Analysis of copy number variations and possible candidate genes in spontaneous abortion by copy number variation sequencing
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ABSTRACT:
SUBMITTER: Bai W
PROVIDER: S-EPMC10616874 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:It is well established that embryonic chromosomal abnormalities (both in the number of chromosomes and the structure) account for 50% of early pregnancy losses. However, little is known regarding the potential differences in the incidence and distribution of chromosomal abnormalities between patients with sporadic abortion (SA) and recurrent pregnancy loss (RPL), let alone the role of submicroscopic copy-number variations (CNVs) in these cases. The aim of the present study was to systematically evaluate the role of embryonic chromosomal abnormalities and CNVs in the etiology of RPL compared with SA. Over a 3-year period, 1556 fresh products of conception (POCs) from miscarriage specimens were investigated using single nucleotide polymorphism array (SNP-array) and CNV sequencing (CNV-seq) in this study, along with further functional enrichment analysis. Chromosomal abnormalities were identified in 57.52% (895/1556) of all cases. Comparisons of the incidence and distributions of chromosomal abnormalities within the SA group and RPL group and within the different age groups were performed. Moreover, 346 CNVs in 173 cases were identified, including 272 duplications, 2 deletions and 72 duplications along with deletions. Duplications in 16q24.3 and 16p13.3 were significantly more frequent in RPL cases, and thereby considered to be associated with RPL. There were 213 genes and 131 signaling pathways identified as potential RPL candidate genes and signaling pathways, respectively, which were centered primarily on six functional categories. The results of the present study may improve our understanding of the etiologies of RPL and assist in the establishment of a population-based diagnostic panel of genetic markers for screening RPL amongst Chinese women.
| S-EPMC7911754 | biostudies-literature
Project description:BackgroundCopy number variation sequencing (CNV-seq) was proven to be a highly effective tool in studying of chromosomal copy number variations (CNVs) in prenatal diagnosis and post-natal cases with developmental abnormalities. However, the overall characteristics of missed abortion (MA) CNVs were largely unexplored.MethodsWe retrospectively analyzed the results of CNV-seq in first-trimester MA. The samples included were single pregnancy loss before 13 gestational weeks, and other potential factors affecting embryonic implantation and development had been excluded. Gene ontology and KEGG enrichment analysis was performed on the smallest overlapping regions (SORs) of high-frequency deletion/duplication.ResultOn the basis of strict inclusion and exclusion criteria, only 152 samples were included in our study. 77 (50.7%) samples displayed chromosome number abnormalities, 32 (21%) showed isolated CNVs, and 43 (28.3%) showed no CNVs. A total of 45 CNVs, ranging in size between 300 Kb and 126.56 Mb were identified, comprising 13 segmental aneuploidies CNVs, and 32 submicroscopic CNVs. Among these CNVs, we screened out four SORs (5q31.3, 5p15.33-p15.2, 8p23.3-p23.2, and 8q22.2-24.3), which were potentially associated with first-term MA. 16 genes were identified as potential miscarriage candidate genes through gene-prioritization analysis, including three genes (MYOM2, SDHA and TPPP) critical for embryonic heart or brain development.ConclusionWe identified some potential candidate CNVs and genes associated with first-trimester MA. 5q31.3 duplications, 5p15.33-p15.2 deletions, 8p23.3-p23.2 deletions and 8p22.2-p24.3 duplications are four potential candidate CNVs. Additionally, MYOM2, SDHA and TPPP are potential genes associated with first-trimester MA.
| S-EPMC10428042 | biostudies-literature
Project description:BackgroundNeurodevelopmental disorders are impairments of brain function that affect emotion, learning, and memory. Copy number variations of contactin genes (CNTNs), including CNTN3, CNTN4, CNTN5, and CNTN6, have been suggested to be associated with these disorders. However, phenotypes have been reported in only a handful of patients with copy number variations involving CNTNs.MethodsFrom January 2009 to January 2013, 3724 patients ascertained through the University of Pittsburgh Medical Center were referred to our laboratory for clinical array comparative genomic hybridization testing. We screened this cohort of patients to identify individuals with the 3p26.3 copy number variations involving the CNTN6 gene, and then retrospectively reviewed the clinical information and family history of these patients to determine the association between the 3p26.3 copy number variations and neurodevelopmental disorders.ResultsFourteen of the 3724 patients had 3p26.3 copy number variations involving the CNTN6 gene. Thirteen of the 14 patients with these CNTN6 copy number variations presented with various neurodevelopmental disorders including developmental delay, autistic spectrum disorders, seizures and attention deficit hyperactivity disorder. Family history was available for 13 of the 14 patients. Twelve of the thirteen families have multiple members with neurodevelopmental and neuropsychiatric disorders including attention deficit hyperactivity disorder, seizures, autism spectrum disorder, intellectual disability, schizophrenia, depression, anxiety, learning disability, and bipolar disorder.ConclusionsOur findings suggest that deletion or duplication of the CNTN6 gene is associated with a wide spectrum of neurodevelopmental behavioral disorders.
| S-EPMC4528395 | biostudies-literature
Project description:Copy number variation (CNV) has been considered to be an important source of genetic variation for important phenotypic traits of livestock. In this study, we performed whole-genome CNV detection on Suhuai (SH) (n = 23), Chinese Min Zhu (MZ) (n = 11), and Large White (LW) (n = 12) pigs based on next-generation sequencing data. The copy number variation regions (CNVRs) were annotated and analyzed, and 10,885, 10,836, and 10,917 CNVRs were detected in LW, MZ, and SH pigs, respectively. Some CNVRs have been randomly selected for verification of the variation type by real-time PCR. We found that SH and LW pigs are closely related, while MZ pigs are distantly related to the SH and LW pigs by CNVR-based genetic structure, PCA, VST, and QTL analyses. A total of 14 known genes annotated in CNVRs were unique for LW pigs. Among them, the cyclin T2 (CCNT2) is involved in cell proliferation and the cell cycle. The FA Complementation Group M (FANCM) is involved in defective DNA repair and reproductive cell development. Ten known genes annotated in 47 CNVRs were unique for MZ pigs. The genes included glycerol-3-phosphate acyltransferase 3 (GPAT3) is involved in fat synthesis and is essential to forming the glycerol triphosphate. Glutathione S-transferase mu 4 (GSTM4) gene plays an important role in detoxification. Eleven known genes annotated in 23 CNVRs were unique for SH pigs. Neuroligin 4 X-linked (NLGN4X) and Neuroligin 4 Y-linked (NLGN4Y) are involved with nerve disorders and nerve signal transmission. IgLON family member 5 (IGLON5) is related to autoimmunity and neural activities. The unique characteristics of LW, MZ, and SH pigs are related to these genes with CNV polymorphisms. These findings provide important information for the identification of candidate genes in the molecular breeding of pigs.
| S-EPMC9280686 | biostudies-literature
Project description:Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.
| S-EPMC3392110 | biostudies-literature
Project description: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 sufficient 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 confirm these CNVs. To further characterize the ciliary phenotypes, high-speed video microscopy analysis (HSVA), transmission electron microscopy (TEM), and immunofluorescence (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 identified 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_1 3707643del, spanning exons 69-71 and exons 77-79 were identified by NGS-based CNV analysis. Abnormalities in DNA copy number were confirmed by qPCR amplification. IF showed that the respiratory cilia of Patient 1 and Patient 2 were deficient in dynein axonemal heavy chain 5 (DNAH5) protein expression. This report identified 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.Supplementary informationThe online version contains supplementary material available at 10.1007/s43657-023-00130-0.
| S-EPMC11003934 | biostudies-literature
Project description:BackgroundCopy number variation (CNV) is a major source of structural variants and has been commonly identified in mammalian genome. It is associated with gene expression and may present a major genetic component of phenotypic diversity. Unlike many other mammalian genomes where CNVs have been well annotated, studies of porcine CNV in diverse breeds are still limited.ResultHere we used Porcine SNP60 BeadChip and PennCNV algorithm to identify 1,315 putative CNVs belonging to 565 CNV regions (CNVRs) in 1,693 pigs from 18 diverse populations. Total 538 out of 683 CNVs identified in a White Duroc?×?Erhualian F2 population fit Mendelian transmission and 6 out of 7 randomly selected CNVRs were confirmed by quantitative real time PCR. CNVRs were non-randomly distributed in the pig genome. Several CNV hotspots were found on pig chromosomes 6, 11, 13, 14 and 17. CNV numbers differ greatly among different pig populations. The Duroc pigs were identified to have the most number of CNVs per individual. Among 1,765 transcripts located within the CNVRs, 634 genes have been reported to be copy number variable genes in the human genome. By integrating analysis of QTL mapping, CNVRs and the description of phenotypes in knockout mice, we identified 7 copy number variable genes as candidate genes for phenotypes related to carcass length, backfat thickness, abdominal fat weight, length of scapular, intermuscle fat content of logissimus muscle, body weight at 240 day, glycolytic potential of logissimus muscle, mean corpuscular hemoglobin, mean corpuscular volume and humerus diameter.ConclusionWe revealed the distribution of the unprecedented number of 565 CNVRs in pig genome and investigated copy number variable genes as the possible candidate genes for phenotypic traits. These findings give novel insights into porcine CNVs and provide resources to facilitate the identification of trait-related CNVs.
| S-EPMC3543711 | biostudies-literature
Project description:Objective5p deletion syndrome, that characterized by cat-like cry and peculiar timbre of voice, is believed to be one of the most common pathogenic copy number variations (CNVs). Variable critical regions on 5p involving a variety of genes contribute to the phenotypic heterogeneity without specific correlation. The objective of this study was to examine the genotype-phenotype correlation of 5p deletion syndrome, and to redefine 5p deletion syndrome relevant regions. In addition, we demonstrate the potential use of whole genome sequencing (WGS) to identify chromosomal breakpoints in prenatal diagnosis.MethodsThree families with women undergoing prenatal diagnosis and two children were recruited. Karyotyping, CNV-seq, fluorescence in situ hybridization, WGS, and Sanger sequencing were performed to identify the chromosomal disorder.ResultsWe reported three families and two children with CNVs of 5p deletion or combined 6p duplication. Five different sizes of 5p deletion were detected and their pathogenicity was determined, including 5p15.33-p15.31 [1-7,700,000, family1-variant of uncertain significance (VUS)], 5p15.33 (1-3,220,000, family 2-VUS), 5p15.33-p15.31 (1-7,040,000, family 3-VUS), 5p15.33-p15.31 (1-8,740,000, child 1-pathogenic) and 5p15.31-p15.1 (8,520,001-18,080,000, child 2-pathogenic). One duplication at 6p25.3-p24.3 (1-10,420,000) was detected and determined as likely pathogenic. The chromosomal breakpoints in family 3 were successfully identified by WGS.ConclusionSome critical genes that were supposed to be causative of the symptoms were identified. Relevant region in 5p deletion syndrome was redefined, and the chr5:7,700,000-8,740,000 region was supposed to be responsible for the cat-like cry. The great potential of WGS in detecting chromosomal translocations was demonstrated. Our findings may pave the way for further research on the prevention, diagnosis, and treatment of related diseases.
| S-EPMC9329539 | biostudies-literature
Project description:Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.
| S-EPMC4834924 | biostudies-literature
Project description:Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
| S-EPMC3077050 | biostudies-literature