating autosomal recessive inherited disease caused by mutations in gene AGXT.Pathogenic mutations of AGXT were mostly reported in Caucasian but infrequently in Asian,especially in Chinese.To update the genotypes of PH1 in the Chinese population,we collected and identified 7 Chinese probands with PH1 from 2013 to 2017 in our center,five of whom had delayed diagnosis and failed in kidney transplantation.Samples of peripheral blood DNA from the 7 patients and their family members were collected and sequencing analysis was performed to test the mutations of gene AGXT.Western blotting and enzyme activity analysis were conducted to evaluate the function of the mutations.Furthermore,a systematic review from 1998 to 2017 was performed to observe the genetic characteristics between Chinese and Caucasian. The results showed that a total of 12 mutations were identified in the 7 pedigrees.To the best of ourknowledge,2 novel variants of A GXT,p.Gly41 Trp and p.Leu33Met,were first reported.Bioinformatics and functional analysis showed that only 7 mutations led to a reduced expression of alanine-glyoxylate amino transferase (AGT)at a protein level.The systematic review revealed significant population heterogeneity in PH1.In conclusion,new genetic subtypes and genetic characteristics of PH1 are updated in the Chinese population. Furthermore,a genotype-phenotype correlation is found in PH1.展开更多
Anophthalmia is defined as a complete absence of one eye or both the eyes,while microphthalmia represents the presence of a small eye within the orbit.The estimated birth prevalence for anophthalmia is approximately 3...Anophthalmia is defined as a complete absence of one eye or both the eyes,while microphthalmia represents the presence of a small eye within the orbit.The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births,and for microphthalmia,it is around 14 per 100000 live births.However,combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals.Microphthalmia is reported to occur in 3.2%to 11.2%of blind children.Anophthalmia and microphthalmia(A/M)are part of a phenotypic spectrum alongside ocular coloboma,hypothesized to share a com-mon genetic basis.Both A/M can occur in isolation or as part of a syndrome.Their complex etiology involves chromosomal aberrations,monogenic inheritance pattern,and the contribution of environmental factors such as gestational-acquired infections,maternal vitamin A deficiency(VAD),exposure to X-rays,solvent misuse,and thalidomide exposure.A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far.Familial cases of A/M have a complex genetic basis,including all Mendelian modes of inheritance,i.e.,autosomal dominant,recessive,and X-linked.Most cases arise sporadically due to de novo mutations.Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M,leading to more effective diagnosis and management strategies.The present review focuses on key genetic factors,developmental abnormalities,and environmental modifiers linked with A/M.It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies,which aim to create innovative treatment options.展开更多
BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic charact...BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.展开更多
Paroxysmal kinesigenic dyskinesia(PKD),the most common type of paroxysmal movement disorder,is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements.PKD is ma...Paroxysmal kinesigenic dyskinesia(PKD),the most common type of paroxysmal movement disorder,is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements.PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.The exact pathophysiological mechanisms of PKD remain unclear,although the function of PRRT2 protein has been well characterized in the last decade.Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2,PKD may be channelopathy or synaptopathy,or both.In addition,the cerebellum is regarded as the key pathogenic area.Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes.Whereas,in PKD,other than the cerebellum,the role of the cerebrum including the cortex and thalamus needs to be further investigated.展开更多
Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvest...Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.展开更多
Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-ons...Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.展开更多
In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1]....In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.展开更多
Objectives The objective of this study was to evaluate the role of genetic screening in a Chinese woman of childbearing age with hypertrophic cardiomyopathy.Methods and Results One 39 year-old woman with presyncope fo...Objectives The objective of this study was to evaluate the role of genetic screening in a Chinese woman of childbearing age with hypertrophic cardiomyopathy.Methods and Results One 39 year-old woman with presyncope for 10 years was admitted.Both of her father and her son died of sudden death and she strongly desire to get another baby. A series of clinical and laboratory studies were performed. Hypertrophic cardiomyopathy was diagnosed finally and implantable Cardioverter Defibrillator was implanted to prevent sudden cardiac death for her.Genomic DNA was isolated and the most common causal genes for hypertrophic cardiomyopathy were screened.A known pathogenetic heterozygous mutation c.700 g】a(p.Argl86Gln) in TNNI3 was found,which was not found in 100 normal control individuals matched for age,sex and geographical region.Because 50%probability of the pathogenetic mutation is inherited to the offsprings,she will get a healthy baby in vitro fertilization which the egg comes from a healthy female donor to prevent from the inherited HCM.Conclusions We found a pathogenetic TNNI3 mutation in a Chinese woman of childbearing age with hypertrophic cardiomyopathy.The genetic screening definite DNA-based diagnosis and help to design a healthy fertilization in vitro for female with hypertrophic cardiomyopathy.展开更多
Global warming imposes a serious threat to global crop production and may cripple the outcome of a successful breeding program.Because the photosystem II(PSII)complex,a protein supercomplex that acts to harvest sunlig...Global warming imposes a serious threat to global crop production and may cripple the outcome of a successful breeding program.Because the photosystem II(PSII)complex,a protein supercomplex that acts to harvest sunlight energy for photosynthetic plants,is sensitive to thermal damage.展开更多
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective d...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.展开更多
Mutations and rearrangements of mitochondrial genes cause plant cytoplasmic male sterility. It is a significant way to utilize hybrid vigor to enhance crop yield. Ogu cytoplasmic male sterility(CMS) is a natural cytop...Mutations and rearrangements of mitochondrial genes cause plant cytoplasmic male sterility. It is a significant way to utilize hybrid vigor to enhance crop yield. Ogu cytoplasmic male sterility(CMS) is a natural cytoplasmic male sterility type discovered in radishes, being successfully transferred to rapeseed and cruciferous vegetables. However, current studies lack depth in exploring the molecular mechanisms of its male sterility. This study confirmed that orf138 is the causal gene for Ogu CMS through the genetic transformation in Arabidopsis. Transcriptome analysis of aborted anthers in different stages suggested that differentially expressed genes(DEGs) are mainly enriched in pathways such as glycerophospholipid metabolism and arginine and proline metabolism. It reveals that key genes involved in lipid metabolism pathways are significantly down-regulated in the sterile line(OguA), including BnaGPAT1, localized within the tapetum mitochondrial and endoplasmic reticulum. This could lead to changes in the metabolism of substances like acylglycerols within the tapetum, causing disruptions in lipid metabolism. This is consistent with morphological and subcellular structural changes in the tapetum and microspore cells, as observed in the transmission electron microscopy. This abnormal lipid metabolism may trigger specific reactive oxygen species(ROS) accumulation in an oxidative stress response, ultimately leading to an aborted microspore. Our study based on transcriptome has deepened our understanding of the molecular mechanisms in Ogu CMS.展开更多
Emerging new races of wheat stem rust(Puccinia graminis f.sp.tritici)are threatening global wheat(Triticum aestivum L.)production.Host resistance is the most effective and environmentally friendly method of controllin...Emerging new races of wheat stem rust(Puccinia graminis f.sp.tritici)are threatening global wheat(Triticum aestivum L.)production.Host resistance is the most effective and environmentally friendly method of controlling stem rust.The stem rust resistance gene Sr59 was previously identified within a T2DS 2RL wheat-rye whole arm translocation,providing broad-spectrum resistance to various stem rust races.Seedling evaluation,molecular marker analysis,and cytogenetic studies identified wheat-rye introgression line#284 containing a new translocation chromosome T2BL 2BS-2RL.This line has demonstrated broad-spectrum resistance to stem rust at the seedling stage.Seedling evaluation and cytogenetic analysis of three backcross populations between the line#284 and the adapted cultivars SLU-Elite,Navruz,and Linkert confirmed that Sr59 is located within the short distal 2RL translocation.This study aimed physical mapping of Sr59 in the 2RL introgression segment and develop a robust molecular marker for marker-assisted selection.Using genotyping-by-sequencing(GBS),GBS-derived SNPs were aligned with full-length annotated rye nucleotide-binding leucine-rich repeat(NLR)genes in the parental lines CS ph1b,SLU238,SLU-Elite,Navruz,and Linkert,as well as in 33 BC4F5progeny.Four NLR genes were identified on the 2R chromosome,with Chr2R_NLR_60 being tightly linked to the Sr59resistance gene.In-silico functional enrichment analysis of the translocated 2RL region(25,681,915 bp)identified 223 genes,with seven candidate genes associated with plant disease resistance and three linked to agronomic performance,contributing to oxidative stress response,protein kinase activity,and cellular homeostasis.These findings facilitate a better understanding of the genetic basis of stem rust resistance provided by Sr59.展开更多
BACKGROUND Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma.However,li...BACKGROUND Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma.However,little is known about tumor-infiltrating immune cells,and the corresponding research results in hepatocellular carcinoma(HCC)are limited.AIM To investigate potential biomarker genes that are important for the development of HCC and to understand how immune cell subsets react throughout this process.METHODS Using single-cell RNA sequencing and T-cell receptor sequencing,the heterogeneity and potential functions of immune cell subpopulations from HCC tissue and normal tissue adjacent to carcinoma,as well as their possible interactions,were analyzed.RESULTS Eight T-cell clusters from patients were analyzed and identified using bioinformatics,including six typical major Tcell clusters and two newly identified T-cell clusters,among which Fc epsilon receptor 1G+T cells were characterized by the upregulation of Fc epsilon receptor 1G,tyrosine kinase binding protein,and T cell receptor delta constant,whereas metallothionein 1E+T cells proliferated significantly in tumors.Differentially expressed genes,such as regulator of cell cycle,cysteine and serine rich nuclear protein 1,SMAD7 and metallothionein 1E,were identified as significantly upregulated in tumors and have potential as biomarkers.In association with T-cell receptor analysis,we inferred the clonal expansion characteristics of each T-cell cluster in HCC patients.CONCLUSION We identified lymphocyte subpopulations and potential biomarker genes critical for HCC development and revealed the clonal amplification of infiltrating T cells.These data provide valuable resources for understanding the response of immune cell subsets in HCC.展开更多
Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients ...Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.展开更多
基金This work was supported by the grants from the Special Project of Ministry of Health (No.201302009)and the National Natural Science Foundation of China (No. 81700300).
文摘Primary hyperoxaluria type 1(PH1)is a rare but devastating autosomal recessive inherited disease caused by mutations in gene AGXT.Pathogenic mutations of AGXT were mostly reported in Caucasian but infrequently in Asian,especially in Chinese.To update the genotypes of PH1 in the Chinese population,we collected and identified 7 Chinese probands with PH1 from 2013 to 2017 in our center,five of whom had delayed diagnosis and failed in kidney transplantation.Samples of peripheral blood DNA from the 7 patients and their family members were collected and sequencing analysis was performed to test the mutations of gene AGXT.Western blotting and enzyme activity analysis were conducted to evaluate the function of the mutations.Furthermore,a systematic review from 1998 to 2017 was performed to observe the genetic characteristics between Chinese and Caucasian. The results showed that a total of 12 mutations were identified in the 7 pedigrees.To the best of ourknowledge,2 novel variants of A GXT,p.Gly41 Trp and p.Leu33Met,were first reported.Bioinformatics and functional analysis showed that only 7 mutations led to a reduced expression of alanine-glyoxylate amino transferase (AGT)at a protein level.The systematic review revealed significant population heterogeneity in PH1.In conclusion,new genetic subtypes and genetic characteristics of PH1 are updated in the Chinese population. Furthermore,a genotype-phenotype correlation is found in PH1.
文摘Anophthalmia is defined as a complete absence of one eye or both the eyes,while microphthalmia represents the presence of a small eye within the orbit.The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births,and for microphthalmia,it is around 14 per 100000 live births.However,combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals.Microphthalmia is reported to occur in 3.2%to 11.2%of blind children.Anophthalmia and microphthalmia(A/M)are part of a phenotypic spectrum alongside ocular coloboma,hypothesized to share a com-mon genetic basis.Both A/M can occur in isolation or as part of a syndrome.Their complex etiology involves chromosomal aberrations,monogenic inheritance pattern,and the contribution of environmental factors such as gestational-acquired infections,maternal vitamin A deficiency(VAD),exposure to X-rays,solvent misuse,and thalidomide exposure.A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far.Familial cases of A/M have a complex genetic basis,including all Mendelian modes of inheritance,i.e.,autosomal dominant,recessive,and X-linked.Most cases arise sporadically due to de novo mutations.Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M,leading to more effective diagnosis and management strategies.The present review focuses on key genetic factors,developmental abnormalities,and environmental modifiers linked with A/M.It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies,which aim to create innovative treatment options.
文摘BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.
基金supported by grants from the National Natural Science Foundation(81330025).
文摘Paroxysmal kinesigenic dyskinesia(PKD),the most common type of paroxysmal movement disorder,is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements.PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.The exact pathophysiological mechanisms of PKD remain unclear,although the function of PRRT2 protein has been well characterized in the last decade.Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2,PKD may be channelopathy or synaptopathy,or both.In addition,the cerebellum is regarded as the key pathogenic area.Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes.Whereas,in PKD,other than the cerebellum,the role of the cerebrum including the cortex and thalamus needs to be further investigated.
基金This work was supported by an Institute for Information and CommunicationsTechnology Promotion (IITP) grant funded by the Korean Government (MSIT) (2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.
基金This work was supported by an Institute for Information and Communications Technology Promotion(IITP)grant funded by the Korean government(MSIT)(2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.
基金Diponegoro University WCRU grant(No.118-03/UN7.6.1/PP/2021).
文摘In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.
文摘Objectives The objective of this study was to evaluate the role of genetic screening in a Chinese woman of childbearing age with hypertrophic cardiomyopathy.Methods and Results One 39 year-old woman with presyncope for 10 years was admitted.Both of her father and her son died of sudden death and she strongly desire to get another baby. A series of clinical and laboratory studies were performed. Hypertrophic cardiomyopathy was diagnosed finally and implantable Cardioverter Defibrillator was implanted to prevent sudden cardiac death for her.Genomic DNA was isolated and the most common causal genes for hypertrophic cardiomyopathy were screened.A known pathogenetic heterozygous mutation c.700 g】a(p.Argl86Gln) in TNNI3 was found,which was not found in 100 normal control individuals matched for age,sex and geographical region.Because 50%probability of the pathogenetic mutation is inherited to the offsprings,she will get a healthy baby in vitro fertilization which the egg comes from a healthy female donor to prevent from the inherited HCM.Conclusions We found a pathogenetic TNNI3 mutation in a Chinese woman of childbearing age with hypertrophic cardiomyopathy.The genetic screening definite DNA-based diagnosis and help to design a healthy fertilization in vitro for female with hypertrophic cardiomyopathy.
文摘Global warming imposes a serious threat to global crop production and may cripple the outcome of a successful breeding program.Because the photosystem II(PSII)complex,a protein supercomplex that acts to harvest sunlight energy for photosynthetic plants,is sensitive to thermal damage.
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.
基金supported by the National Natural Science Foundation of China (31930032)。
文摘Mutations and rearrangements of mitochondrial genes cause plant cytoplasmic male sterility. It is a significant way to utilize hybrid vigor to enhance crop yield. Ogu cytoplasmic male sterility(CMS) is a natural cytoplasmic male sterility type discovered in radishes, being successfully transferred to rapeseed and cruciferous vegetables. However, current studies lack depth in exploring the molecular mechanisms of its male sterility. This study confirmed that orf138 is the causal gene for Ogu CMS through the genetic transformation in Arabidopsis. Transcriptome analysis of aborted anthers in different stages suggested that differentially expressed genes(DEGs) are mainly enriched in pathways such as glycerophospholipid metabolism and arginine and proline metabolism. It reveals that key genes involved in lipid metabolism pathways are significantly down-regulated in the sterile line(OguA), including BnaGPAT1, localized within the tapetum mitochondrial and endoplasmic reticulum. This could lead to changes in the metabolism of substances like acylglycerols within the tapetum, causing disruptions in lipid metabolism. This is consistent with morphological and subcellular structural changes in the tapetum and microspore cells, as observed in the transmission electron microscopy. This abnormal lipid metabolism may trigger specific reactive oxygen species(ROS) accumulation in an oxidative stress response, ultimately leading to an aborted microspore. Our study based on transcriptome has deepened our understanding of the molecular mechanisms in Ogu CMS.
基金the financial support from FORMAS(2018-01029)the Swedish Institute(01132-2022)for supporting Ivan Motsnyi’s visit and research at Swedish University of Agricultural Sciences。
文摘Emerging new races of wheat stem rust(Puccinia graminis f.sp.tritici)are threatening global wheat(Triticum aestivum L.)production.Host resistance is the most effective and environmentally friendly method of controlling stem rust.The stem rust resistance gene Sr59 was previously identified within a T2DS 2RL wheat-rye whole arm translocation,providing broad-spectrum resistance to various stem rust races.Seedling evaluation,molecular marker analysis,and cytogenetic studies identified wheat-rye introgression line#284 containing a new translocation chromosome T2BL 2BS-2RL.This line has demonstrated broad-spectrum resistance to stem rust at the seedling stage.Seedling evaluation and cytogenetic analysis of three backcross populations between the line#284 and the adapted cultivars SLU-Elite,Navruz,and Linkert confirmed that Sr59 is located within the short distal 2RL translocation.This study aimed physical mapping of Sr59 in the 2RL introgression segment and develop a robust molecular marker for marker-assisted selection.Using genotyping-by-sequencing(GBS),GBS-derived SNPs were aligned with full-length annotated rye nucleotide-binding leucine-rich repeat(NLR)genes in the parental lines CS ph1b,SLU238,SLU-Elite,Navruz,and Linkert,as well as in 33 BC4F5progeny.Four NLR genes were identified on the 2R chromosome,with Chr2R_NLR_60 being tightly linked to the Sr59resistance gene.In-silico functional enrichment analysis of the translocated 2RL region(25,681,915 bp)identified 223 genes,with seven candidate genes associated with plant disease resistance and three linked to agronomic performance,contributing to oxidative stress response,protein kinase activity,and cellular homeostasis.These findings facilitate a better understanding of the genetic basis of stem rust resistance provided by Sr59.
基金Supported by the Scientific Research Topic of Jiangsu Provincial Health Care Commission,No.M2021017the High-level Talent Research Project of the Second Hospital of Nanjing,No.0313504the Nanjing Second Hospital Academic Leader Program,No.0313506.
文摘BACKGROUND Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma.However,little is known about tumor-infiltrating immune cells,and the corresponding research results in hepatocellular carcinoma(HCC)are limited.AIM To investigate potential biomarker genes that are important for the development of HCC and to understand how immune cell subsets react throughout this process.METHODS Using single-cell RNA sequencing and T-cell receptor sequencing,the heterogeneity and potential functions of immune cell subpopulations from HCC tissue and normal tissue adjacent to carcinoma,as well as their possible interactions,were analyzed.RESULTS Eight T-cell clusters from patients were analyzed and identified using bioinformatics,including six typical major Tcell clusters and two newly identified T-cell clusters,among which Fc epsilon receptor 1G+T cells were characterized by the upregulation of Fc epsilon receptor 1G,tyrosine kinase binding protein,and T cell receptor delta constant,whereas metallothionein 1E+T cells proliferated significantly in tumors.Differentially expressed genes,such as regulator of cell cycle,cysteine and serine rich nuclear protein 1,SMAD7 and metallothionein 1E,were identified as significantly upregulated in tumors and have potential as biomarkers.In association with T-cell receptor analysis,we inferred the clonal expansion characteristics of each T-cell cluster in HCC patients.CONCLUSION We identified lymphocyte subpopulations and potential biomarker genes critical for HCC development and revealed the clonal amplification of infiltrating T cells.These data provide valuable resources for understanding the response of immune cell subsets in HCC.
基金supported by the grants from the National Natural Science Foundation of China to Zhi-Ying Wu(82230062,Beijing),Qiao Wei(82402156,Beijing),and Wanzhong Ge(31970668,Beijing)the research foundation for distinguished scholar of Zhejiang University(188020-193810101/089,Hangzhou)to Zhi-Ying Wu
文摘Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.
文摘对浙江瑞安、福建宁德、福建东张水库3个地理群体共31例香鱼(Plecoglossus altivelis)的线粒体细胞色素b(Cyt b)基因和线粒体D-loop区序列进行了PCR扩增、序列测定、核苷酸组成和多态性分析。Cytb基因中,A、T、C和G4种核苷酸的比例分别为19.72%、29.71%、32.25%和18.32%,A+T含量为49.43%,G+C含量为50.57%。D-loop区序列中,A、T、C和G4种核苷酸的比例分别为29.99%、29.29%、23.80%和16.92%,A+T含量为59.28%,G+C含量为40.72%。在长度为1141bp的Cytb基因序列中,仅存在1个变异位点,核苷酸多样性指数(π值)为0.00028,31个样本中仅出现两种单倍型;857 bp 长的D-loop区序列中,仅存在5个变异位点,核苷酸多样性指数(π值)为0.00199,仅出现5种单倍型。这表明闽浙地区香鱼的遗传多样性水平很低,应当加大对香鱼的保护力度。
