scholarly journals Copy Number Variations Analysis Identifies QPRT as a Candidate Gene Associated With Susceptibility for Solitary Functioning Kidney

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao Y. Zhou ◽  
Hao Y. Zheng ◽  
Li Han ◽  
Yan Wang ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Candidate Gene ◽  
Copy Number ◽  
Copy Number Variations ◽  
Renal Tubules ◽  
Human Embryonic Kidney ◽  
Solitary Functioning Kidney ◽  
Triple X Syndrome ◽  
Pathogenic Cnvs ◽  
Functioning Kidney

BackgroundThe lack of understanding of molecular pathologies of the solitary functioning kidney makes improving and strengthening the continuity of care between pediatric and adult nephrological patients difficult. Copy number variations (CNVs) account for a molecular cause of solitary functioning kidney, but characterization of the pathogenic genes remains challenging.MethodsIn our prospective cohort study, 99 fetuses clinically diagnosed with a solitary functioning kidney were enrolled and evaluated using chromosomal microarray analysis (CMA). The genetic drivers for the pathogenic CNVs were analyzed. We characterized QPRT localization in fetal kidneys using immunohistochemistry and its expression in adult kidneys using quantitative RT-PCR. Further, QPRT was knocked down using siRNA in human embryonic kidney (HEK293T) cells, and the cell cycle and proliferation were tested.ResultsBesides one Triple X syndrome and one Down syndrome, we identified a total of 45 CNVs out of 34 subjects. Among the 14 pathogenic CNVs, CNV 16p11.2 reached the highest number of records with the phenotype of kidney anomalies in the Decipher database. Among the 26 genes within the 16p11.2 region, as a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, QPRT was distinctly localized in renal tubules but was barely observed in renal interstitial and glomeruli in fetal kidneys. The loss of QPRT prevented cells’ efficient transition into S phase, affected cell-cycle progression, and abrogated proliferation of human embryonic kidney cells.ConclusionOur data suggest that QPRT is a candidate gene associated with susceptibility for solitary functioning kidney. The CNVs discovered in our study exhibit great potential for future applications in genetic counseling and pregnancy management.

scholarly journals Detection of Clinically Relevant Copy Number Variations and Genes in a Bangladeshi Cohort of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Hosneara Akter ◽  
Muhammad Mizanur Rahman ◽  
Shaoli Sarker ◽  
Mohammed Basiruzzaman ◽  
Mazharul Islam ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Critical Role ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Potential Candidate ◽  
Female Ratio ◽  
Pathogenic Cnvs

Abstract Background: Copy number variations (CNVs) play a critical role into the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple gene constraint metrics (i.e. “Critical-Exon Genes (CEGs)”) were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show severe social communication deficit (p=0.014) and overall ASD symptoms severity (p=0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs and identified PSMC3 gene as a potential candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis therapeutics and management of NDD patients.

scholarly journals Clinical Utility and the Yield of Single Nucleotide Polymorphism Array in Prenatal Diagnosis of Fetal Central Nervous System Abnormalities

2021 ◽  
Vol 8 ◽  
Author(s):  
Meiying Cai ◽  
Hailong Huang ◽  
Liangpu Xu ◽  
Na Lin
Keyword(s):  
Central Nervous System ◽  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Karyotype Analysis ◽  
Snp Array ◽  
Copy Number Variations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pathogenic Cnvs

Applying single nucleotide polymorphism (SNP) array to identify the etiology of fetal central nervous system (CNS) abnormality, and exploring its association with chromosomal abnormalities, copy number variations, and obstetrical outcome. 535 fetuses with CNS abnormalities were analyzed using karyotype analysis and SNP array. Among the 535 fetuses with CNS abnormalities, chromosomal abnormalities were detected in 36 (6.7%) of the fetuses, which were consistent with karyotype analysis. Further, additional 41 fetuses with abnormal copy number variations (CNVs) were detected using SNP array (the detection rate of additional abnormal CNVs was 7.7%). The rate of chromosomal abnormalities, but not that of pathogenic CNVs in CNS abnormalities with other ultrasound abnormalities was significantly higher than that in isolated CNS abnormalities. The rates of chromosomal abnormalities and pathogenic CNVs in fetuses with spine malformation (50%), encephalocele (50%), subependymal cyst (20%), and microcephaly (16.7%) were higher than those with other isolated CNS abnormalities. The pregnancies for 36 cases with chromosomal abnormalities, 18 cases with pathogenic CNVs, and three cases with VUS CNVs were terminated. SNP array should be used in the prenatal diagnosis of fetuses with CNS abnormalities, which can enable better prenatal assessment and genetic counseling, and affect obstetrical outcomes.

scholarly journals Frequency of CDK2 , CCNE1 Copy Number Variation in Acral Melanoma and Implications for CDK Inhibitor in Targeted Therapy

2020 ◽  
Author(s):  
Xiaowen Wu ◽  
Junya Yan ◽  
Jiayi Yu ◽  
Jinyu Yu ◽  
Zhiyuan Cheng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Targeted Therapy ◽  
Copy Number Variation ◽  
Copy Number ◽  
Melanoma Cells ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Cdk Inhibitor ◽  
Acral Melanoma ◽  
Number Variation

Abstract Background: Acral melanoma have a high frequency of cell cycle-related gene copy number variation. However, the status and clinical significance of CNVs of CDK 2 and CCNE1 have not been fully elucidated. Methods: A total of 490 acral melanoma samples were examined for CNVs of CDK 2 and CCNE1 using QuantiGenePlex DNA Assay. Correlations of CDK2 and CCNE1 CNVs to clinicopathologic features and prognosis of acral melanoma were evaluated.The sensitivity of cell lines and cell-derived xenograft (CDX) containing CCNE1 CNVs to CDK inhibitor AT7519,Dinaciclib and proteasome inhibitor Bortezomib were also analyzed. Results: Among the 490 samples,140 cases, 139 cases and 39 cases respectively showed CDK2 gain (28.5%), CCNE1 gain (28.3%) and CDK2 gain plus CCNE1 gain (8.0%).The median progression-free survival (PFS) time for acral patients with CCNE1 gain was significantly shorter than that for patients without CCNE1 gain (17.0 versus 27.0 months; P =0.002). Furthermore, CCNE1 gain was an independent prognostic factor for patients receiving chemotherapy. The pan-CDK inhibitor AT7519 could inhibit the cell proliferation, induce apoptosis and cause cell cycle arrest in G2 phase of acral melanoma cells and inhibit the tumor growth of CDX with CCNE1 gain. Dinaciclib and Bortezomib showed CCNE1 copy number independent inhibitory effects on the proliferation of melanoma cells. Conclusions: CDK2 and CCNE1 copy number variations were frequent in acral melanoma and CCNE1 gain may be a useful biomarker to predict the outcome of receiving chemotherapy in patients with acral melanoma. In addition, our study provides a basis for the use of CDK inhibitor in the treatment of acral melanoma. Keywords: acral melanoma, targeted therapy, CDK2 , CCNE1 , copy number variation

scholarly journals Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Wang ◽  
Bin Zhang ◽  
Lingna Zhou ◽  
Qin Zhou ◽  
Yingping Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Screening ◽  
Comprehensive Evaluation ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Non Invasive ◽  
Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs &gt; 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

scholarly journals Application of Copy Number Variation Detection to Fetal Diagnosis of Echogenic Intracardiac Focus During Pregnancy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yaxian Song ◽  
Jingjing Xu ◽  
Hongmiao Li ◽  
Jiong Gao ◽  
Limin Wu ◽  
...  
Keyword(s):  
Heart Development ◽  
Copy Number ◽  
Maternal Age ◽  
Chromosomal Abnormalities ◽  
Cardiac Development ◽  
Copy Number Variations ◽  
Fetal Diagnosis ◽  
Increased Risk ◽  
Pathogenic Cnvs ◽  
Number Variation

Echogenic intracardiac focus (EIF) is one of the most common ultrasound soft markers (USMs) in prenatal screening. However, the association of EIF with chromosomal abnormalities is still controversial. From January 2018 to April 2020, a total of 571 fetuses with USMs in our center were enrolled, among which 150 (26.27%) presented EIFs. We analyzed the karyotype anomalies and copy number variations (CNVs) in fetuses who presented EIFs by comparing their ultrasound indications, maternal ages and gestational stages. There were no statistically significant differences in the incidence of chromosomal abnormalities between fetuses with EIFs and the fetuses with USMs (4.00 vs. 7.71%, p = 0.112). Additionally, the incidence of chromosomal abnormalities was not related to maternal age (4.10% in maternal age below 35 yeas vs. 3.57% in maternal age above 35, p = 1.000). Interestingly, after 28 weeks of gestation, fetuses with EIFs showed more chromosomal abnormalities (20.00%) than that in the group before 28 weeks of gestation (2.22%, p = 0.014), and this result was attributed to the detection of pathogenic CNVs. After birth, 25 of children conducted cardiac development re-examination. Among them, 9 (36%, 9/25) were diagnosed with congenital heart disease, primarily patent foramen oval and ventricular septal defects (7/9, 77.77%). We concluded that the appearance of EIFs in early or mid-trimester would not indicate an increased risk of fetal chromosomal abnormalities. However, the persistence of EIFs in late trimester was associated with a higher risk of pathology-related CNVs and its persistent appearance may indicate heart development defects after birth. Thus, our results suggest that CNV detection has its advantages in prenatal diagnosis, especially for those with EIFs that persist in the third trimester.

scholarly journals Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle 

2021 ◽  
Author(s):  
Xingyu Zhang ◽  
Bo Wang ◽  
Guoling You ◽  
Ying Xiang ◽  
Qihua Fu ◽  
...  
Keyword(s):  
Copy Number ◽  
Trisomy 21 ◽  
Single Ventricle ◽  
Snp Array ◽  
Copy Number Variations ◽  
Chinese Children ◽  
Atrioventricular Canal ◽  
Rare Cnvs ◽  
Pathogenic Cnvs ◽  
Complete Atrioventricular

Abstract Background: Congenital heart disease (CHD) is the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here, we screened pathogenic CNVs in Chinese children with two rare types of CHD, complete atrioventricular canal (CAVC) and single ventricle (SV) .Methods：We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases.Results: Among 262 CAVC patients, we identified 44 rare CNVs in 43 individuals (16.4 %, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 88.6% rare CNVs (39/44) were duplications of 21q11.2-21q22.3, which were categorized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1 (24:15), and the rate of pulmonary hypertension (PH) was 41% (16/39). Additionally, 6 rare CNVs were identified in the SV patients (2.3%, 6/259), and none of them was trisomy 21.Conclusions: Our study identified 50 rare CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two rare CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and higher incidence of PH. The presence of rare CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

Genomic profiling identified novel prognostic biomarker in Chinsese glioma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14538-e14538
Author(s):  
Hainan Li ◽  
Changguo Shan ◽  
Chongzhu Fan ◽  
Shengnan Wu ◽  
Mingyao Lai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Survival Data ◽  
Copy Number ◽  
Copy Number Variations ◽  
Occurrence Rate ◽  
Molecular Diagnostic ◽  
Poor Overall Survival ◽  
Tissue Samples ◽  
Pik3ca Mutations

e14538 Background: Molecular charactersitcs are essential for the classification and grading of gliomas. However, majority of current understanding is based on public databases that might not accurately reflect the Asian population. Here, we studied the mutation landscape of Chinese glioma patients in hope to provide new insights for glioma prognosis and treatment. Methods: Tissue samples from 112 glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their prognostic effect using overall survival data. Pathway-based survival analysis was peformed using top ten predefined oncogenic pathways. Results: We identified similar prevalence of currently established molecular diagnostic markers of glioma, including TP53 (33%), EGFR(26%), TERT (24%), PTEN (21%), ATRX (14%), BRAF (13%) and IDH1/2 (6%). Among all genetic abberations with more than 5% occurrence rate, four mutations and four copy number gains were significantly associated with poor overall survival (univariate, P < 0.05). Of these, TERT mutations (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.31 to 7.49; P = 0.01) and EGFR amplification (HR, 2.67; 95% CI, 1.20 to 5.95; P = 0.02) remained significant after adjusting for clinical parameters. Similarly, PIK3CA mutations, which was also frequently mutated in glioma but not used for clinical classification, were found to correlate with poor prognosis (HR, 2.61; 95% CI, 1.19 to 5.74; P = 0.02). Additionally, we have also identified MCL1 amplification as a potential novel biomarker for glioma (HR, 2.73; 95% CI, 1.47 to 5.07; P < 0.001), which was seldom reported in the TCGA database and might possibly be ancestral specific giving its high prevelance in our cohort (found in 32% patients). Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12 to 2.95; P = 0.02) and cell cycle pathways (HR, 2.04; 95% CI, 1.2 to 3.47; P < 0.001), both of which stayed meaningful after adjusting for clinical factors. Conclusions: In this study, we discovered PIK3CA mutations and MCL1 amplification as novel prognostic markers of glioma. We also demonstrated shorter survival with abnormal PI3K and cell cycle pathways that provided an intergrative understanding of glioma.

scholarly journals Cytogenomic Changes in Sporadic Colorectal Cancer and Surrounding Nonneoplastic Tissues: The Relevance of Subtelomeric Copy Number Variations

2021 ◽  
Author(s):  
Mariana Rocha ◽  
Evelin Aline Zanardo ◽  
Alexandre Torchio Dias ◽  
Fabrícia Andréia Rosa Madia ◽  
Thaís Virgínia Moura Machado Costa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number ◽  
Copy Number Variations ◽  
Sporadic Colorectal Cancer ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pathogenic Cnvs ◽  
Mechanism Of Carcinogenesis ◽  
Tumor Genome ◽  
Dependent Probe

Abstract The purpose of this study was to investigate the relevance of subtelomeric cytogenomic changes in patients with sporadic colorectal cancer (CRC) using multiplex ligation-dependent probe amplification (MLPA) and single nucleotide polymorphism arrays. The results revealed pathogenic genomic alterations in the TNFRS18 (1p), CHL1 (3p), TRIML2 (4q), FBXO25 (8p), NKX3-1 (8p), RECQL4 (8q), DOCK8 (9p), ZMYND11 (10p), KDM5A (12p), PSPC1 (13q), ADPRTL2 (14q), MTA1 (14q), DECR2 (16p), GAS8 (16q), THOC1 (18p), CTDP1 (18q), SOX12 (20p), ADRM1 (20q), UCKL1 (20q), OPRL1 (20q), IL17RA (22q), and SYBL1 (Xq) genes. We detected copy number variations (CNVs) with frequencies greater than 40% in the probes located in 20q, which contains very important genes in the study of tumors. These findings showed instability in the tumor genome and altered regions associated with cell migration, transcription activation, apoptosis, and immune system deregulation. Unexpectedly, we detected concomitant pathogenic CNVs in tumors and surrounding tissues. Our data suggest that characterizing the genomic CRC profile is an important contribution to better understanding instability as a mechanism of carcinogenesis in CRC patients.

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