Copy number variation and susceptibility to human disorders (Review)

Department of Biological Sciences, Oakland University, Rochester, MI, USA. .
Molecular Medicine Reports (Impact Factor: 1.55). 02/2009; 2(2):143-7. DOI: 10.3892/mmr_00000074
Source: PubMed


A large number of analyses of a new form of genetic variation, known as copy number variation (CNV), have been published recently as a new tool for understanding the genetic basis of complex traits such as diabetes, asthma, Crohn's disease, autism and bipolar disorder. Through the use of different types of genome-wide scanning procedures, CNVs have been shown to be associated with several complex and common disorders, including nervous system disorders. One of the common features of the regions associated with the complex and common disorders identified thus far is the presence of CNVs and segmental duplications. Segmental duplications lead to genome instability. Because of their location and nature (several contain genes), many CNVs have functional consequences, such as gene dosage alteration, the disruption of genes and the modulation of the activities of other genes. Therefore, these genetic variations have an influence on phenotypes, the susceptibility of an individual to disease, drug response and human genome evolution. These types of variants (gain and loss of DNA) are not restricted to humans, having also been identified in other organisms. Our current knowledge regarding CNVs and their heritability is still rudimentary, due to their location in regions of complex genomic structure and to the technical limitations of association studies. Future advances in the technology will aid in the construction of a new CNV map, used to find the genes underlying common diseases and to understand familial genetic conditions, severe developmental defects in humans and other organisms, and genome evolution.

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    • "Since the 1998 review that coined and defined the term “genomic disorders” [18], a multitude of genomic disorders caused by genomic rearrangements have been identified [19], and many of them manifest neurological features, including mental impairments, autistic features, and psychiatric disorders [20,21]. This finding is because there are many dosage-sensitive genes related to nervous system functions. "
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    ABSTRACT: Background Triplication is a rare chromosomal anomaly. We identified a de novo triplication of 11q12.3 in a patient with developmental delay, distinctive facial features, and others. In the present study, we discuss the mechanism of triplications that are not embedded within duplications and potential genes which may contribute to the phenotype. Results The identified triplication of 11q12.3 was 557 kb long and not embedded within the duplicated regions. The aberrant region was overlapped with the segment reported to be duplicated in 2 other patients. The common phenotypic features in the present patient and the previously reported patient were brain developmental delay, finger abnormalities (including arachnodactuly, camptodactyly, brachydactyly, clinodactyly, and broad thumbs), and preauricular pits. Conclusions Triplications that are not embedded within duplicated regions are rare and sometimes observed as the consequence of non-allelic homologous recombination. The de novo triplication identified in the present study is novel and not embedded within the duplicated region. In the 11q12.3 region, many copy number variations were observed in the database. This may be the trigger of this rare triplication. Because the shortest region of overlap contained 2 candidate genes, STX5 and CHRM1, which show some relevance to neuronal functions, we believe that the genomic copy number gains of these genes may be responsible for the neurological features seen in these patients.
    Full-text · Article · Apr 2013 · Molecular Cytogenetics
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    • "As previously shown, copy number variants can have an impact on phenotypic variation mainly due to gene-dosage effects [80], and are often associated with disease susceptibility [38-40,81]. In this analysis, CNVRs were found to be enriched for genes with functions related to environmental response, such as immune and sensory functions previously noticed in other species [10,25,27,33,35]. "
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    ABSTRACT: Copy number variations (CNVs), which represent a significant source of genetic diversity in mammals, have been shown to be associated with phenotypes of clinical relevance and to be causative of disease. Notwithstanding, little is known about the extent to which CNV contributes to genetic variation in cattle. We designed and used a set of NimbleGen CGH arrays that tile across the assayable portion of the cattle genome with approximately 6.3 million probes, at a median probe spacing of 301 bp. This study reports the highest resolution map of copy number variation in the cattle genome, with 304 CNV regions (CNVRs) being identified among the genomes of 20 bovine samples from 4 dairy and beef breeds. The CNVRs identified covered 0.68% (22 Mb) of the genome, and ranged in size from 1.7 to 2,031 kb (median size 16.7 kb). About 20% of the CNVs co-localized with segmental duplications, while 30% encompass genes, of which the majority is involved in environmental response. About 10% of the human orthologous of these genes are associated with human disease susceptibility and, hence, may have important phenotypic consequences. Together, this analysis provides a useful resource for assessment of the impact of CNVs regarding variation in bovine health and production traits.
    Full-text · Article · May 2010 · BMC Genomics
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    ABSTRACT: We have performed an analysis of a family with kidney-yang deficiency syndrome (KDS) in order to determine the structural genomic variations through a novel approach designated as "copy number variants" (CNVs). Twelve KDS subjects and three healthy spouses from this family were included in this study. Genomic DNA samples were genotyped utilizing an Affymetrix 100 K single nucleotide polymorphism array, and CNVs were identified by Copy Number Algorithm (CNAT4.0, Affymetrix). Our results demonstrate that 447 deleted and 476 duplicated CNVs are shared among KDS subjects within the family. The homologus ratio of deleted CNVs was as high as 99.78%. One-copy-duplicated CNVs display mid-range homology. For two copies of duplicated CNVs (CNV(4)), a markedly heterologous ratio was observed. Therefore, with the important exception of CNV(4), our data shows that CNVs shared among KDS subjects display typical Mendelian inheritance. A total of 113 genes with established functions were identified from the CNV flanks; significantly enriched genes surrounding CNVs may contribute to certain adaptive benefit. These genes could be classified into categories including: binding and transporter, cell cycle, signal transduction, biogenesis, nerve development, metabolism regulation and immune response. They can also be included into three pathways, that is, signal transduction, metabolic processes and immunological networks. Particularly, the results reported here are consistent with the extensive impairments observed in KDS patients, involving the mass-energy-information-carrying network. In conclusion, this article provides the first set of CNVs from KDS patients that will facilitate our further understanding of the genetic basis of KDS and will allow novel strategies for a rational therapy of this disease.
    Full-text · Article · Jun 2011 · Evidence-based Complementary and Alternative Medicine
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