Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of...Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.展开更多
Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphol...Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphological subtypes and the grading system used in lung non-mucinous adenocarcinoma(LNMA).Methods:We developed a whole genome copy number variation(WGCNV)scoring system and applied next generation sequencing to evaluate CNVs present in 91 LNMA tumor samples.Results:Higher histological grades,aggressive subtypes and more advanced TNM staging were associated with an increased WGCNV score,particularly in CNV regions enriched for tumor suppressor genes and oncogenes.In addition,we demonstrate that 24-chromosome CNV profiling can be performed reliably from specific cell types(<100 cells)isolated by sample laser capture microdissection.Conclusions:Our findings suggest that the WGCNV scoring system we developed may have potential value as an adjunct test for predicting the prognosis of patients diagnosed with LNMA.展开更多
AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males ...AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males and 128 females) with chronic hepatitis B virus infection (CHB) and 300 patients (135 females and 165 males) with acute hepatitis B virus infection (AHB) as controls. All CHB patients were further categorized according to disease progression after HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). Copy numbers of the TLR7 gene were measured using the AccuCopy method chi(2) tests were used to evaluate the association between TLR7 CNVs and infection type. P values, odds ratios, and 95% confidence intervals (CIs) were used to estimate the effects of risk. RESULTS Among male patients, there were significant differences between the AHB group and CHB group in the distribution of TLR7 CNVs. Low copy numberof TLR7 was significantly associated with chronic HBV infection (OR = 0.329, 95% CI: 0.229-0.473, P > 0.001). Difference in TLR7 copy number was also found between AHB and CHB female patients, with low copy number again associated with an increased risk of chronic HBV infection (OR = 0.292, 95% CI: 0.173- 0.492, P < 0.001). However, there were no significant differences in TLR7 copy number among the three types of chronic HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). In addition, there was no association between TLR7 copy number and titer of the HBV e antigen. CONCLUSION Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.展开更多
As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),wh...As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),which focus mainly on the single-nucleotide polymorphisms.Little attention has been paid to examine the role of copy number variations(CNVs)in refractive error and myopia.This study adopted a systematic strategy to investigate the role of CNVs in high myopia.In the discovery phase,a pilot GWAS suggests putative CNVs for follow-up.Multiplex ligation-dependent probe amplification was then used to quantify the copy number of 89 CNV segments in 737 case-control samples in the second phase and then 24 top-ranking CNVs in a second group of 1,029 case-control samples in the final validation phase.This validation phase identified 22 significant CNVs.Further work is needed to examine the role of these few CNVs in myopia development.展开更多
Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful b...Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.展开更多
Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was th...Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.展开更多
Primary ciliary dyskinesia(PCD)is a rare disorder characterized by extensive genetic heterogeneity.However,in the genetic pathogenesis of PCD,copy number variation(CNV)has not received sufcient attention and has rarel...Primary ciliary dyskinesia(PCD)is a rare disorder characterized by extensive genetic heterogeneity.However,in the genetic pathogenesis of PCD,copy number variation(CNV)has not received sufcient attention and has rarely been reported,especially in China.Next-generation sequencing(NGS)followed by targeted CNV analysis was used in patients highly suspected to have PCD with negative results in routine whole-exome sequencing(WES)analysis.Quantitative real-time polymerase chain reaction(qPCR)and Sanger sequencing were used to confrm these CNVs.To further characterize the ciliary phenotypes,high-speed video microscopy analysis(HSVA),transmission electron microscopy(TEM),and immunofuorescence(IF)analysis were used.Patient 1(F1:II-1),a 0.6-year-old girl,came from a nonconsanguineous family-I.She presented with situs inversus totalis,neonatal respiratory distress,and sinusitis.The nasal nitric oxide level was markedly reduced.The respiratory cilia beat with reduced amplitude.TEM revealed shortened outer dynein arms(ODA)of cilia.chr5:13717907-13722661del spanning exons 71–72 was identifed by NGS-based CNV analysis.Patient 2(F2:IV-4),a 37-year-old man,and his eldest brother Patient 3(F2:IV-2)came from a consanguineous family-II.Both had sinusitis,bronchiectasis and situs inversus totalis.The respiratory cilia of Patient 2 and Patient 3 were found to be uniformly immotile,with ODA defects.Two novel homozygous deletions chr5:13720087_13733030delinsGTTTTC and chr5:13649539_13707643del,spanning exons 69–71 and exons 77–79 were identifed by NGS-based CNV analysis.Abnormalities in DNA copy number were confrmed by qPCR amplifcation.IF showed that the respiratory cilia of Patient 1 and Patient 2 were defcient in dynein axonemal heavy chain 5(DNAH5)protein expression.This report identifed three novel DNAH5 disease-associated variants by WES-based CNV analysis.Our study expands the genetic spectrum of PCD with DNAH5 in the Chinese population.展开更多
Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent...Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.展开更多
Diffuse large B-cell lymphoma(DLBCL)is the aggressive form of haematological malignancies with relapse/refractory in∼40%of cases.It mostly develops due to accumulation of various genetic and epigenetic variations tha...Diffuse large B-cell lymphoma(DLBCL)is the aggressive form of haematological malignancies with relapse/refractory in∼40%of cases.It mostly develops due to accumulation of various genetic and epigenetic variations that contribute to its aggressiveness.Though large-scale structural alterations have been reported in DLBCL,their functional role in pathogenesis and as potential targets for therapy is not yet well understood.In this study we performed detection and analysis of copy number variations(CNVs)in 11 human DLBCL cell lines(4 activated B-cell–like[ABC]and 7 germinal-centre B-cell–like[GCB]),that serve as model systems for DLBCL cancer cell biology.Significant heterogeneity observed in CNV profiles of these cell lines and poor prognosis associated with ABC subtype indicates the importance of individualized screening for diagnostic and prognostic targets.Functional analysis of key cancer genes exhibiting copy alterations across the cell lines revealed activation/disruption of ten potentially targetable immuno-oncogenic pathways.Genome guided in silico therapy that putatively target these pathways is elucidated.Based on our analysis,five CNV-genes associated with worst survival prognosis are proposed as potential prognostic markers of DLBCL.展开更多
Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify...Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify loci associated with awn length.Bulked-segregant RNA sequencing and linkage mapping identified a single dominant locus in a 0.3 cM interval on chromosome 5AL.Five genes were in the interval,including the recently cloned awn inhibitor B1.Although a single copy of the B1 gene was detected in 7D12,SY20 carried five copies of the gene.Increased copy number of B1 in SY20enhanced gene expression.Based on sequence variation among the promoter regions of five B1 gene copies in SY20,two dominant markers were developed and found to cosegregate with B1 in a population of 931 wheat accessions.All 77 awnless accessions harbored sequence variations in the B1 promoter regions similar to those of SY20 and thus carried multiple copies of the gene,whereas 15 randomly selected awned wheats carried only one copy.These results suggest that an increase in copy number of the B1 gene is associated with inhibition of awn length.展开更多
AIM:To investigate the genetic and clinical characteristics of patients with a large heterozygous copy number deletion on 7q31.31-7q31.32.METHODS:A family with familial exudative vitreoretinopathy(FEVR)phenotype was i...AIM:To investigate the genetic and clinical characteristics of patients with a large heterozygous copy number deletion on 7q31.31-7q31.32.METHODS:A family with familial exudative vitreoretinopathy(FEVR)phenotype was included in the study.Whole-exome sequencing(WES)was initially used to locate copy number variations(CNVs)on 7q31.31-31.32,but failed to detect the precise breakpoint.The long-read sequencing,Oxford Nanopore sequencing Technology(ONT)was used to get the accurate breakpoint which is verified by quantitative real-time polymerase chain reaction(QPCR)and Sanger Sequencing.RESULTS:The proband,along with her father and younger brother,were found to have a heterozygous 4.5 Mb CNV deletion located on 7q31.31-31.32,which included the FEVRrelated gene TSPAN12.The specific deletion was confirmed as del(7)(q31.31q31.32)chr7:g.119451239_123956818del.The proband exhibited a phase 2A FEVR phenotype,characterized by a falciform retinal fold,macular dragging,and peripheral neovascularization with leaking of fluorescence.These symptoms led to a significant decrease in visual acuity in both eyes.On the other hand,the affected father and younger brother showed a milder phenotype.CONCLUSION:The heterozygous CNV deletion located on 7q31.31-7q31.32 is associated with the FEVR phenotype.The use of long-read sequencing techniques is essential for accurate molecular diagnosis of genetic disorders.展开更多
Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laborato...Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laboratory tests,treatment process,and outcomes of three patients with positive cytomegalovirus load detected by CNV-seq for fetal chromosomes and cytomegalovirus load,and literature review was done simutaneoubly.Results:In all three cases,the amniotic fluid cytomegalovirus load was less than 105 Copies/ml,and there were no significant neurological abnormalities observed during pregnancy or postpartum follow-up.There is no literature review on the application of CNV-seq technology in the detection of cytomegalovirus infection,only literature reports on genome analysis of CMV-DNA in confirmed patients were available.Conclusion:CNV-seq can be used to detect cytomegalovirus load,which may have a certain degree of predictive value for fetal outcome.CNV-seq can simultaneously detect fetal chromosomes and pathogenic microorganisms,which is of great significance for the prevention and control of birth defects.展开更多
In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and t...In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and their evolutionary history remain unclear.We scanned PERVs in the current pig reference genome(assembly Build 11.1),and identified 36 long complete or near-complete PERVs(lc PERVs)and 23 short incomplete PERVs(si PERVs).Besides three known PERVs(PERV-A,-B,and-C),four novel types(PERV-JX1,-JX2,-JX3,and-JX4)were detected in this study.According to evolutionary analyses,the newly discovered PERVs were more ancient,and PERV-Bs probably experienced a bottleneck~0.5 million years ago(Ma).By analyzing63 high-quality porcine whole-genome resequencing data,we found that the PERV copy numbers in Chinese pigs were lower(32.0±4.0)than in Western pigs(49.1±6.5).Additionally,the PERV sequence diversity was lower in Chinese pigs than in Western pigs.Regarding the lc PERV copy numbers,PERV-A and-JX2 in Western pigs were higher than in Chinese pigs.Notably,Bama Xiang(BMX)pigs had the lowest PERV copy number(27.8±5.1),and a BMX individual had no PERV-C and the lowest PERV copy number(23),suggesting that BMX pigs were more suitable for screening and/or modification as xenograft donors.Furthermore,we identified 451 PERV transposon insertion polymorphisms(TIPs),of which 86 were shared by all 10 Chinese and Western pig breeds.Our findings provide systematic insights into the genomic distribution,variation,evolution,and possible biological function of PERVs.展开更多
Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic...Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic and local therapeutic approaches.Using The Cancer Genome Atlas(TCGA),we examined the relationship between copy number variation(CNV)of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1(SMARCC1)and distant metastatic illness in patients with CC.Methods Genetic sequencing data of all relevant CC patients and clinical features were collected from TCGA using R.There were 506 CC patients with CNV and clinical outcome data.The CNV of SMARCC1 was examined for its correlation with distant metastatic disease using the TCGA CC dataset(M1 vs.M0).After adjusting for age,sex,T stage,N stage,adjuvant chemotherapy,microsatellite instability(MSI),and surgical margin status,univariate and multivariate logistic regression analyses were performed.Results SMARCC1 CNV was linked to distant metastatic disease(P=0.012 and 0.008 in univariate and multivariate analysis,respectively);positive lymph nodes and margin status were also associated with distal metastases(all P<0.01).MSI,T stage,N stage,adjuvant treatment,sex,race,and MSI were not associated with metastases(all P>0.05).Conclusion SMARCC1 CNV is associated with distant metastatic disease in patients with CC.In individuals with CC,such genetic profiles might be utilized therapeutically to support optimal systemic treatment options against local treatments for CC,such as radiation therapy,pending additional confirmation.展开更多
<strong>Objective:</strong> <span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">DNA copy number alterati...<strong>Objective:</strong> <span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">DNA copy number alterations and difference expression are frequently observed in ovarian cancer. The purpose of this way was to pinpoint gene expression change that w</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">as</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> associated with alterations in DNA copy number and could therefore enlighten some potential oncogenes and stability genes with functional roles in cancers, and investigated the bioinformatics significance for those correlated genes</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">. </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Method: </span></b></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;">We obtained the DNA copy </span><span style="font-family:Verdana;">number and mRNA expression data from the Cancer Genomic Atlas and</span><span style="font-family:Verdana;"> identified the most statistically significant copy number alteration regions using the GISTIC. Then identified the significance genes between the tumor samples within the copy number alteration regions and analyzed the correlation using a binary matrix. The selected genes were subjected to bio</span><span><span style="font-family:Verdana;">informatics analysis using GSEA tool. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> GISTIC analysis results</span></span><span style="font-family:Verdana;"> showed there were 45 significance copy number amplification regions in the ovarian cancer, SAM and Fisher’s exact test found there have 40 genes can affect the expression level, which located in the amplification regions. That means we obtained 40 genes which have a correlation between copy number amplification and drastic up- and down-expression, which p-value < 0.05 (Fisher’s exact test) and an FDR < 0.05. GSEA enrichment analysis found these genes w</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">ere</span></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> overlapped with the several published studies which were focused on the gene study of tumorigenesis. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> The use of statistics and bioinformatics to analyze the microarray data can found an interaction network involved.</span></span></span></span><span style="font-family:""> <a name="OLE_LINK16"></a><a name="OLE_LINK10"></a><span><span style="font-family:Verdana;">The combination of the copy number data and expression has pro</span><span style="font-family:Verdana;">vided a short list of candidate genes that are consistent with tumor</span><span style="font-family:Verdana;"> driving roles. These would offer new ideas for early diagnosis and treat target of ovarian cancer.</span></span></span>展开更多
Background:Heterotaxy(HTX)is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease(CHD).The aim of this study was to analyze rare copy number variations(CNVs)in a HTX/CHD cohor...Background:Heterotaxy(HTX)is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease(CHD).The aim of this study was to analyze rare copy number variations(CNVs)in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.Methods:Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients,and available samples from parents were used to confirm the inheritance pattern.Potential candidate genes in CNVs region were prioritized via the DECIPHER database,and PNPLA4 was identified as the leading candidate gene.To validate,we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model,followed by a series of transcriptomic,biochemical and cellular analyses.Results:Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients(12.5%).Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort,and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD.PNPLA4 is expressed in the lateral plate mesoderm,which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation,and in the neural crest cell lineage.Through a series of in vivo and in vitro analyses at the molecular and cellular levels,we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production.Conclusions:Our findings demonstrated a significant association between CNVs and HTX/CHD.Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.展开更多
BACKGROUND The clinical manifestations of trisomy 7 mosaicism are diverse and nonspecific,so prenatal diagnosis is very difficult.CASE SUMMARY Two pregnant women with abnormal prenatal screening results were included....BACKGROUND The clinical manifestations of trisomy 7 mosaicism are diverse and nonspecific,so prenatal diagnosis is very difficult.CASE SUMMARY Two pregnant women with abnormal prenatal screening results were included.One was a 22-year-old woman(G1P0).At 31st week of gestation,ultrasound revealed that the posterior horn of the left lateral ventricle was 10 mm and the right renal pelvis had a separation of 7 mm.The other pregnant woman was 33 years old(G2P1L1A0),and her fetus was found to have a cardiac malformation at the 24th week of gestation.Copy number variation sequencing,whole-exome sequencing and karyotype analysis were carried out after amniocentesis,and both fetuses were diagnosed with trisomy 7 mosaicism.After parental counseling,one woman continued the pregnancy,and the other woman terminated the pregnancy.CONCLUSION In trisomy 7 mosaicism,the low proportion of trisomy does not lead to abortion,but can result in abnormal fetal development,which can be detected via ultrasound.Therefore,clinicians need to pay more attention to various aspects of fetal growth and development,combining with imaging,cellular,molecular genetics and other methods to perform comprehensive evaluations of fetuses to provide more reliable genetic counseling for pregnant women.展开更多
Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility...Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility,invasion,and metastasis.However,their specific contributions across different cancer types remain unclear.Methods:We conducted a pan-cancer bioinformatics analysis of FSCN genes using data from The Cancer Genome Atlas.This included differential expression patterns,copy number variations(CNVs),mutations,methylation status,and correlations with tumor mutational burden,microsatellite instability,and immune checkpoint molecule expression.Differential expression was analyzed using DESeq2,while CNV and mutation analyses utilized GISTIC2.0 and MuTect2.Methylation data were assessed using the Illumina Human Methylation 450K BeadChip.Results:FSCN1 and FSCN2 showed significant differential expression in multiple cancers,often correlating with poor prognosis.FSCN3 exhibited less variability but a protective role in certain contexts.CNV analysis indicated frequent gene gains in FSCN genes,correlating with increased expression.FSCN3 had a higher mutation rate,suggesting genetic instability.Methylation analysis showed hypomethylation of FSCN1 and FSCN2 in tumors compared to normal tissues,whereas FSCN3 had minor changes.Significant associations were found between FSCN gene expression and tumor mutational burden,microsatellite instability,and immune checkpoint molecules,suggesting their involvement in tumor immunogenicity and the immune microenvironment.Conclusions:This pan-cancer analysis highlights the multifaceted roles of FSCN genes in cancer biology,emphasizing their potential as biomarkers and therapeutic targets.FSCN1 and FSCN2 are associated with poor prognosis and aggressive phenotypes,while FSCN3 shows protective roles in specific contexts.These findings offer new avenues for cancer diagnosis and treatment,particularly in personalized medicine.Future studies should validate these findings and explore the underlying mechanisms to fully harness the clinical potential of FSCN family proteins in oncology.展开更多
BACKGROUND Copy number variation(CNV)has become widely recognized in recent years due to the extensive use of gene screening in developmental disorders and epilepsy research.1q21.1 microduplication syndrome is a rare ...BACKGROUND Copy number variation(CNV)has become widely recognized in recent years due to the extensive use of gene screening in developmental disorders and epilepsy research.1q21.1 microduplication syndrome is a rare CNV disease that can manifest as multiple congenital developmental disorders,autism spectrum disorders,congenital malformations,and congenital heart defects with genetic heterogeneity.CASE SUMMARY We reported a pediatric patient with 1q21.1 microduplication syndrome,and carried out a literature review to determine the correlation between 1q21.1microduplication and its phenotypes.We summarized the patient’s medical history and clinical symptoms,and extracted genomic DNA from the patient,her parents,elder brother,and sister.The patient was an 8-mo-old girl who was hospitalized for recurrent convulsions over a 2-mo period.Whole exon sequencing and whole genome low-depth sequencing(CNV-seq)were then performed.Whole exon sequencing detected a 1.58-Mb duplication in the CHR1:145883867-147465312 region,which was located in the 1q21.1 region.Family analysis showed that the pathogenetic duplication fragment,which was also detected in her elder brother’s DNA originated from the mother.CONCLUSION Whole exon sequencing combined with quantitative polymerase chain reaction can provide an accurate molecular diagnosis in children with 1q21.1 microduplication syndrome,which is of great significance for genetic counseling and early intervention.展开更多
BACKGROUND Quantitative fluorescent polymerase chain reaction(QF-PCR)is a rapid prenatal diagnostic method for abnormalities on chromosomes 21,18,and 13 and sex chromosomal aneuploidy.However,the value of QF-PCR in di...BACKGROUND Quantitative fluorescent polymerase chain reaction(QF-PCR)is a rapid prenatal diagnostic method for abnormalities on chromosomes 21,18,and 13 and sex chromosomal aneuploidy.However,the value of QF-PCR in diagnosing chromosomal structural abnormalities is limited.In this article,we report a confusing QF-PCR finding in a pregnant woman who underwent amniocentesis.CASE SUMMARY The short tandem repeat marker AMXY(Xp22.2/Yp11.2)located on the sex chromosome exhibited a trisomic biallelic pattern,indicating that the karyotype of the fetus might be 47,XYY.Chromosome analysis performed on cultured amniocytes showed a normal male karyotype of the fetus.Copy number variation sequencing confirmed a 500 kb duplication at Yp11.2-Yp11.2(chrY:6610001_7110000)and a 250 kb duplication at Yp11.2-Yp11.2(chrY:7110001_7360000).CONCLUSION In conclusion,the comprehensive application of different methods could achieve a higher detection rate and accuracy for the prenatal diagnosis of chromosomal disorders through chromosomal testing.展开更多
基金Dongguan City Social Development Project(Project number:20161081101023)。
文摘Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.
基金grants from Beijing Hospital Key Research Program(121 Research Program,No.BJ2019-195)。
文摘Objective:Histology grade,subtypes and TNM stage of lung adenocarcinomas are useful predictors of prognosis and survival.The aim of the study was to investigate the relationship between chromosomal instability,morphological subtypes and the grading system used in lung non-mucinous adenocarcinoma(LNMA).Methods:We developed a whole genome copy number variation(WGCNV)scoring system and applied next generation sequencing to evaluate CNVs present in 91 LNMA tumor samples.Results:Higher histological grades,aggressive subtypes and more advanced TNM staging were associated with an increased WGCNV score,particularly in CNV regions enriched for tumor suppressor genes and oncogenes.In addition,we demonstrate that 24-chromosome CNV profiling can be performed reliably from specific cell types(<100 cells)isolated by sample laser capture microdissection.Conclusions:Our findings suggest that the WGCNV scoring system we developed may have potential value as an adjunct test for predicting the prognosis of patients diagnosed with LNMA.
基金Supportedby National Natural Science Foundation of China,No.81273142
文摘AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection. METHODS This study included 623 patients (495 males and 128 females) with chronic hepatitis B virus infection (CHB) and 300 patients (135 females and 165 males) with acute hepatitis B virus infection (AHB) as controls. All CHB patients were further categorized according to disease progression after HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). Copy numbers of the TLR7 gene were measured using the AccuCopy method chi(2) tests were used to evaluate the association between TLR7 CNVs and infection type. P values, odds ratios, and 95% confidence intervals (CIs) were used to estimate the effects of risk. RESULTS Among male patients, there were significant differences between the AHB group and CHB group in the distribution of TLR7 CNVs. Low copy numberof TLR7 was significantly associated with chronic HBV infection (OR = 0.329, 95% CI: 0.229-0.473, P > 0.001). Difference in TLR7 copy number was also found between AHB and CHB female patients, with low copy number again associated with an increased risk of chronic HBV infection (OR = 0.292, 95% CI: 0.173- 0.492, P < 0.001). However, there were no significant differences in TLR7 copy number among the three types of chronic HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). In addition, there was no association between TLR7 copy number and titer of the HBV e antigen. CONCLUSION Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.
文摘As a complex disease,myopia is the most common eye disease worldwide.Many myopia susceptibility genes or variants have been successfully identified in the past years by genome-wide genetic association studies(GWAS),which focus mainly on the single-nucleotide polymorphisms.Little attention has been paid to examine the role of copy number variations(CNVs)in refractive error and myopia.This study adopted a systematic strategy to investigate the role of CNVs in high myopia.In the discovery phase,a pilot GWAS suggests putative CNVs for follow-up.Multiplex ligation-dependent probe amplification was then used to quantify the copy number of 89 CNV segments in 737 case-control samples in the second phase and then 24 top-ranking CNVs in a second group of 1,029 case-control samples in the final validation phase.This validation phase identified 22 significant CNVs.Further work is needed to examine the role of these few CNVs in myopia development.
基金Beijing Natural Science Foundation(No.7181002)Capital’s Funds for Health Improvement and Research(No.2018-1-1021)National Key Research&Development Program of China(No.2016YFC0901404)
文摘Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.
基金Supported in parts by grants from the Swedish Cancer Society(CAN 2010/255),the Swedish Research Council(08712),Tore Nilson Foundation,Assar Gabrielsson Foundation(AB Volvo),Jubileumskliniken Foundation,IngaBritt&Arne Lundberg Research Foundation,Swedish and Gothenburg Medical Societies and the Medical Faculty,University of Gothenburg,VGR 19/00,1019/00.
文摘Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.
基金Shanghai Natural Science Foundation of Science and Technology Innovation Action Plan(Grant Number:21ZR1410200 and 21ZR1409900).
文摘Primary ciliary dyskinesia(PCD)is a rare disorder characterized by extensive genetic heterogeneity.However,in the genetic pathogenesis of PCD,copy number variation(CNV)has not received sufcient attention and has rarely been reported,especially in China.Next-generation sequencing(NGS)followed by targeted CNV analysis was used in patients highly suspected to have PCD with negative results in routine whole-exome sequencing(WES)analysis.Quantitative real-time polymerase chain reaction(qPCR)and Sanger sequencing were used to confrm these CNVs.To further characterize the ciliary phenotypes,high-speed video microscopy analysis(HSVA),transmission electron microscopy(TEM),and immunofuorescence(IF)analysis were used.Patient 1(F1:II-1),a 0.6-year-old girl,came from a nonconsanguineous family-I.She presented with situs inversus totalis,neonatal respiratory distress,and sinusitis.The nasal nitric oxide level was markedly reduced.The respiratory cilia beat with reduced amplitude.TEM revealed shortened outer dynein arms(ODA)of cilia.chr5:13717907-13722661del spanning exons 71–72 was identifed by NGS-based CNV analysis.Patient 2(F2:IV-4),a 37-year-old man,and his eldest brother Patient 3(F2:IV-2)came from a consanguineous family-II.Both had sinusitis,bronchiectasis and situs inversus totalis.The respiratory cilia of Patient 2 and Patient 3 were found to be uniformly immotile,with ODA defects.Two novel homozygous deletions chr5:13720087_13733030delinsGTTTTC and chr5:13649539_13707643del,spanning exons 69–71 and exons 77–79 were identifed by NGS-based CNV analysis.Abnormalities in DNA copy number were confrmed by qPCR amplifcation.IF showed that the respiratory cilia of Patient 1 and Patient 2 were defcient in dynein axonemal heavy chain 5(DNAH5)protein expression.This report identifed three novel DNAH5 disease-associated variants by WES-based CNV analysis.Our study expands the genetic spectrum of PCD with DNAH5 in the Chinese population.
基金supported by the National Basic Research Program of China(No.2012CB944600)the National Key Research and Development Program of China(No.2016YFC0905100)+1 种基金the National Natural Science Foundation of China(Nos.31521003,31625015,31571297,31601046,31525014 and 91331204)the Science and Technology Commission of Shanghai Municipality(No.16YF1413900)
文摘Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.
文摘Diffuse large B-cell lymphoma(DLBCL)is the aggressive form of haematological malignancies with relapse/refractory in∼40%of cases.It mostly develops due to accumulation of various genetic and epigenetic variations that contribute to its aggressiveness.Though large-scale structural alterations have been reported in DLBCL,their functional role in pathogenesis and as potential targets for therapy is not yet well understood.In this study we performed detection and analysis of copy number variations(CNVs)in 11 human DLBCL cell lines(4 activated B-cell–like[ABC]and 7 germinal-centre B-cell–like[GCB]),that serve as model systems for DLBCL cancer cell biology.Significant heterogeneity observed in CNV profiles of these cell lines and poor prognosis associated with ABC subtype indicates the importance of individualized screening for diagnostic and prognostic targets.Functional analysis of key cancer genes exhibiting copy alterations across the cell lines revealed activation/disruption of ten potentially targetable immuno-oncogenic pathways.Genome guided in silico therapy that putatively target these pathways is elucidated.Based on our analysis,five CNV-genes associated with worst survival prognosis are proposed as potential prognostic markers of DLBCL.
基金supported by the National Key Research and Development Program of China(2018YFD0300501)。
文摘Wheat awns contribute to photosynthesis and grain production.In this study,an F2population and F2:3families from a cross between the awned line 7D12 and the Chinese awnless variety Shiyou 20(SY20)were used to identify loci associated with awn length.Bulked-segregant RNA sequencing and linkage mapping identified a single dominant locus in a 0.3 cM interval on chromosome 5AL.Five genes were in the interval,including the recently cloned awn inhibitor B1.Although a single copy of the B1 gene was detected in 7D12,SY20 carried five copies of the gene.Increased copy number of B1 in SY20enhanced gene expression.Based on sequence variation among the promoter regions of five B1 gene copies in SY20,two dominant markers were developed and found to cosegregate with B1 in a population of 931 wheat accessions.All 77 awnless accessions harbored sequence variations in the B1 promoter regions similar to those of SY20 and thus carried multiple copies of the gene,whereas 15 randomly selected awned wheats carried only one copy.These results suggest that an increase in copy number of the B1 gene is associated with inhibition of awn length.
基金Supported by the National Natural Science Foundation of China(No.82060183)Ningxia Natural Science Foundation(No.2022AAC03388)the Key Research and Development Project of Ningxia Hui Autonomous Region(No.2021BEG02045,No.2020BEG03044).
文摘AIM:To investigate the genetic and clinical characteristics of patients with a large heterozygous copy number deletion on 7q31.31-7q31.32.METHODS:A family with familial exudative vitreoretinopathy(FEVR)phenotype was included in the study.Whole-exome sequencing(WES)was initially used to locate copy number variations(CNVs)on 7q31.31-31.32,but failed to detect the precise breakpoint.The long-read sequencing,Oxford Nanopore sequencing Technology(ONT)was used to get the accurate breakpoint which is verified by quantitative real-time polymerase chain reaction(QPCR)and Sanger Sequencing.RESULTS:The proband,along with her father and younger brother,were found to have a heterozygous 4.5 Mb CNV deletion located on 7q31.31-31.32,which included the FEVRrelated gene TSPAN12.The specific deletion was confirmed as del(7)(q31.31q31.32)chr7:g.119451239_123956818del.The proband exhibited a phase 2A FEVR phenotype,characterized by a falciform retinal fold,macular dragging,and peripheral neovascularization with leaking of fluorescence.These symptoms led to a significant decrease in visual acuity in both eyes.On the other hand,the affected father and younger brother showed a milder phenotype.CONCLUSION:The heterozygous CNV deletion located on 7q31.31-7q31.32 is associated with the FEVR phenotype.The use of long-read sequencing techniques is essential for accurate molecular diagnosis of genetic disorders.
基金Hainan Natural Science Foundation(821RC699)Hainan Natural Science Foundation(822RC825)+1 种基金Hainan Provincial Health Industry Research Project(22A200242)Key R&D Plan of Hainan Province(ZDYF2020225)。
文摘Objective:To summarize the application value of copy number variant sequencing(CNV-seq)in the detection of fetal chromosome and cytomegalovirus load.Methods:The study analyzed the clinical basic data,relevant laboratory tests,treatment process,and outcomes of three patients with positive cytomegalovirus load detected by CNV-seq for fetal chromosomes and cytomegalovirus load,and literature review was done simutaneoubly.Results:In all three cases,the amniotic fluid cytomegalovirus load was less than 105 Copies/ml,and there were no significant neurological abnormalities observed during pregnancy or postpartum follow-up.There is no literature review on the application of CNV-seq technology in the detection of cytomegalovirus infection,only literature reports on genome analysis of CMV-DNA in confirmed patients were available.Conclusion:CNV-seq can be used to detect cytomegalovirus load,which may have a certain degree of predictive value for fetal outcome.CNV-seq can simultaneously detect fetal chromosomes and pathogenic microorganisms,which is of great significance for the prevention and control of birth defects.
基金supported by the National Swine Industry and Technology System of China(nycytx-009)National Natural Science Foundation of China(31672383)。
文摘In pig-to-human xenotransplantation,the transmission risk of porcine endogenous retroviruses(PERVs)is of great concern.However,the distribution of PERVs in pig genomes,their genetic variation among Eurasian pigs,and their evolutionary history remain unclear.We scanned PERVs in the current pig reference genome(assembly Build 11.1),and identified 36 long complete or near-complete PERVs(lc PERVs)and 23 short incomplete PERVs(si PERVs).Besides three known PERVs(PERV-A,-B,and-C),four novel types(PERV-JX1,-JX2,-JX3,and-JX4)were detected in this study.According to evolutionary analyses,the newly discovered PERVs were more ancient,and PERV-Bs probably experienced a bottleneck~0.5 million years ago(Ma).By analyzing63 high-quality porcine whole-genome resequencing data,we found that the PERV copy numbers in Chinese pigs were lower(32.0±4.0)than in Western pigs(49.1±6.5).Additionally,the PERV sequence diversity was lower in Chinese pigs than in Western pigs.Regarding the lc PERV copy numbers,PERV-A and-JX2 in Western pigs were higher than in Chinese pigs.Notably,Bama Xiang(BMX)pigs had the lowest PERV copy number(27.8±5.1),and a BMX individual had no PERV-C and the lowest PERV copy number(23),suggesting that BMX pigs were more suitable for screening and/or modification as xenograft donors.Furthermore,we identified 451 PERV transposon insertion polymorphisms(TIPs),of which 86 were shared by all 10 Chinese and Western pig breeds.Our findings provide systematic insights into the genomic distribution,variation,evolution,and possible biological function of PERVs.
基金Supported by a grant from the Joint Project of Southwest Medical University-Three Affiliated Hospitals(No.2017-ZRQN-028).
文摘Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer(CC).The discovery of genetic changes linked to metastatic CC might aid in the development of systemic and local therapeutic approaches.Using The Cancer Genome Atlas(TCGA),we examined the relationship between copy number variation(CNV)of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1(SMARCC1)and distant metastatic illness in patients with CC.Methods Genetic sequencing data of all relevant CC patients and clinical features were collected from TCGA using R.There were 506 CC patients with CNV and clinical outcome data.The CNV of SMARCC1 was examined for its correlation with distant metastatic disease using the TCGA CC dataset(M1 vs.M0).After adjusting for age,sex,T stage,N stage,adjuvant chemotherapy,microsatellite instability(MSI),and surgical margin status,univariate and multivariate logistic regression analyses were performed.Results SMARCC1 CNV was linked to distant metastatic disease(P=0.012 and 0.008 in univariate and multivariate analysis,respectively);positive lymph nodes and margin status were also associated with distal metastases(all P<0.01).MSI,T stage,N stage,adjuvant treatment,sex,race,and MSI were not associated with metastases(all P>0.05).Conclusion SMARCC1 CNV is associated with distant metastatic disease in patients with CC.In individuals with CC,such genetic profiles might be utilized therapeutically to support optimal systemic treatment options against local treatments for CC,such as radiation therapy,pending additional confirmation.
文摘<strong>Objective:</strong> <span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">DNA copy number alterations and difference expression are frequently observed in ovarian cancer. The purpose of this way was to pinpoint gene expression change that w</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">as</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> associated with alterations in DNA copy number and could therefore enlighten some potential oncogenes and stability genes with functional roles in cancers, and investigated the bioinformatics significance for those correlated genes</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">. </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Method: </span></b></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;">We obtained the DNA copy </span><span style="font-family:Verdana;">number and mRNA expression data from the Cancer Genomic Atlas and</span><span style="font-family:Verdana;"> identified the most statistically significant copy number alteration regions using the GISTIC. Then identified the significance genes between the tumor samples within the copy number alteration regions and analyzed the correlation using a binary matrix. The selected genes were subjected to bio</span><span><span style="font-family:Verdana;">informatics analysis using GSEA tool. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> GISTIC analysis results</span></span><span style="font-family:Verdana;"> showed there were 45 significance copy number amplification regions in the ovarian cancer, SAM and Fisher’s exact test found there have 40 genes can affect the expression level, which located in the amplification regions. That means we obtained 40 genes which have a correlation between copy number amplification and drastic up- and down-expression, which p-value < 0.05 (Fisher’s exact test) and an FDR < 0.05. GSEA enrichment analysis found these genes w</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">ere</span></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> overlapped with the several published studies which were focused on the gene study of tumorigenesis. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> The use of statistics and bioinformatics to analyze the microarray data can found an interaction network involved.</span></span></span></span><span style="font-family:""> <a name="OLE_LINK16"></a><a name="OLE_LINK10"></a><span><span style="font-family:Verdana;">The combination of the copy number data and expression has pro</span><span style="font-family:Verdana;">vided a short list of candidate genes that are consistent with tumor</span><span style="font-family:Verdana;"> driving roles. These would offer new ideas for early diagnosis and treat target of ovarian cancer.</span></span></span>
基金supported by the National Key Research and Development Project of China(No.2021YFC2701000)Natural Science Foundation of China(Nos.82270312 and 82370309)+1 种基金Shanghai Basic Research Project of Science and Technology Innovation Action Plan(No.20JC1418300)CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-002).
文摘Background:Heterotaxy(HTX)is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease(CHD).The aim of this study was to analyze rare copy number variations(CNVs)in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.Methods:Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients,and available samples from parents were used to confirm the inheritance pattern.Potential candidate genes in CNVs region were prioritized via the DECIPHER database,and PNPLA4 was identified as the leading candidate gene.To validate,we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model,followed by a series of transcriptomic,biochemical and cellular analyses.Results:Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients(12.5%).Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort,and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD.PNPLA4 is expressed in the lateral plate mesoderm,which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation,and in the neural crest cell lineage.Through a series of in vivo and in vitro analyses at the molecular and cellular levels,we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production.Conclusions:Our findings demonstrated a significant association between CNVs and HTX/CHD.Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.
文摘BACKGROUND The clinical manifestations of trisomy 7 mosaicism are diverse and nonspecific,so prenatal diagnosis is very difficult.CASE SUMMARY Two pregnant women with abnormal prenatal screening results were included.One was a 22-year-old woman(G1P0).At 31st week of gestation,ultrasound revealed that the posterior horn of the left lateral ventricle was 10 mm and the right renal pelvis had a separation of 7 mm.The other pregnant woman was 33 years old(G2P1L1A0),and her fetus was found to have a cardiac malformation at the 24th week of gestation.Copy number variation sequencing,whole-exome sequencing and karyotype analysis were carried out after amniocentesis,and both fetuses were diagnosed with trisomy 7 mosaicism.After parental counseling,one woman continued the pregnancy,and the other woman terminated the pregnancy.CONCLUSION In trisomy 7 mosaicism,the low proportion of trisomy does not lead to abortion,but can result in abnormal fetal development,which can be detected via ultrasound.Therefore,clinicians need to pay more attention to various aspects of fetal growth and development,combining with imaging,cellular,molecular genetics and other methods to perform comprehensive evaluations of fetuses to provide more reliable genetic counseling for pregnant women.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility,invasion,and metastasis.However,their specific contributions across different cancer types remain unclear.Methods:We conducted a pan-cancer bioinformatics analysis of FSCN genes using data from The Cancer Genome Atlas.This included differential expression patterns,copy number variations(CNVs),mutations,methylation status,and correlations with tumor mutational burden,microsatellite instability,and immune checkpoint molecule expression.Differential expression was analyzed using DESeq2,while CNV and mutation analyses utilized GISTIC2.0 and MuTect2.Methylation data were assessed using the Illumina Human Methylation 450K BeadChip.Results:FSCN1 and FSCN2 showed significant differential expression in multiple cancers,often correlating with poor prognosis.FSCN3 exhibited less variability but a protective role in certain contexts.CNV analysis indicated frequent gene gains in FSCN genes,correlating with increased expression.FSCN3 had a higher mutation rate,suggesting genetic instability.Methylation analysis showed hypomethylation of FSCN1 and FSCN2 in tumors compared to normal tissues,whereas FSCN3 had minor changes.Significant associations were found between FSCN gene expression and tumor mutational burden,microsatellite instability,and immune checkpoint molecules,suggesting their involvement in tumor immunogenicity and the immune microenvironment.Conclusions:This pan-cancer analysis highlights the multifaceted roles of FSCN genes in cancer biology,emphasizing their potential as biomarkers and therapeutic targets.FSCN1 and FSCN2 are associated with poor prognosis and aggressive phenotypes,while FSCN3 shows protective roles in specific contexts.These findings offer new avenues for cancer diagnosis and treatment,particularly in personalized medicine.Future studies should validate these findings and explore the underlying mechanisms to fully harness the clinical potential of FSCN family proteins in oncology.
文摘BACKGROUND Copy number variation(CNV)has become widely recognized in recent years due to the extensive use of gene screening in developmental disorders and epilepsy research.1q21.1 microduplication syndrome is a rare CNV disease that can manifest as multiple congenital developmental disorders,autism spectrum disorders,congenital malformations,and congenital heart defects with genetic heterogeneity.CASE SUMMARY We reported a pediatric patient with 1q21.1 microduplication syndrome,and carried out a literature review to determine the correlation between 1q21.1microduplication and its phenotypes.We summarized the patient’s medical history and clinical symptoms,and extracted genomic DNA from the patient,her parents,elder brother,and sister.The patient was an 8-mo-old girl who was hospitalized for recurrent convulsions over a 2-mo period.Whole exon sequencing and whole genome low-depth sequencing(CNV-seq)were then performed.Whole exon sequencing detected a 1.58-Mb duplication in the CHR1:145883867-147465312 region,which was located in the 1q21.1 region.Family analysis showed that the pathogenetic duplication fragment,which was also detected in her elder brother’s DNA originated from the mother.CONCLUSION Whole exon sequencing combined with quantitative polymerase chain reaction can provide an accurate molecular diagnosis in children with 1q21.1 microduplication syndrome,which is of great significance for genetic counseling and early intervention.
文摘BACKGROUND Quantitative fluorescent polymerase chain reaction(QF-PCR)is a rapid prenatal diagnostic method for abnormalities on chromosomes 21,18,and 13 and sex chromosomal aneuploidy.However,the value of QF-PCR in diagnosing chromosomal structural abnormalities is limited.In this article,we report a confusing QF-PCR finding in a pregnant woman who underwent amniocentesis.CASE SUMMARY The short tandem repeat marker AMXY(Xp22.2/Yp11.2)located on the sex chromosome exhibited a trisomic biallelic pattern,indicating that the karyotype of the fetus might be 47,XYY.Chromosome analysis performed on cultured amniocytes showed a normal male karyotype of the fetus.Copy number variation sequencing confirmed a 500 kb duplication at Yp11.2-Yp11.2(chrY:6610001_7110000)and a 250 kb duplication at Yp11.2-Yp11.2(chrY:7110001_7360000).CONCLUSION In conclusion,the comprehensive application of different methods could achieve a higher detection rate and accuracy for the prenatal diagnosis of chromosomal disorders through chromosomal testing.
