AIM To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease(VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHO...AIM To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease(VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing. RESULTS A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease(CD) or CDlike intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients(16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo(interquartile range(IQR): 4 to 78) and 43.5 mo(IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group(P = 0.001). However, there were no significant differences between weight-forage and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency. CONCLUSION A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.展开更多
Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn disease...Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.展开更多
Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 46...Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.展开更多
Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis bu...Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.展开更多
Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases,...Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.展开更多
Appealing to the Clifford analysis and matching pursuits, we study the adaptive decompositions of functions of several variables of finite energy under the dictionaries consisting of shifted Cauchy kernels. This is a ...Appealing to the Clifford analysis and matching pursuits, we study the adaptive decompositions of functions of several variables of finite energy under the dictionaries consisting of shifted Cauchy kernels. This is a realization of matching pursuits among shifted Cauchy kernels in higher-dimensional spaces. It offers a method to process signals in arbitrary dimensions.展开更多
A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesit...A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.展开更多
The enhanced power graph P_(E)(S)of a semigroup S is a simple graph whose vertex set is S and two vertices a,y∈S are adjacent if and only if c,y∈(z)for some z∈S,where(z)is the subsemigroup generated by z.In this pa...The enhanced power graph P_(E)(S)of a semigroup S is a simple graph whose vertex set is S and two vertices a,y∈S are adjacent if and only if c,y∈(z)for some z∈S,where(z)is the subsemigroup generated by z.In this paper,we first describe the structure of P_(E)(S)for an arbitrary semigroup S,and then discuss the connectedness of P_(E)(S).Further,we characterize the semigroup S in the cases when P_(E)(S)is separately a complete,bipartite,regular,tree and null graph.The planarity,together with the minimum degree and independence number,of P_(E)(S)is also investigated.The chromatic number of a spanning subgraph,i.e.,the cyclic graph,of P_(E)(S)is proved to be countable.In the final part of this paper,we construct an example of a semigroup S such that the chromatic number of P_(E)(S)need not be countable.展开更多
Background Monogenic lupus is defined as systemic lupus erythematosus(SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance.However,because th...Background Monogenic lupus is defined as systemic lupus erythematosus(SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance.However,because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE,it causes a delay in diagnosis and treatment.Currently,there is a lack of early identification models for clinical practitioners to provide early clues for recognition.Our goal was to create a clinical model for the early identification of pediatric monogenic lupus,thereby facilitating early and precise diagnosis and treatment for patients.Methods This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022.The control group consisted of classical SLE patients recruited at a 1:2 ratio.Patients were randomly divided into a training group and a validation group at a 7:3 ratio.A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot.The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve(AUC)index.Results A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included.Among the monogenic lupus cases(with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years),a total of 18 gene mutations were identified.The variables included in the coefficient plot were age of onset,recurrent infections,intracranial calcifications,growth and developmental delay,abnormal muscle tone,lymphadenopathy/hepatosplenomegaly,and chilblain-like skin rash.Our model demonstrated satisfactory diagnostic performance through internal validation,with an AUC value of 0.97(95% confidence interval=0.92–0.97).Conclusions We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and develo展开更多
We study the adaptive decomposition of functions in the monogenic Hardy spaces H2by higher order Szeg kernels under the framework of Clifford algebra and Clifford analysis,in the context of unit ball and half space.Th...We study the adaptive decomposition of functions in the monogenic Hardy spaces H2by higher order Szeg kernels under the framework of Clifford algebra and Clifford analysis,in the context of unit ball and half space.This is a sequel and a higher-dimensional generalization of our recent study on the complex Hardy spaces.展开更多
Monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance patterns.Despite over 50 associated genetic disorders,accurate diagnoses and management of mon...Monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance patterns.Despite over 50 associated genetic disorders,accurate diagnoses and management of monogenic diabetes remain inadequate,underscoring insufficient clinician awareness.The disease spectrum encompasses maturity-onset diabetes of the young(MODY),characterized by distinct genetic mutations affecting insulin secretion,and neonatal diabetes mellitus(NDM)-a heterogeneous group of severe hyperglycemic disorders in infants.Mitochondrial diabetes,autoimmune monogenic diabetes,genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape.A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY.NDM diagnosis warrants immediate molecular genetic testing for infants under six months.Identifying these genetic defects presents a unique opportunity for precision medicine.Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes.Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes.The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.展开更多
Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early det...Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being.The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity.In rare instances,mutations leading to severe insulin resistance can also result in the development of diabetes.Individuals diagnosed with specific types of monogenic diabetes,which are commonly found,can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes.Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments.This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.展开更多
Previous studies have documented the occurrence of glyphosate-resistant （GR） goosegrass （Eleusine indica （L.） Gaertn.） and, in at least some cases, resistance is due to an altered target site. Research was perfo...Previous studies have documented the occurrence of glyphosate-resistant （GR） goosegrass （Eleusine indica （L.） Gaertn.） and, in at least some cases, resistance is due to an altered target site. Research was performed to determine if an altered target site was responsible for GR in a Tennessee, United States goosegrass population （TennGR）. DNA sequencing revealed a mutation in TennGR plants conferring the Prol06Ser 5-enolpyruvylshikimate-3-phosphate synthase （EPSPS） substitution previously identified in other GR populations. F2 populations were derived from TennGR plants crossed with plants from a glyphosate-susceptible population （TennGS） and analyzed for their response to glyphosate and genotyped at the EPSPS locus. Plants from the F2 populations segregated 1：2：1 sensitive：intermediate：resistant in response to a selec- tive dose of glyphosate, and these responses co-segregated with the EPSPS genotypes （PP106, PS106, and SS106）. To separately investigate the effect of the Prol06Ser substitution on GR, glyphosate dose-response curves and 50% effective dose （EDso） values were compared among the three genotypes and the two parental populations. The SS106 genotype was 3.4-fold resistant relative to the PP106 genotype, identical to the resistance level obtained when comparing the resistant and susceptible parental populations. We conclude that the mutation conferring a Prol06Ser EPSPS mutation is solely responsible for GR in the TennGR goosegrass population.展开更多
Monogenic lines,which carried 23 genes for blast resistance were tested and used donors to transfer resistance genes by crossing method.The results under blast nursery revealed that 9 genes from 23 genes were suscepti...Monogenic lines,which carried 23 genes for blast resistance were tested and used donors to transfer resistance genes by crossing method.The results under blast nursery revealed that 9 genes from 23 genes were susceptible to highly susceptible under the three locations(Sakha,Gemmeza,and Zarzoura in Egypt);Pia,Pik,Pik-p,Piz-t,Pita,Pi b,Pi,Pi 19 and Pi 20.While,the genes Pii,Pik-s,Pik-h,Pi z,Piz-5,Pi sh,Pi 3,Pi 1,Pi 5,Pi 7,Pi 9,Pi 12,Pikm and Pita-2 were highly resistant at the same locations.Clustering analysis confirmed the results,which divided into two groups;the first one included all the susceptible genes,while the second one included the resistance genes.In the greenhouse test,the reaction pattern of five races produced 100%resistance under artificial inoculation with eight genes showing complete resistance to all isolates.The completely resistant genes:Pii,Pik-s,Piz,Piz-5(=bi2)(t),Pita(=Pi4)(t),Pita,Pi b and Pi1 as well as clustering analysis confirmed the results.In the F1 crosses,the results showed all the 25 crosses were resistant for leaf blast disease under field conditions.While,the results in F2 population showed seven crosses with segregation ratio of 15(R):1(S),two cross gave segregated ratio of 3 R:1 S and one gave 13:3.For the identification of blast resistance genes in the parental lines,the marker K3959,linked to Pik-s gene and the variety IRBLKS-F5 carry this gene,which was from the monogenic line.The results showed that four genotypes;Sakha 105,Sakha 103,Sakha 106 and IRBLKS-F5 were carrying Pik-s gene,while was absent in the Sakha 101,Sakha 104,IRBL5-M,IRBL9-W,IRBLTACP1 and IRBL9-W(R)genotypes.As for Pi 5 gene,the results showed that it was present in Sakha 103 and Sakha 104 varieties and absent in the rest of the genotypes.In addition,Pita-Pita-2 gene was found in the three Egyptian genotypes(Sakha 105,Sakha 101 and Sakha 104)plus IRBLTACP1 monogenetic.In F2 generation,six populations were used to study the inheritance of blast resistance and specific primers to confirm the ratio and identif展开更多
Knowledge of the geographic distribution and frequency of avirulence genes will contribute to the development of strategies to effectively use rice varieties that carry various resistances genes, including combination...Knowledge of the geographic distribution and frequency of avirulence genes will contribute to the development of strategies to effectively use rice varieties that carry various resistances genes, including combinations of varieties in mixture cropping systems. Here, we analyzed the geographic distribution and frequencies of avirulence genes in rice blast fungus using samples collected from 11 prefectures across Yunnan province, China. A total of 467 single spore isolates were assayed for pathotypes based on their reaction to 20 rice blast resistance monogenic lines. The results revealed that frequencies of avirulence genes among 10 prefectures showed insignificant difference, but frequencies of avirulenee genes in Xishuangbanna showed significant differences compared to the remaining 10 prefectures. The avirulence genes Avr-Pi9, Avr-Piz and Avr-Pizt were observed at the highest frequency in blast isolates from the 11 prefectures; their average frequency was greater than 80%. Our results imply that the composition and distribution of rice genetic diversity are more important than climate and other environment conditions for formation and maintenance of rice blast fungus genetic diversity. Using average frequencies, the avirulence genes can be categorized into 4 groups. There were significant differences of frequencies of avirulence genes among different groups, while insignificant differences observed within any group. These results will provide useful information for evaluation of resistance genes and effective management of rice blast disease.展开更多
Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early d...Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early detection and geneticallyfocused treatment of neonatal diabetes and maturity-onset diabetes of theyoung can significantly improve long-term health and well-being. The etiology ofmonogenic diabetes in childhood is primarily attributed to genetic variationsaffecting the regulatory genes responsible for beta-cell activity. In rare instances,mutations leading to severe insulin resistance can also result in the developmentof diabetes. Individuals diagnosed with specific types of monogenic diabetes,which are commonly found, can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguishindividuals with type 1 or 2 diabetes from those more prone to monogenicdiabetes. Genetic screening with appropriate findings and interpretations isessential to establish a prognosis and to guide the choice of therapies andmanagement of these interrelated ailments. This review aims to design a comprehensiveliterature summarizing genetic insights into monogenetic diabetes inchildren and adolescents as well as summarizing their diagnosis and management.展开更多
基金Supported by Zhejiang Province Medical Platform Backbone,No.2017KY436
文摘AIM To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease(VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing. RESULTS A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease(CD) or CDlike intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients(16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo(interquartile range(IQR): 4 to 78) and 43.5 mo(IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group(P = 0.001). However, there were no significant differences between weight-forage and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency. CONCLUSION A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.
基金the Foundation of National Key R&D Program of China of Research on Application Demonstration and Evaluation of Comprehensive Prevention And Control Technology of Birth Defects(Grant No.2018YFC1002700)Zhejiang R&D Research Project Research on New Technologies for Birth Health,Birth Safety and Perinatal Disease Diagnosis and Treatment(Grant No.2021C03099).
文摘Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.
基金partially supported by grants from the Ministry of Science and Technology of China(2016YFC1000306)the Beijing Municipal Science and Technology Commission Foundation(Z181100001918003)+1 种基金the Beijing Municipal Commission of Health and Family Planning Foundation(2018-21141,2020-4-1144)Beihang University&Capital Medical University Advanced Innovation Center for Big Data-Based Precision Medicine Plan(BHME-201905)。
文摘Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.
基金supported by Ministry of Science and Technology Project (2017YFC1001302 and 2016YFC0906400)the Grant of Shanghai Brain-Intelligence Project from the Shanghai Science and Technology Committee (STCSM) (16JC1420500)Shanghai Jiao Tong University Medical Engineering Cross Research Foundation (YG2014MS07)
文摘Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.
文摘Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.
基金supported by Macao FDCT(098/2012/A3)Research Grant of the University of Macao(UL017/08-Y4/MAT/QT01/FST)+1 种基金National Natural Science Funds for Young Scholars(10901166)Sun Yat-sen University Operating Costs of Basic ResearchProjects to Cultivate Young Teachers(11lgpy99)
文摘Appealing to the Clifford analysis and matching pursuits, we study the adaptive decompositions of functions of several variables of finite energy under the dictionaries consisting of shifted Cauchy kernels. This is a realization of matching pursuits among shifted Cauchy kernels in higher-dimensional spaces. It offers a method to process signals in arbitrary dimensions.
基金supported by grants from Shanghai Outstanding Academic Leaders(20XD1433300)Medical-Engineering Cross Foundation of Shanghai Jiao Tong University(YG2021ZD20)+3 种基金Shuguang Project(21SG11),Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212700)Shanghai Research Center for Endocrine,Metabolic Diseases(2022ZZ01002)Shanghai Sixth People’s Hospital Grant(ynhg202204)Shanghai Municipal Key Clinical Specialty.
文摘A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
基金the support of MATRICS Grant(MTR/2018/000779)funded by SERB,India.
文摘The enhanced power graph P_(E)(S)of a semigroup S is a simple graph whose vertex set is S and two vertices a,y∈S are adjacent if and only if c,y∈(z)for some z∈S,where(z)is the subsemigroup generated by z.In this paper,we first describe the structure of P_(E)(S)for an arbitrary semigroup S,and then discuss the connectedness of P_(E)(S).Further,we characterize the semigroup S in the cases when P_(E)(S)is separately a complete,bipartite,regular,tree and null graph.The planarity,together with the minimum degree and independence number,of P_(E)(S)is also investigated.The chromatic number of a spanning subgraph,i.e.,the cyclic graph,of P_(E)(S)is proved to be countable.In the final part of this paper,we construct an example of a semigroup S such that the chromatic number of P_(E)(S)need not be countable.
基金supported by National Key R&D Program of China(2021YFC2702005)National High Level Hospital Clinical Research Funding(2022-PUMCH-B-079).
文摘Background Monogenic lupus is defined as systemic lupus erythematosus(SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance.However,because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE,it causes a delay in diagnosis and treatment.Currently,there is a lack of early identification models for clinical practitioners to provide early clues for recognition.Our goal was to create a clinical model for the early identification of pediatric monogenic lupus,thereby facilitating early and precise diagnosis and treatment for patients.Methods This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022.The control group consisted of classical SLE patients recruited at a 1:2 ratio.Patients were randomly divided into a training group and a validation group at a 7:3 ratio.A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot.The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve(AUC)index.Results A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included.Among the monogenic lupus cases(with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years),a total of 18 gene mutations were identified.The variables included in the coefficient plot were age of onset,recurrent infections,intracranial calcifications,growth and developmental delay,abnormal muscle tone,lymphadenopathy/hepatosplenomegaly,and chilblain-like skin rash.Our model demonstrated satisfactory diagnostic performance through internal validation,with an AUC value of 0.97(95% confidence interval=0.92–0.97).Conclusions We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and develo
基金supported by Macao FDCT 056/2010/A3 and research grant of the University of Macao(Grant No.UL017/08-Y4/MAT/QT01/FST)
文摘We study the adaptive decomposition of functions in the monogenic Hardy spaces H2by higher order Szeg kernels under the framework of Clifford algebra and Clifford analysis,in the context of unit ball and half space.This is a sequel and a higher-dimensional generalization of our recent study on the complex Hardy spaces.
文摘Monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance patterns.Despite over 50 associated genetic disorders,accurate diagnoses and management of monogenic diabetes remain inadequate,underscoring insufficient clinician awareness.The disease spectrum encompasses maturity-onset diabetes of the young(MODY),characterized by distinct genetic mutations affecting insulin secretion,and neonatal diabetes mellitus(NDM)-a heterogeneous group of severe hyperglycemic disorders in infants.Mitochondrial diabetes,autoimmune monogenic diabetes,genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape.A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY.NDM diagnosis warrants immediate molecular genetic testing for infants under six months.Identifying these genetic defects presents a unique opportunity for precision medicine.Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes.Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes.The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.
文摘Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being.The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity.In rare instances,mutations leading to severe insulin resistance can also result in the development of diabetes.Individuals diagnosed with specific types of monogenic diabetes,which are commonly found,can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes.Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments.This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.
文摘Previous studies have documented the occurrence of glyphosate-resistant （GR） goosegrass （Eleusine indica （L.） Gaertn.） and, in at least some cases, resistance is due to an altered target site. Research was performed to determine if an altered target site was responsible for GR in a Tennessee, United States goosegrass population （TennGR）. DNA sequencing revealed a mutation in TennGR plants conferring the Prol06Ser 5-enolpyruvylshikimate-3-phosphate synthase （EPSPS） substitution previously identified in other GR populations. F2 populations were derived from TennGR plants crossed with plants from a glyphosate-susceptible population （TennGS） and analyzed for their response to glyphosate and genotyped at the EPSPS locus. Plants from the F2 populations segregated 1：2：1 sensitive：intermediate：resistant in response to a selec- tive dose of glyphosate, and these responses co-segregated with the EPSPS genotypes （PP106, PS106, and SS106）. To separately investigate the effect of the Prol06Ser substitution on GR, glyphosate dose-response curves and 50% effective dose （EDso） values were compared among the three genotypes and the two parental populations. The SS106 genotype was 3.4-fold resistant relative to the PP106 genotype, identical to the resistance level obtained when comparing the resistant and susceptible parental populations. We conclude that the mutation conferring a Prol06Ser EPSPS mutation is solely responsible for GR in the TennGR goosegrass population.
基金Authors extend their appreciation to Deanship of Scientific Research,King Faisal University,Saudi Arabia,for supporting this research(NA000112).
文摘Monogenic lines,which carried 23 genes for blast resistance were tested and used donors to transfer resistance genes by crossing method.The results under blast nursery revealed that 9 genes from 23 genes were susceptible to highly susceptible under the three locations(Sakha,Gemmeza,and Zarzoura in Egypt);Pia,Pik,Pik-p,Piz-t,Pita,Pi b,Pi,Pi 19 and Pi 20.While,the genes Pii,Pik-s,Pik-h,Pi z,Piz-5,Pi sh,Pi 3,Pi 1,Pi 5,Pi 7,Pi 9,Pi 12,Pikm and Pita-2 were highly resistant at the same locations.Clustering analysis confirmed the results,which divided into two groups;the first one included all the susceptible genes,while the second one included the resistance genes.In the greenhouse test,the reaction pattern of five races produced 100%resistance under artificial inoculation with eight genes showing complete resistance to all isolates.The completely resistant genes:Pii,Pik-s,Piz,Piz-5(=bi2)(t),Pita(=Pi4)(t),Pita,Pi b and Pi1 as well as clustering analysis confirmed the results.In the F1 crosses,the results showed all the 25 crosses were resistant for leaf blast disease under field conditions.While,the results in F2 population showed seven crosses with segregation ratio of 15(R):1(S),two cross gave segregated ratio of 3 R:1 S and one gave 13:3.For the identification of blast resistance genes in the parental lines,the marker K3959,linked to Pik-s gene and the variety IRBLKS-F5 carry this gene,which was from the monogenic line.The results showed that four genotypes;Sakha 105,Sakha 103,Sakha 106 and IRBLKS-F5 were carrying Pik-s gene,while was absent in the Sakha 101,Sakha 104,IRBL5-M,IRBL9-W,IRBLTACP1 and IRBL9-W(R)genotypes.As for Pi 5 gene,the results showed that it was present in Sakha 103 and Sakha 104 varieties and absent in the rest of the genotypes.In addition,Pita-Pita-2 gene was found in the three Egyptian genotypes(Sakha 105,Sakha 101 and Sakha 104)plus IRBLTACP1 monogenetic.In F2 generation,six populations were used to study the inheritance of blast resistance and specific primers to confirm the ratio and identif
基金supported by the National Natural Science Fund (30860161)National Basic Research Program (No. 2011CB100400)The Ministry of Science and Technology of China,the Natural Science Fund (2010ZC173)
文摘Knowledge of the geographic distribution and frequency of avirulence genes will contribute to the development of strategies to effectively use rice varieties that carry various resistances genes, including combinations of varieties in mixture cropping systems. Here, we analyzed the geographic distribution and frequencies of avirulence genes in rice blast fungus using samples collected from 11 prefectures across Yunnan province, China. A total of 467 single spore isolates were assayed for pathotypes based on their reaction to 20 rice blast resistance monogenic lines. The results revealed that frequencies of avirulence genes among 10 prefectures showed insignificant difference, but frequencies of avirulenee genes in Xishuangbanna showed significant differences compared to the remaining 10 prefectures. The avirulence genes Avr-Pi9, Avr-Piz and Avr-Pizt were observed at the highest frequency in blast isolates from the 11 prefectures; their average frequency was greater than 80%. Our results imply that the composition and distribution of rice genetic diversity are more important than climate and other environment conditions for formation and maintenance of rice blast fungus genetic diversity. Using average frequencies, the avirulence genes can be categorized into 4 groups. There were significant differences of frequencies of avirulence genes among different groups, while insignificant differences observed within any group. These results will provide useful information for evaluation of resistance genes and effective management of rice blast disease.
文摘Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early detection and geneticallyfocused treatment of neonatal diabetes and maturity-onset diabetes of theyoung can significantly improve long-term health and well-being. The etiology ofmonogenic diabetes in childhood is primarily attributed to genetic variationsaffecting the regulatory genes responsible for beta-cell activity. In rare instances,mutations leading to severe insulin resistance can also result in the developmentof diabetes. Individuals diagnosed with specific types of monogenic diabetes,which are commonly found, can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguishindividuals with type 1 or 2 diabetes from those more prone to monogenicdiabetes. Genetic screening with appropriate findings and interpretations isessential to establish a prognosis and to guide the choice of therapies andmanagement of these interrelated ailments. This review aims to design a comprehensiveliterature summarizing genetic insights into monogenetic diabetes inchildren and adolescents as well as summarizing their diagnosis and management.
