scholarly journals Prenatal Diagnosis and Molecular Cytogenetic Characterization of Copy Number Variations on 4p15.2p16.3, Xp22.31, and 12p11.1q11 in a Fetus with Ultrasound Anomalies: A Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Han Zhang ◽  
Qi Xi ◽  
Xiangyin Liu ◽  
Fagui Yue ◽  
Hongguo Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Genetic Disorders ◽  
Chromosomal Rearrangements ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosome 2 ◽  
Cytogenetic Characterization

Chromosomal rearrangements, such as duplications/deletions, can lead to a variety of genetic disorders. Herein, we reported a prenatal case with right aortic arch and aberrant left subclavian artery, consisting of a complex chromosomal copy number variations. Routine cytogenetic analysis described the chromosomal karyotype as 46,XY, add (2)(q37) for the fetus. However, the chromosomal microarray analysis (CMA) identified a 22.4 Mb duplication in chromosome 4p16.3p15.2, a 3.96 Mb microduplication in 12p11.1q11, and a 1.68 Mb microdeletion in Xp22.31. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe was found to hybridize to the terminal of chromosome 2q on the fetus, thus confirming that the extra genetic materials of chromosome 2 was actually trisomy 4p detected through CMA. Meanwhile, the parental karyotypes were normal, which proved that the add (2) was de novo for fetus. The duplication of Wolf-Hirschhorn syndrome critical region (WHSCR) and X-linked recessive ichthyosis associated with Xp22.31 deletion separately were considered potentially pathogenic causes although other abnormalities involving these syndromes were not observed. For prenatal cases, the combined utilization of ultrasonography, traditional cytogenetic, and molecular diagnosis technology will enhance better diagnostic benefits, offer more detailed genetic counselling, and assess the prognosis of the fetuses.

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 > 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 High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study

2020 ◽  
Vol 66 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Yu Sun ◽  
Xiantao Ye ◽  
Yanjie Fan ◽  
Lili Wang ◽  
Xiaomei Luo ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Copy Number Variations ◽  
Systematic Evaluation ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Large Sample Size ◽  
Analytical Sensitivity ◽  
Capture Sequencing

Abstract Background Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis. Methods We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method. Results The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49). Conclusions These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.

Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

2015 ◽  
Vol 146 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Weiqiang Liu ◽  
Rui Zhang ◽  
Jun Wei ◽  
Huimin Zhang ◽  
Guojiu Yu ◽  
...  
Keyword(s):  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Imprinting Disorders ◽  
Genome Wide ◽  
Number Variation ◽  
Efficient Alternative

Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.

scholarly journals Mosaic duplication of 8q24.1q24.3 detected by chromosomal microarray but not karyotyping in two unrelated fetuses with cardiac defects

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shaobin Lin ◽  
Shufang Huang ◽  
Xueling Ou ◽  
Heng Gu ◽  
Yonghua Wang ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Copy Number ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cardiac Defects ◽  
Prenatal Genetic Diagnosis ◽  
Tumor Tissues ◽  
Number Variation

Abstract Background Discordance between traditional cytogenetic and molecular cytogenetic tests is rare but not uncommon. The explanation of discordance between two genetic methods is difficult but especially important for genetic counseling, particularly for prenatal genetic diagnosis. Case presentation Two unrelated fetuses were diagnosed with cardiac defects by prenatal ultrasound examination, and invasive cordocentesis was performed to obtain cord blood samples for prenatal genetic diagnosis. For both fetuses, chromosomal microarray analysis (CMA) detected a novel approximately 27-Mb mosaic duplication with a high copy number of approximately six to seven copies on chromosome 8q24.1q24.3 that was not identified by karyotyping. To exclude artificial errors and validate laboratory detection results, multiple procedures including copy number variation sequencing, fluorescence in situ hybridization, and short tandem repeat and single-nucleotide polymorphism genotype comparison were performed, confirming the discordant results between CMA and karyotyping. The potential causes of discordance between CMA and karyotyping using fetal blood lymphocytes are discussed; we suggest that extrachromosomal DNA or cell-free DNA fragmentation originating from certain tumor tissues with 8q24.1q24.3 duplication might deserve further investigation. Conclusions This study may be helpful for prenatal evaluation and genetic counseling for subsequent patients with similar mosaic 8q24.1q24.3 duplications. Additionally, more cases and further research are needed to understand whether mosaic 8q24.1q24.3 duplication is associated with certain genetic disorders and to investigate the causes of discordance between molecular and morphological methods.

scholarly journals Optical Genome Mapping as a Next-Generation Cytogenomic Tool for Detection of Structural and Copy Number Variations for Prenatal Genomic Analyses

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 398
Author(s):  
Nikhil Shri Sahajpal ◽  
Hayk Barseghyan ◽  
Ravindra Kolhe ◽  
Alex Hastie ◽  
Alka Chaubey
Keyword(s):  
Copy Number ◽  
Southern Blotting ◽  
Genome Mapping ◽  
Genetic Disorders ◽  
Prenatal Testing ◽  
Standard Of Care ◽  
Copy Number Variations ◽  
Repeat Expansion ◽  
Chromosomal Microarray ◽  
Next Generation

Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders.

scholarly journals Performance of Chromosomal Microarray Analysis for Detection of Copy Number Variations in Fetal Echogenic Bowel

2021 ◽  
Vol Volume 14 ◽  
pp. 1431-1438
Author(s):  
Xiangqun Fan ◽  
Hailong Huang ◽  
Xiyao Lin ◽  
Huili Xue ◽  
Meiying Cai ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Copy Number ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis

scholarly journals Translational Study of Copy Number Variations in Schizophrenia

2021 ◽  
Vol 23 (1) ◽  
pp. 457
Author(s):  
Min-Chih Cheng ◽  
Wei-Hsien Chien ◽  
Yu-Shu Huang ◽  
Ting-Hsuan Fang ◽  
Chia-Hsiang Chen
Keyword(s):  
Screening Test ◽  
Copy Number ◽  
Large Scale ◽  
Cost Effective ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Two Stage ◽  
Translational Study ◽  
Analysis Group

Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

scholarly journals Large mosaic copy number variations confer autism risk

2020 ◽  
Author(s):  
Maxwell A. Sherman ◽  
Rachel E. Rodin ◽  
Giulio Genovese ◽  
Caroline Dias ◽  
Alison R. Barton ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Clinical Symptoms ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosome 2 ◽  
Simons Simplex Collection ◽  
Post Mortem Brain ◽  
Significant Burden

AbstractAlthough germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.

scholarly journals A retrospective study of noninvasive prenatal testing for chromosome aneuploidies and subchromosomal copy number variations in 24359 single pregnancies

2020 ◽  
Author(s):  
yuefang Liu ◽  
Longfei Cheng ◽  
Yuan Peng ◽  
Zhe Liang ◽  
Xin Jin ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Copy Number ◽  
False Negative ◽  
Prenatal Testing ◽  
Clinical Information ◽  
Copy Number Variations ◽  
Trisomy 13 ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis

Abstract Background: With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by non-invasive prenatal testing(NIPT). Our study is aimed to review the efficacy of NIPT as a screening test for aneuploidies and subchromosomal copy number variations (CNVs) in 24359 single pregnancies.Methods: A total of 24359 single pregnancies with different clinical features were retrospectively analyzed. Pathogenicity of abnormal NIPT results were assessed according to American College of Medical Genetics and Genomics(ACMG). Chromosome aneuploidies and subchromosomal CNVs were confirmed by karyotyping and chromosomal microarray analysis(CMA). Results: A total of 442 pregnancies (442/24359,1.9%) were with abnormal NIPT results. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), and sex chromosome aneuploidies (SCAs) was 84.8%, 54.2%, 11.1% an 40.5% respectively. The PPV for subchromosomal CNVs was 59.0% (46/78). The clinical information, prenatal diagnosis results and follow-up results of 46 true positive cases, 6 cases with subchromosomal CNVs inconsistent with NIPT and 1 case of false negative were also demonstrated in detail.Conclusion: Our data have potential significance in demonstrating the significance of NIPT not only for common whole chromosome aneuploidies but also for subchromosomal CNV. Besides, the clinical information, prenatal diagnosis results and follow-up results of 52 cases with subchromosomal CNV and 1 case of false negative would provide important guidance for genetic counseling.

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