scholarly journals Clinical Validation of a Non-Invasive Prenatal Test for Genome-Wide Detection of Fetal Copy Number Variants

2015 ◽  
Author(s):  
Roy B Lefkowitz ◽  
John A Tynan ◽  
Tong Liu ◽  
Yijin Wu ◽  
Amin R Mazloom ◽  
...  
Keyword(s):  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Karyotype Analysis ◽  
Copy Number Variants ◽  
Trisomy 13 ◽  
Clinical Validation ◽  
Fetal Sex ◽  
Non Invasive ◽  
Genome Wide ◽  
Wide Range

Background: Current cell-free DNA (cfDNA) assessment of fetal chromosomes does not analyze and report on all chromosomes. Hence, a significant proportion of fetal chromosomal abnormalities are not detectable by current non-invasive methods. Here we report the clinical validation of a novel NIPT designed to detect genome-wide gains and losses of chromosomal material ≥7 Mb and losses associated with specific deletions <7 Mb. Objective: The objective of this study is to provide a clinical validation of the sensitivity and specificity of a novel NIPT for detection of genome-wide abnormalities. Study Design: This retrospective, blinded study included maternal plasma collected from 1222 study subjects with pregnancies at increased risk for fetal chromosomal abnormalities that were assessed for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), fetal sex, genome-wide copy number variants (CNVs) 7 Mb and larger, and select deletions smaller than 7 Mb. Performance was assessed by comparing test results with findings from G-band karyotyping, microarray data, or high coverage sequencing. Results: Clinical sensitivity within this study was determined to be 100% for T21, T18, T13, and SCAs, and 97.7% for genome-wide CNVs. Clinical specificity within this study was determined to be 100% for T21, T18, and T13, and 99.9% for SCAs and CNVs. Fetal sex classification had an accuracy of 99.6%. Conclusion: This study has demonstrated that genome-wide non-invasive prenatal testing (NIPT) for fetal chromosomal abnormalities can provide high resolution, sensitive, and specific detection of a wide range of sub-chromosomal and whole chromosomal abnormalities that were previously only detectable by invasive karyotype analysis. In some instances, this NIPT also provided additional clarification about the origin of genetic material that had not been identified by invasive karyotype analysis.

scholarly journals Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

2019 ◽  
Author(s):  
Junhua Rao ◽  
Lihua Peng ◽  
Fang Chen ◽  
Hui Jiang ◽  
Chunyu Geng ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Whole Genome ◽  
Genome Wide ◽  
Wide Range ◽  
Distribution Sensitivity ◽  
Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

scholarly journals Genome-wide cell-free DNA screening: a focus on copy-number variants

2021 ◽  
Author(s):  
Jill Rafalko ◽  
Erica Soster ◽  
Samantha Caldwell ◽  
Eyad Almasri ◽  
Thomas Westover ◽  
...  
Keyword(s):  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Cell Free Dna ◽  
Predictive Values ◽  
Free Dna ◽  
Genome Wide ◽  
Cfdna Screening ◽  
Diagnostic Outcomes

Abstract Purpose Of 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. Methods Cases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. Results CNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1–79.5%) and 71.8% (95% CI: 65.5–77.4%) for “fetal-only” events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5–68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6–97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. Conclusion Genome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

scholarly journals The Value of Non-Invasive Prenatal Testing in the Diagnosis of Birth Defects: Insights from a Large Multicentre Study in Southern China

2021 ◽  
Author(s):  
Meiying Cai ◽  
Na Lin ◽  
Xuemei Chen ◽  
Ying Li ◽  
Min Lin ◽  
...  
Keyword(s):  
Multicentre Study ◽  
Pregnant Women ◽  
Chromosomal Abnormalities ◽  
Southern China ◽  
Prenatal Testing ◽  
Copy Number Variations ◽  
Trisomy 13 ◽  
Detection Rates ◽  
Non Invasive ◽  
Large Multicentre Study

Abstract Non-invasive prenatal testing (NIPT) is a fast, safe, and non-disruptive diagnostic method. At present, few studies have evaluated the screening efficiency of NIPT positive predictive value (PPV) in study subjects. Here, the results of NIPT in pregnant women were retrospectively analysed, and the detection rate, PPV and follow-up data were evaluated to determine its clinical value. A large multicentre study was conducted involving 52,855 pregnant women who received NIPT. Based on gestational age, amniotic fluid or umbilical cord blood were extracted for simultaneous karyotype and chromosome microarray analysis (CMA) in NIPT-positive patients. Among the 52,855 cases, 754 were NIPT-positive, with a positivity rate of 1.4%. Karyotype analysis and/or CMA confirmed 323 cases of chromosomal abnormalities, with a PPV of 45.1%. PPV of Trisomy 21 (T21), Trisomy 18 (T18), Trisomy 13 (T13), sex chromosomal aneuploidies (SCA) and copy number variations (CNV) were 78.9%, 35.3%, 22.2%, 36.9% and 32.9%, respectively. The PPV of T21, T18, and T13 increased with age whereas, the PPV of SCA and CNVs had little correlation with age. The PPV was significantly high in patients with advanced age along with an abnormal ultrasound.NIPT had a high PPV for T21, and a low PPV for T13 and T18, while screening for SCA and CNVs showed clinical significance. However, in case of NIPT screening for SCA and CNVs, simultaneous karyotype and CMA should be performed to increase the detection rates. Interventional prenatal diagnosis is still required in NIPT-positive cases to avoid false positives or unnecessary termination of pregnancy.

scholarly journals RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing

2016 ◽  
Vol 15 ◽  
pp. CIN.S36612 ◽  
Author(s):  
Lun-Ching Chang ◽  
Biswajit Das ◽  
Chih-Jian Lih ◽  
Han Si ◽  
Corinne E. Camalier ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Estimation Methods ◽  
Single Nucleotide Variants ◽  
False Positive Error ◽  
Reference Set ◽  
Genome Wide ◽  
Whole Exome

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly ( r = 0.96–0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

scholarly journals Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder

2011 ◽  
Vol 17 (4) ◽  
pp. 421-432 ◽  
Author(s):  
L Priebe ◽  
F A Degenhardt ◽  
S Herms ◽  
B Haenisch ◽  
M Mattheisen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Early Onset ◽  
Copy Number ◽  
Copy Number Variants ◽  
Genome Wide ◽  
Genome Wide Survey

High Resolution Genomic Profiling in CLL Using SNP Oligonucleotide Microarrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2946-2946
Author(s):  
Justyna Rawluk ◽  
Dietmar Pfeifer ◽  
Milena Pantic ◽  
Hendrik Veelken
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Fish Analysis ◽  
Genomic Profiling ◽  
Genetic Changes ◽  
Genome Wide ◽  
Custom Made ◽  
Wide Range ◽  
The Common ◽  
Regions Of Homozygosity

Abstract Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by different recurrent chromosomal aberrations with prognostic significance. Therefore, convenient genome-wide assays to identify genetic changes with high accuracy are required to assess the risk category of an individual patient, and to identify genetic mechanisms underlying the malignant transformation. Array-based CGH with custom-made chips has been proposed for this purpose (Schwaenen et al., 2004). We analyzed unselected peripheral blood cells from 50 consecutive CLL patients (33 with mutated IgVH genes) for the presence of genetic changes using Affymetrix 10k and 50k SNP mapping arrays that allow copy number analysis with a mean intermarker distance 300 kb and 60 kb, respectively. The detection limit of the assay with respect to tumor cell content was 25 to 40 % as assessed by validation experiments with a commercially available panel of FISH probes for typical recurrent CLL aberrations. 14 cases (28%) failed to show any detectable abnormalities. Among the common prognostically important aberrations, we readily identified del13q14 in 26 (52%), trisomy 12 in 9 (18%), del11q22 in 6 (12%), and del17p13 in 3 cases (6%). In 9 cases, additional losses in 17q (3 cases), 14q (2 cases), 5q (2 cases), 1q, 18p and 20q were detected. Likewise, multiple gains like trisomy 3, dup17q and dup2p (2 cases) were diagnosed. In addition to their convenient detection, size and extent of genomic aberrations can be defined with high resolution due to the precise positional information of the SNPs: In 2 out of 6 patients with a del11q22, in which deletion of the ATM (ataxia-telangiectasia mutated) gene is thought to represent the critical event, the ATM gene was present, but a 1Mb deletion around the RDX (radixin) gene was revealed. These deletions were missed by FISH analysis with ATM-spanning probes. Similarly, TP53 was still present in 1 of 3 patients with del17p13, despite the common assumption that this deletion causes the loss of a TP53 allele. An observed gain of 2p16 could be narrowed down to a 3Mb region containing the REL gene. Overexpression of REL may contribute to resistance to DNA-damage-induced apoptosis in CLL cells in vitro (Vallat et al., 2003). Finally, both the 10k and 50k SNP arrays showed the extent of the most frequent del13q14 in a wide range with a size distribution of 500kb to over 30Mb. However, for a more reliable detection of the del13q14 core region, the 50k array may be preferable to the 10k version, since this region is covered by 34 compared to 4 SNPs, respectively. Unexpectedly, 3 of 6 cases with a homozygous del13q14 showed loss of heterozygosity (LOH) associated with a normal copy number distal to the del13q14 extending to the telomere. A similar phenomenon has recently been described in AML patients (Raghavan et al., 2005) and can be explained by a somatic recombination event. Preliminary analyses demonstrated additional large regions of homozygosity ranging from 3 to over 20Mb on various chromosomes in at least 12 CLL cases. In conclusion, genomic profiling with Affymetrix SNP microarrays is an efficient screening method for simultaneous genome-wide detection of submicroscopic aberrations. Information on genotype with dosis information reveals hitherto undetected regions of homozygosity that may harbor imprinted genes or loss-of-function alleles with importance for the pathogenesis of CLL.

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