目的比较TruSeq^(®)Exome与NimbleGen SeqCap EZ Human Exome两种外显子捕获试剂在脑瘫患儿中的捕获性能差异,为临床遗传学研究和诊断提供技术选择依据。方法纳入48例散发脑瘫患儿外周血样本,分别采用TruSeq(DNA探针)和NimbleGen(...目的比较TruSeq^(®)Exome与NimbleGen SeqCap EZ Human Exome两种外显子捕获试剂在脑瘫患儿中的捕获性能差异,为临床遗传学研究和诊断提供技术选择依据。方法纳入48例散发脑瘫患儿外周血样本,分别采用TruSeq(DNA探针)和NimbleGen(RNA探针)构建外显子组文库,经Illumina HiSeq 2000平台测序。通过生物信息学分析评估比对率、目标区域覆盖度、变异检出一致性等指标,并基于脑瘫相关基因集(2293个基因)分析捕获性能的临床相关性,采用配对t检验进行统计学分析(显著性阈值α=0.05)。结果NimbleGen和TruSeq两种外显子组捕获试剂盒在基础数据质量(比对率、插入片段长度)和GC含量上差异无统计学意义。然而,在关键性能指标上呈现互补特征,NimbleGen在特定深度覆盖上表现更优(1×覆盖率,P=1.84×10^(-5);20×覆盖率,P=1.49×10^(-20));而TruSeq则展现出更高的Indel检测灵敏度(TruSeq vs.NimbleGen:11371±1689 vs.11274±1670,P=3.24×10^(-7))和罕见变异捕获能力(TruSeq vs.NimbleGen:3164±766 vs.3072±774,P=1.20×10^(-4)),并成功检出所有11个阳性致病变异(包括NimbleGen漏检的2例)。结论TruSeq凭借更优的变异检出率更适合临床诊断场景,而NimbleGen的覆盖稳定性可能有利于研究性项目。展开更多
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Who...The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.展开更多
Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were id...Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were identified and captured by interphase fluorescence in situ hybridisation(iFISH).Single cell whole exome sequencing(WES)was performed and the corresponding bioinformatics data were analysed.OCT4+cells were successfully detected in peripheral blood collected from all four Stage I lung cancer patients.Moreover,the tumour mutational burden(TMB)values observed for OCT4+samples from the same patients were slightly smaller than those of the OCT4−samples;the difference was not statistically significant(P>0.05).Thirteen and six characteristic mutations were found in negative samples and positive samples,respectively.The findings indicate that this methodology provides a potential diagnostic index for the early detection of NSCLC.展开更多
For the recent expansion of renewable energy applications, Wind Energy System (WES) is receiving much interest all over the world. However, area load change and abnormal conditions lead to mismatches in frequency and ...For the recent expansion of renewable energy applications, Wind Energy System (WES) is receiving much interest all over the world. However, area load change and abnormal conditions lead to mismatches in frequency and scheduled power interchanges between areas. These mismatches have to be corrected by the LFC system. This paper, therefore, proposes a new robust frequency control technique involving the combination of conventional Proportional-Integral (PI) and Model Predictive Control (MPC) controllers in the presence of wind turbines (WT). The PI-MPC technique has been designed such that the effect of the uncertainty due to governor and turbine parameters variation and load disturbance is reduced. A frequency response dynamic model of a single-area power system with an aggregated generator unit is introduced, and physical constraints of the governors and turbines are considered. The proposed technique is tested on the single-area power system, for enhancement of the network frequency quality. The validity of the proposed method is evaluated by computer simulation analyses using Matlab Simulink. The results show that, with the proposed PI-MPC combination technique, the overall closed loop system performance demonstrated robustness regardless of the presence of uncertainties due to variations of the parameters of governors and turbines, and loads disturbances. A performance comparison between the proposed control scheme, the classical PI control scheme and the MPC is carried out confirming the superiority of the proposed technique in presence of doubly fed induction generator (DFIG) WT.展开更多
Background:No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy(HCM)populations.Methods:This cross-sectional study included Chinese patients(n=593)with HCM ...Background:No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy(HCM)populations.Methods:This cross-sectional study included Chinese patients(n=593)with HCM and controls(n=491)who underwent whole-exomesequencing.Rare variants in 16 validated HCM genes were assessed and compared with a United Kingdom HCM cohort(n=1232)and controls(n=344745).Results:Chinese HCM patients have a higher proportion of rare variants(52.8%vs 13.6%,P<0.001)but have a similar proportion ofpathogenic(P)or likely pathogenic(LP)variants compared to the UK cohort.In addition,the Chinese cohort had additional associationswith the combined thin filament genes(P=1.29E−9)and myosin light chain genes(P=4.43E−3).The United Kingdom cohort wassignificantly associated with MYBPC3 non-truncating variants(P=2.99E−7).By classifying variants using the tool genebe,the variantsof uncertain significance were minimized to 46.8% compared to other tools(63.3% by Intervar;91.3% by CardioClassifier).Furthermore,we report that c.3624del in MYBPC3 and c.300C>G in TNNT2 account for 2.9% and 1.5% of all Chinese HCM cases,respectively.Conclusion:Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are lesslikely to be classified as P/LP variants in HCM genes than those of European origin.The variants of c.3624del in MYBPC3 and c.300C>Gin TNNT2 were specific to Chinese individuals and provide important insights into the ethnic differences of HCM genetic architecture.展开更多
Birth defects are caused by multiple factors,such as chromosome abnormality,environmental factors,and maternal factors.In this study,we focused on exploring the genetic causes of a non-consanguineous couple who suffer...Birth defects are caused by multiple factors,such as chromosome abnormality,environmental factors,and maternal factors.In this study,we focused on exploring the genetic causes of a non-consanguineous couple who suffered from four times of unsuccessful pregnancy due to unexplained recurrent fetal malformations with similar symptoms and normal chromosome copy number variations.Using trio-whole exome sequencing(trio-WES) for this couple and one of the affected fetuses,we found a mutation,c.1996 delC on the maternal imprinted gene MAGEL2 that was carried by the affected fetus and husband,leading to Schaaf-Yang syndrome.To screen this mutation,we further performed preimplantation genetic diagnosis(PGD) strategy followed by a gene pedigree validation and pathogenicity analysis.After the transfer of a PGD-screened embryo,a normal newborn without previous abnormal symptoms was born(February 15,2019).We present the first data that identified a pathogenic gene(MAGEL2 c.1996 delC) in a fetus with Schaaf-Yang syndrome in the EAS(East Asian) database and overcame this genetic defect by using processed PGD for this couple based on the WES results.展开更多
基金supported by the National Natural Science Foundation of China (Nos. 31522034 and 81730038)the National High Technology Research and Development Program Grant (2015AA020407)
文摘The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
基金the National Natural Science Foundation of China(No.81773273)。
文摘Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were identified and captured by interphase fluorescence in situ hybridisation(iFISH).Single cell whole exome sequencing(WES)was performed and the corresponding bioinformatics data were analysed.OCT4+cells were successfully detected in peripheral blood collected from all four Stage I lung cancer patients.Moreover,the tumour mutational burden(TMB)values observed for OCT4+samples from the same patients were slightly smaller than those of the OCT4−samples;the difference was not statistically significant(P>0.05).Thirteen and six characteristic mutations were found in negative samples and positive samples,respectively.The findings indicate that this methodology provides a potential diagnostic index for the early detection of NSCLC.
文摘For the recent expansion of renewable energy applications, Wind Energy System (WES) is receiving much interest all over the world. However, area load change and abnormal conditions lead to mismatches in frequency and scheduled power interchanges between areas. These mismatches have to be corrected by the LFC system. This paper, therefore, proposes a new robust frequency control technique involving the combination of conventional Proportional-Integral (PI) and Model Predictive Control (MPC) controllers in the presence of wind turbines (WT). The PI-MPC technique has been designed such that the effect of the uncertainty due to governor and turbine parameters variation and load disturbance is reduced. A frequency response dynamic model of a single-area power system with an aggregated generator unit is introduced, and physical constraints of the governors and turbines are considered. The proposed technique is tested on the single-area power system, for enhancement of the network frequency quality. The validity of the proposed method is evaluated by computer simulation analyses using Matlab Simulink. The results show that, with the proposed PI-MPC combination technique, the overall closed loop system performance demonstrated robustness regardless of the presence of uncertainties due to variations of the parameters of governors and turbines, and loads disturbances. A performance comparison between the proposed control scheme, the classical PI control scheme and the MPC is carried out confirming the superiority of the proposed technique in presence of doubly fed induction generator (DFIG) WT.
基金supported by grants from the Natural ScienceFoundation of China(grant No.82202248)the Natural ScienceFoundation of Sichuan Province(grant No.23NSFSC4589)+8 种基金1·3·5 projects for Artificial Intelligence,West China Hospital,Sichuan University(grant No.ZYAI24003)support from the NIHR Birmingham HPRU,NIHR Birmingham BRC,Nanocommons H2020-EU(731032)MAESTRIA(grant agreement ID 965286)CRUCK(PRCNPG-Nov23/100001)HYPERMARKER(grant agreement ID 101095480)PARC(grantAgreement No 101057014)the MRC Heath Data ResearchUK(HDRUK/CFC/01)HDRUK midlands regional communityproject(QQ2)initiatives funded by UK Research and Innovation,Department of Health and Social Care(England)and the devolved administrations,and leading medical research charities.
文摘Background:No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy(HCM)populations.Methods:This cross-sectional study included Chinese patients(n=593)with HCM and controls(n=491)who underwent whole-exomesequencing.Rare variants in 16 validated HCM genes were assessed and compared with a United Kingdom HCM cohort(n=1232)and controls(n=344745).Results:Chinese HCM patients have a higher proportion of rare variants(52.8%vs 13.6%,P<0.001)but have a similar proportion ofpathogenic(P)or likely pathogenic(LP)variants compared to the UK cohort.In addition,the Chinese cohort had additional associationswith the combined thin filament genes(P=1.29E−9)and myosin light chain genes(P=4.43E−3).The United Kingdom cohort wassignificantly associated with MYBPC3 non-truncating variants(P=2.99E−7).By classifying variants using the tool genebe,the variantsof uncertain significance were minimized to 46.8% compared to other tools(63.3% by Intervar;91.3% by CardioClassifier).Furthermore,we report that c.3624del in MYBPC3 and c.300C>G in TNNT2 account for 2.9% and 1.5% of all Chinese HCM cases,respectively.Conclusion:Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are lesslikely to be classified as P/LP variants in HCM genes than those of European origin.The variants of c.3624del in MYBPC3 and c.300C>Gin TNNT2 were specific to Chinese individuals and provide important insights into the ethnic differences of HCM genetic architecture.
基金supported by the National Natural Science Foundation of China(31522034,81521002,81730038)the National High Technology Research and Development Program(2015AA020407)
文摘Birth defects are caused by multiple factors,such as chromosome abnormality,environmental factors,and maternal factors.In this study,we focused on exploring the genetic causes of a non-consanguineous couple who suffered from four times of unsuccessful pregnancy due to unexplained recurrent fetal malformations with similar symptoms and normal chromosome copy number variations.Using trio-whole exome sequencing(trio-WES) for this couple and one of the affected fetuses,we found a mutation,c.1996 delC on the maternal imprinted gene MAGEL2 that was carried by the affected fetus and husband,leading to Schaaf-Yang syndrome.To screen this mutation,we further performed preimplantation genetic diagnosis(PGD) strategy followed by a gene pedigree validation and pathogenicity analysis.After the transfer of a PGD-screened embryo,a normal newborn without previous abnormal symptoms was born(February 15,2019).We present the first data that identified a pathogenic gene(MAGEL2 c.1996 delC) in a fetus with Schaaf-Yang syndrome in the EAS(East Asian) database and overcame this genetic defect by using processed PGD for this couple based on the WES results.
