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.

scholarly journals Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

2021 ◽  
Vol 14 (1) ◽  
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 ◽  
Genome Wide ◽  
Number Variation ◽  
Complete Atrioventricular

Abstract Background Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. 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 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2–21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2–21q22.3 duplication (14.89%) in CAVC cohort. Conclusions Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

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 The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

2018 ◽  
Vol 7 (3) ◽  
pp. 28 ◽  
Author(s):  
Francesca Scionti ◽  
Maria Di Martino ◽  
Licia Pensabene ◽  
Valentina Bruni ◽  
Daniela Concolino
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Snp Array ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Unknown Significance ◽  
Pathogenic Cnvs ◽  
Line Test

Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.

scholarly journals Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Meiying Cai ◽  
Na Lin ◽  
Linjuan Su ◽  
Xiaoqing Wu ◽  
Xiaorui Xie ◽  
...  
Keyword(s):  
Copy Number ◽  
Pregnancy Termination ◽  
Snp Array ◽  
Late Pregnancy ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Snp Analysis ◽  
Fetal Ultrasound ◽  
Structural Abnormalities ◽  
Pathogenic Cnvs

Abstract Many fetuses are found to have ultrasonic abnormalities in the late pregnancy. The association of fetal ultrasound abnormalities in late pregnancy with copy number variations (CNVs) is unclear. We attempted to explore the relationship between types of ultrasonically abnormal late pregnancy fetuses and CNVs. Fetuses (n = 713) with ultrasound-detected abnormalities in late pregnancy and normal karyotypes were analyzed. Of these, 237 showed fetal sonographic structural malformations and 476 showed fetal non-structural abnormalities. Single nucleotide polymorphism (SNP)-based chromosomal microarray (CMA) was performed on the Affymetrix CytoScan HD platform. Using the SNP array, abnormal CNVs were detected in 8.0% (57/713) of the cases, with pathogenic CNVs in 32 cases and variants of uncertain clinical significance (VUS) in 25 cases. The detection rate of abnormal CNVs in fetuses with sonographic structural malformations (12.7%, 30/237) was significantly higher (P = 0.001) than that in the fetuses with non-structural abnormalities (5.7%, 27/476). Overall, we observed that when fetal sonographic structural malformations or non-structural abnormalities occurred in the third trimester of pregnancy, the use of SNP analysis could improve the accuracy of prenatal diagnosis and reduce the rate of pregnancy termination.

scholarly journals “Abnormal vertebral patterns in genetically heterogeneous deceased fetuses and neonates: evidence of selection against variations”

2019 ◽  
Author(s):  
Pauline C. Schut ◽  
Erwin Brosens ◽  
Frietson Galis ◽  
Clara M. A. Ten Broek ◽  
Inge M.M. Baijens ◽  
...  
Keyword(s):  
Copy Number ◽  
Single Nucleotide Polymorphism Array ◽  
Copy Number Variations ◽  
Cervical Region ◽  
Nucleotide Polymorphism ◽  
Rare Cnvs ◽  
Single Nucleotide ◽  
Neonatal Deaths ◽  
Coding Regions ◽  
Cervical Ribs

AbstractObjectiveTo assess the vertebral pattern in a cohort of deceased fetuses and neonates, and to study the possible impact of DNA Copy Number Variations (CNVs) in coding regions and/or disturbing enhancers on the development of the vertebral pattern.MethodRadiographs of 445 fetuses and infants, deceased between 2009 and 2015, were assessed. Terminations of pregnancies, stillbirths and neonatal deaths were included. Patients were excluded if the vertebral pattern could not be determined. Copy number profiles of 265 patients were determined using single nucleotide polymorphism array.Results274/374 patients (73.3%) had an abnormal vertebral pattern. Cervical ribs were present in 188/374 (50.3%) and were significantly more common in stillbirths (69/128 (53.9%)) and terminations of pregnancies (101/188 (53.7%)), compared to live births (18/58, 31.0%, p = 0.006). None of the rare CNVs were recurrent or overlapped candidate genes for vertebral patterning.ConclusionThe presence of an abnormal vertebral pattern, particularly in the cervical region, could be a sign of disruption at critical, highly interactive and conserved stages of embryogenesis. The vertebral pattern might provide valuable information regarding fetal and neonatal outcome. CNV analyses did not identify a mutual genetic cause for the occurrence of vertebral patterning abnormalities, indicating genetic heterogeneity.

scholarly journals A large data resource of genomic copy number variation across neurodevelopmental disorders

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Mehdi Zarrei ◽  
Christie L. Burton ◽  
Worrawat Engchuan ◽  
Edwin J. Young ◽  
Edward J. Higginbotham ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Population Control ◽  
Large Data ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Genomic Disorder ◽  
Rare Cnvs ◽  
Data Resource ◽  
Compulsive Disorder

Abstract Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

scholarly journals Integrating genomic correlation structure improves copy number variations detection

2020 ◽  
Author(s):  
Xizhi Luo ◽  
Fei Qin ◽  
Guoshuai Cai ◽  
Feifei Xiao
Keyword(s):  
Copy Number ◽  
Snp Array ◽  
Copy Number Variations ◽  
Correlation Structure ◽  
Supplementary Information ◽  
Dependence Structure ◽  
Random Pattern ◽  
Genomic Correlation ◽  
Equal Chance ◽  
Cnv Detection

Abstract Motivation Copy number variation plays important roles in human complex diseases. The detection of copy number variants (CNVs) is identifying mean shift in genetic intensities to locate chromosomal breakpoints, the step of which is referred to as chromosomal segmentation. Many segmentation algorithms have been developed with a strong assumption of independent observations in the genetic loci, and they assume each locus has an equal chance to be a breakpoint (i.e. boundary of CNVs). However, this assumption is violated in the genetics perspective due to the existence of correlation among genomic positions, such as linkage disequilibrium (LD). Our study showed that the LD structure is related to the location distribution of CNVs, which indeed presents a non-random pattern on the genome. To generate more accurate CNVs, we proposed a novel algorithm, LDcnv, that models the CNV data with its biological characteristics relating to genetic dependence structure (i.e. LD). Results We theoretically demonstrated the correlation structure of CNV data in SNP array, which further supports the necessity of integrating biological structure in statistical methods for CNV detection. Therefore, we developed the LDcnv that integrated the genomic correlation structure with a local search strategy into statistical modeling of the CNV intensities. To evaluate the performance of LDcnv, we conducted extensive simulations and analyzed large-scale HapMap datasets. We showed that LDcnv presented high accuracy, stability and robustness in CNV detection and higher precision in detecting short CNVs compared to existing methods. This new segmentation algorithm has a wide scope of potential application with data from various high-throughput technology platforms. Availability and implementation https://github.com/FeifeiXiaoUSC/LDcnv. Supplementary information Supplementary data are available at Bioinformatics online.

High-Resolution Genomic Profiling of Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukaemia (ALL) Identified Novel Recurrent Copy Number Variations Involved in Both Pathogenesis and Resistance to Tyrosine Kinase Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 230-230
Author(s):  
Ilaria Iacobucci ◽  
E. Ottaviani ◽  
A. Astolfi ◽  
S. Soverini ◽  
N. Testoni ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Complex Disease ◽  
B Lymphocyte ◽  
Philadelphia Chromosome ◽  
Snp Array ◽  
Copy Number Variations ◽  
Imatinib Resistance ◽  
Copy Number State ◽  
Monosomy 7

Abstract The Ph chromosome is the most frequent cytogenetic aberration associated with ALL and it represents the single most significant adverse prognostic marker. Despite the encouraging results achieved with imatinib, resistance develops rapidly and is quickly followed by disease progression. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors driving both the disease and resistance remains to be defined. In order to identify at submicroscopic level genetic lesions driving leukemogenesis and resistance, we profiled until now the genomes of 18 patients, out of 55 Ph+ ALL patients treated in our institute, at diagnosis (n=11) or at the time of haematological relapse (n=7) during therapy with imatinib or dasatinib. 250 ng of genomic DNA were processed on 500K single nucleotide polymorphism (SNP) array according to protocols provided by the manufacturer (Affymetrix Inc., Santa Clara, CA, USA). The median SNP call rate of analysed samples was 96%. Raw signal data were analyzed by BRLMM algorithm and copy number state was calculated with respect to a set of 48 Hapmap normal individuals and a diploid reference set of samples obtained from acute leukaemia cases in remission. Regions of amplification and deletion were visualized by Integrated Genome Browser and mapped to RefSeq to identify the specific genes involved in the lesion. Our analysis identified multiple copy number alterations per case, with deletions outnumbering amplification almost 3:1. Lesions varied from loss or gain of complete chromosome arms (trisomy 4, monosomy 7, loss of 9p, 10q, 14q, 16q and gain of 1q and 17q) to microdeletions and microduplications targeting genomic intervals. The recurring microdeletions that we detected in at least 50% of patients (both at diagnosis and at relapse) included 1p36.21 (PRAMEF), 3q29 (TFCR), 7p14.1 (AMPH), 8p23 (DEFB105A), 14q11.2 (DAD1), 16p13.11 (PDXDC1, NTAN1, RRN3), 16p11.2 (SNP) and 19p13.2 (CARM1, SMARCA4). A common microamplification was 4q13.2 (TMPRSS11E) and 17q21.31. Some genomic alterations were identified in genes regulating B-lymphocyte differentiation, such as PAX5 (n=3), BLNK (n=1) and VPREB1 (n=6) and in genes with an established role in leukemogenesis, such as MDS, BTG1, MLLT3 and RUNX1. Furthermore, many of the deletions detected included genes encoded for phosphatase proteins (e.g. PTPRD, PPP1R9B, PTPN18) and for zinc-finger proteins without any difference between diagnosis and resistance. It is noteworthy that some lesions felt in regions lacking annotated genes (loss: 2p11.2, 3p12.3, 7q11.21 and 14q32.33; gain: 8q23.3 and 13q21.1). Using high-resolution genome wide approach we showed that Ph+ ALL is a more complex disease characterized by multiple genomic anomalies which may provide new insights into the mechanisms underlying leukemogenesis and may be used as targets for existing or novel drugs. Supported by: European LeukemiaNet, COFIN 2003, Novartis Oncology Clinical Development, AIL.

scholarly journals Evaluation of Chromosomal Abnormalities and Copy Number Variations in Fetuses with Ultrasonic Soft Markers

2020 ◽  
Author(s):  
Meiying Cai ◽  
Na Lin ◽  
Liangpu Xu ◽  
hailong huang
Keyword(s):  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Snp Array ◽  
Copy Number Variations ◽  
Clinical Value ◽  
Obstetrical Outcomes ◽  
Genetic Abnormalities ◽  
Significant Difference ◽  
Snp Array Analysis ◽  
Soft Marker

Abstract Background: Some ultrasonic soft markers can be found during ultrasound examination. However, the etiology of the fetuses with ultrasonic soft markers is still unknown. This study aimed to evaluate the genetic etiology and clinical value of chromosomal abnormalities and copy number variations (CNVs) in fetuses with ultrasonic soft markers.Methods: Among 1131 fetuses, 729 had single ultrasonic soft marker, 322 had two ultrasonic soft markers, and 80 had three or more ultrasonic soft markers. All fetuses underwent conventional karyotyping, followed by single nucleotide polymorphism (SNP) array analysis. Results: Among 1131 fetuses with ultrasonic soft markers, 46 had chromosomal abnormalities. In addition to the 46 fetuses with chromosomal abnormalities consistent with the results of the karyotyping analysis, the SNP array identified additional 6.1% (69/1131) abnormal CNVs. The rate of abnormal CNVs in fetuses with ultrasonic soft marker, two ultrasonic soft markers, three or more ultrasonic soft markers were 6.2%, 6.2%, and 5.0%, respectively. No significant difference was found in the rate of abnormal CNVs among the groups.Conclusions: Genetic abnormalities affect obstetrical outcomes. The SNP array can fully complement conventional karyotyping in fetuses with ultrasonic soft markers, improve detection rate of chromosomal abnormalities, and affect obstetrical outcomes.

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.

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