Evaluation Of Copy Number Variations Research Articles

Detection of Copy Number Variations in Breast Cancer Samples Using Single-nucleotide Polymorphism-targeted Massively Multiplexed PCR

Evaluation of copy number variation (CNV) in tumor tissues typically involves SNP microarray or aCGH. These methods have high whole-genome resolution, but require large amounts of input material, have high fixed costs, and falter on FFPE samples. Here, we employ a 28,000-plex SNP-targeted PCR with NGS, targeting chromosomes 1, 2, 13, 18, 21 and X, and regions 4p16, 5p15, 7q11, 15q, 17p, 22q11, and 22q13, to detect CNVs from fresh and FFPE samples. An accuracy of 100% was demonstrated on 96 samples: 25 unaffected and 71 affected (minimum 3 samples per region).

Leveraging next-generation phenotyping and pan-omics to identify novel biomarkers and pharmaceutical targets for cardiovascular disease.

Leveraging next-generation phenotyping and pan-omics to identify novel biomarkers and pharmaceutical targets for cardiovascular disease.

CNVinspector: a web-based tool for the interactive evaluation of copy number variations in single patients and in cohorts

ObjectivesMany genetic disorders are caused by copy number variations (CNVs) in the human genome. However, the large number of benign CNV polymorphisms makes it difficult to delineate causative variants for...

Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways

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.

Mitochondrial and ion channel gene alterations in autism

To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).

Differential Diagnosis of Disorders of Sex Development (DSD) by Molecular Genetic Analyses

Sex determination and differentiation require the balanced and sequential activation of transcription factors, signaling molecules, hormones and their receptors. Disorders of sex development (DSD) have heterogeneous groups of etiologies caused by mutations or deletions of genes involved in sex development. The DSD is categorized into 46, XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Precise diagnosis is essential for sex assignment, surgical correction of external genitalia, prevention of gonadal tumors, psychiatric support, and genetic counseling. The increased genetic knowledge in the field has opened up new diagnostic possibilities. The first line genetic testing for DSD is the assessment of the karyotype and the SRY gene. The follow-up genetic tests are performed for confirmatory diagnosis; the evaluation of copy number variants by array comparative genomic hybridization (CGH), direct sequencing of a specific gene, and functional analyses of mutations. A lot of genes can be analyzed by molecular laboratories and the number of available genes is growing. DNA analyses should be done under clinical assessment on the basis of family history, prenatal history, physical findings focused on external genitalia, endocrinologic data, and radiologic findings. Genetic counseling is essential to help patients and their families understand the disease status and the risk for recurrence in future pregnancies, and participate in the process of sex assignment. Children with DSD should be managed with a multidisciplinary team, including pediatric endocrinology, molecular genetics, cytogenetics, neonatology, urology, and psychiatry.

American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants

Genomic microarrays used to assess DNA copy number are now recommended as first-tier tests for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Application of this technology has resulted in the discovery of widespread copy number variation in the human genome, both polymorphic variation in healthy individuals and novel pathogenic copy number imbalances. To assist clinical laboratories in the evaluation of copy number variants and to promote consistency in interpretation and reporting of genomic microarray results, the American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation. These guidelines apply primarily to evaluation of constitutional copy number variants detected in the postnatal setting.

Evolving applications of microarray analysis in prenatal diagnosis

Evaluation of copy number variation by microarray analysis has significant advantages over standard metaphase karyotyping and is quickly becoming the primary means of postnatal genetic evaluation for neonates and infants with dysmorphic features or cognitive difficulties. Before this technology is routinely used for prenatal diagnosis, further evaluation of its value and the clinical dilemmas it may introduce requires further study. This article reviews the recent literature on array technology use in prenatal diagnosis. The use of microarray analysis for routine prenatal diagnosis is still being investigated. Use in certain prenatal situations such as the fetus with structural anomalies or those who are stillborn appears to add important, clinically relevant information. There are a broad range of array designs available and recent research has focused on the appropriate design for prenatal testing. Patient counseling may occasionally be difficult because of the uncertain phenotype associated with some array findings. We present a brief overview of microarray technology including benefits and limitations. Previous research regarding use of microarray in prenatal diagnosis including specific scenarios of anomalous fetuses and abnormal karyotype is reviewed. Current guidelines and the authors' recommendations are presented.