Skip to main content Accessibility help
×
Home
Hostname: page-component-cf9d5c678-h2mp8 Total loading time: 0.695 Render date: 2021-07-31T13:51:05.139Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

The clinical context of copy number variation in the human genome

Published online by Cambridge University Press:  09 March 2010

Charles Lee
Affiliation:
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Stephen W. Scherer
Affiliation:
The Centre for Applied Genomics and Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Corresponding

Abstract

During the past five years, copy number variation (CNV) has emerged as a highly prevalent form of genomic variation, bridging the interval between long-recognised microscopic chromosomal alterations and single-nucleotide changes. These genomic segmental differences among humans reflect the dynamic nature of genomes, and account for both normal variations among us and variations that predispose to conditions of medical consequence. Here, we place CNVs into their historical and medical contexts, focusing on how these variations can be recognised, documented, characterised and interpreted in clinical diagnostics. We also discuss how they can cause disease or influence adaptation to an environment. Various clinical exemplars are drawn out to illustrate salient characteristics and residual enigmas of CNVs, particularly the complexity of the data and information associated with CNVs relative to that of single-nucleotide variation. The potential is immense for CNVs to explain and predict disorders and traits that have long resisted understanding. However, creative solutions are needed to manage the sudden and overwhelming burden of expectation for laboratories and clinicians to assay and interpret these complex genomic variations as awareness permeates medical practice. Challenges remain for understanding the relationship between genomic changes and the phenotypes that might be predicted and prevented by such knowledge.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Lejeune, J., Gautier, M. and Turpin, R. (1959) [Study of somatic chromosomes from 9 mongoloid children.]. Comptes rendus hebdomadaires des séances de l'Académie des sciences 248, 1721-1722 [Article in French]Google Scholar
2Iafrate, A.J. et al. (2004) Detection of large-scale variation in the human genome. Nature Genetics 36, 949-951CrossRefGoogle ScholarPubMed
3Sebat, J. et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305, 525-528CrossRefGoogle ScholarPubMed
4Ford, C.E. et al. (1959) A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome). Lancet 1, 711-713CrossRefGoogle Scholar
5Jacobs, P.A. and Strong, J.A. (1959) A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183, 302-303CrossRefGoogle ScholarPubMed
6Feuk, L., Carson, A.R. and Scherer, S.W. (2006) Structural variation in the human genome. Nature Reviews Genetics 7, 85-97CrossRefGoogle ScholarPubMed
7Scherer, S.W. et al. (2007) Challenges and standards in integrating surveys of structural variation. Nature Genetics 39, S7-15CrossRefGoogle ScholarPubMed
8Lee, C., Iafrate, A.J. and Brothman, A.R. (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nature Genetics 39, S48-54CrossRefGoogle ScholarPubMed
9Conrad, D.F. et al. (2006) A high-resolution survey of deletion polymorphism in the human genome. Nature Genetics 38, 75-81CrossRefGoogle ScholarPubMed
10Khaja, R. et al. (2006) Genome assembly comparison identifies structural variants in the human genome. Nature Genetics 38, 1413-1418CrossRefGoogle ScholarPubMed
11Beckmann, J.S., Estivill, X. and Antonarakis, S.E. (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature Reviews Genetics 8, 639-646CrossRefGoogle ScholarPubMed
12Wain, L.V., Armour, J.A. and Tobin, M.D. (2009) Genomic copy number variation, human health, and disease. Lancet 374, 340-350CrossRefGoogle ScholarPubMed
13Conrad, D.F. et al. (2009) Origins and functional impact of copy number variation in the human genome. Nature Oct 7; [Epub ahead of print]Google ScholarPubMed
14Buchanan, J.A. and Scherer, S.W. (2008) Contemplating effects of genomic structural variation. Genetics in Medicine 10, 639-647CrossRefGoogle ScholarPubMed
15Varki, A., Geschwind, D.H. and Eichler, E.E. (2008) Explaining human uniqueness: genome interactions with environment, behaviour and culture. Nature Reviews Genetics 9, 749-763CrossRefGoogle ScholarPubMed
16Redon, R. et al. (2006) Global variation in copy number in the human genome. Nature 444, 444-454CrossRefGoogle ScholarPubMed
17Emanuel, B.S. and Shaikh, T.H. (2001) Segmental duplications: an ‘expanding’ role in genomic instability and disease. Nature Reviews Genetics 2, 791-800CrossRefGoogle ScholarPubMed
18Scherer, S.W. et al. (2003) Human chromosome 7: DNA sequence and biology. Science 300, 767-772CrossRefGoogle ScholarPubMed
19Fredman, D. et al. (2004) Complex SNP-related sequence variation in segmental genome duplications. Nature Genetics 36, 861-866CrossRefGoogle ScholarPubMed
20Cheung, J. et al. (2003) Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biology 4, R25CrossRefGoogle ScholarPubMed
21Kim, P.M. et al. (2008) Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history. Genome Research 18, 1865-1874CrossRefGoogle ScholarPubMed
22Stankiewicz, P. and Lupski, J.R. (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18, 74-82CrossRefGoogle ScholarPubMed
23Lupski, J.R. et al. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219-232CrossRefGoogle ScholarPubMed
24Emanuel, B.S. and Saitta, S.C. (2007) From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nature Reviews Genetics 8, 869-883CrossRefGoogle ScholarPubMed
25Moore, J.K. and Haber, J.E. (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Molecular and Cellular Biology 16, 2164-2173CrossRefGoogle ScholarPubMed
26Conrad, D.F. and Hurles, M.E. (2007) The population genetics of structural variation. Nature Genetics 39, S30-36CrossRefGoogle ScholarPubMed
27Zhang, F. et al. (2009) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genetics 41, 849-853CrossRefGoogle ScholarPubMed
28Lee, J.A., Carvalho, C.M. and Lupski, J.R. (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235-1247CrossRefGoogle ScholarPubMed
29Carvalho, C.M. et al. (2009) Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Human Molecular Genetics 18, 2188-2203CrossRefGoogle ScholarPubMed
30Hastings, P.J. et al. (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10, 551-564CrossRefGoogle ScholarPubMed
31Hastings, P.J., Ira, G. and Lupski, J.R. (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genetics 5, e1000327CrossRefGoogle ScholarPubMed
32Koolen, D.A. et al. (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nature Genetics 38, 999-1001CrossRefGoogle ScholarPubMed
33Shaw-Smith, C. et al. (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nature Genetics 38, 1032-1037CrossRefGoogle ScholarPubMed
34Stefansson, H. et al. (2005) A common inversion under selection in Europeans. Nature Genetics 37, 129-137CrossRefGoogle ScholarPubMed
35Visser, R. et al. (2005) Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. American Journal of Human Genetics 76, 52-67CrossRefGoogle ScholarPubMed
36Osborne, L.R. et al. (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nature Genetics 29, 321-325CrossRefGoogle ScholarPubMed
37Scherer, S.W. and Osborne, L.R. (2006) Williams-Beuren syndrome. In Genomic Disorders: The Genomic Basis of Disease ( Lupski, J.R. and Stankiewicz, P., eds), pp. 221-236, Humana Press, Totowa, NJ, USACrossRefGoogle Scholar
38McCarroll, S.A. et al. (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genetics 40, 1166-1174CrossRefGoogle ScholarPubMed
39Zhang, J. et al. (2006) Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenetic and Genome Research 115, 205-214CrossRefGoogle ScholarPubMed
40Levy, S. et al. (2007) The diploid genome sequence of an individual human. PLoS Biology 5, e254CrossRefGoogle ScholarPubMed
41Wheeler, D.A. et al. (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872-876CrossRefGoogle ScholarPubMed
42Lander, E.S. et al. (2001) Initial sequencing and analysis of the human genome. Nature 409, 860-921CrossRefGoogle ScholarPubMed
43International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431, 931-945CrossRefGoogle ScholarPubMed
44Venter, J.C. et al. (2001) The sequence of the human genome. Science 291, 1304-1351CrossRefGoogle ScholarPubMed
45Maher, B. (2008) Personal genomes: the case of the missing heritability. Nature 456, 18-21CrossRefGoogle ScholarPubMed
46Manolio, T.A. et al. (2009) Finding the missing heritability of complex diseases. Nature 461, 747-753CrossRefGoogle ScholarPubMed
47Cook, E.H. Jr, and Scherer, S.W. (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919-923CrossRefGoogle ScholarPubMed
48Carter, N.P. (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nature Genetics 39, S16-21CrossRefGoogle ScholarPubMed
49Wang, J. et al. (2008) The diploid genome sequence of an Asian individual. Nature 456, 60-65CrossRefGoogle ScholarPubMed
50Bentley, D.R. et al. (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53-59CrossRefGoogle ScholarPubMed
51Ahn, S.M. et al. (2009) The first Korean genome sequence and analysis: full genome sequencing for a socio-ethnic group. Genome Research 19, 1622-1629CrossRefGoogle ScholarPubMed
52Kim, J.I. et al. (2009) A highly annotated whole-genome sequence of a Korean individual. Nature 460, 1011-1015Google ScholarPubMed
53McKernan, K.J. et al. (2009) Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Research 19, 1527-1541CrossRefGoogle Scholar
54Drmanac, R. et al. Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78-81CrossRefGoogle ScholarPubMed
55Alkan, C. et al. (2009) Personalized copy number and segmental duplication maps using next-generation sequencing. Nature Genetics 41, 1061-1067CrossRefGoogle ScholarPubMed
56Chiang, D.Y. et al. (2009) High-resolution mapping of copy-number alterations with massively parallel sequencing. Nature Methods 6, 99-103CrossRefGoogle ScholarPubMed
57Lupski, J.R. (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends in Genetics 14, 417-422CrossRefGoogle ScholarPubMed
58Hüffmeier, U. et al. (2009) Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. Journal of Investigative Dermatology Dec 17; [Epub ahead of print]Google ScholarPubMed
59de Cid, R. et al. (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genetics 41, 211-215CrossRefGoogle ScholarPubMed
60Shlien, A. et al. (2008) Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proceedings of the National Academy of Sciences of the United States of America 105, 11264-11269CrossRefGoogle ScholarPubMed
61Diskin, S.J. et al. (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459, 987-991CrossRefGoogle ScholarPubMed
62Lupski, J.R. (2007) Genomic rearrangements and sporadic disease. Nature Genetics 39, S43-47CrossRefGoogle ScholarPubMed
63Cahan, P. et al. (2009) The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nature Genetics 41, 430-437CrossRefGoogle ScholarPubMed
64Henrichsen, C.N., Chaignat, E. and Reymond, A. (2009) Copy number variants, diseases and gene expression. Human Molecular Genetics 18, R1-8CrossRefGoogle ScholarPubMed
65Dathe, K. et al. (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. American Journal of Human Genetics 84, 483-492CrossRefGoogle ScholarPubMed
66Stranger, B.E. et al. (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes.Science 315, 848-853CrossRefGoogle ScholarPubMed
67Merla, G. et al. (2006) Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. American Journal of Human Genetics 79, 332-341CrossRefGoogle ScholarPubMed
68Firth, H.V. et al. (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. American Journal of Human Genetics 84, 524-533CrossRefGoogle ScholarPubMed
69Miller, D.T. et al. (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. Journal of Medical Genetics 46, 242-248CrossRefGoogle ScholarPubMed
70Sharp, A.J. et al. (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40, 322-328CrossRefGoogle ScholarPubMed
71O'Donovan, M.C., Kirov, G. and Owen, M.J. (2008) Phenotypic variations on the theme of CNVs. Nature Genetics 40, 1392-1393CrossRefGoogle ScholarPubMed
72Brunetti-Pierri, N. et al. (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics 40, 1466-1471CrossRefGoogle ScholarPubMed
73Mefford, H.C. et al. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359, 1685-1699CrossRefGoogle ScholarPubMed
74Carlson, C. et al. (1997) Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. American Journal of Human Genetics 61, 620-629CrossRefGoogle ScholarPubMed
75Driscoll, D.A. et al. (1992) Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. American Journal of Medical Genetics 44, 261-268CrossRefGoogle ScholarPubMed
76Coppinger, J. et al. (2009) Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region. Human Molecular Genetics 18, 1377-1383CrossRefGoogle ScholarPubMed
77Klopocki, E. et al. (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. American Journal of Human Genetics 80, 232-240CrossRefGoogle ScholarPubMed
78Uhrig, S. et al. (2007) Impact of array comparative genomic hybridization-derived information on genetic counseling demonstrated by prenatal diagnosis of the TAR (thrombocytopenia-absent-radius) syndrome-associated microdeletion 1q21.1. American Journal of Human Genetics 81, 866-868CrossRefGoogle ScholarPubMed
79Prior, T.W. (2007) Spinal muscular atrophy diagnostics. Journal of Child Neurology 22, 952-956CrossRefGoogle ScholarPubMed
80Schonherr, N. et al. (2007) The centromeric 11p15 imprinting centre is also involved in Silver-Russell syndrome. Journal of Medical Genetics 44, 59-63CrossRefGoogle ScholarPubMed
81Feuk, L. et al. (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. American Journal of Human Genetics 79, 965-972CrossRefGoogle ScholarPubMed
82Bruder, C.E. et al. (2008) Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. American Journal of Human Genetics 82, 763-771CrossRefGoogle ScholarPubMed
83Piotrowski, A. et al. (2008) Somatic mosaicism for copy number variation in differentiated human tissues. Human Mutation 29, 1118-1124CrossRefGoogle ScholarPubMed
84Gervasini, C. et al. (2007) High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics 90, 567-573CrossRefGoogle ScholarPubMed
85Roelfsema, J.H. and Peters, D.J. (2007) Rubinstein-Taybi syndrome: clinical and molecular overview. Expert Reviews in Molecular Medicine 9, 1-16CrossRefGoogle ScholarPubMed
86Schorry, E.K. et al. (2008) Genotype-phenotype correlations in Rubinstein-Taybi syndrome. American Journal of Medical Genetics Part A 146A, 2512-2519CrossRefGoogle ScholarPubMed
87Kozlowski, P. et al. (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Human Genetics 121, 389-400CrossRefGoogle ScholarPubMed
88Robinson, D.O. et al. (2008) Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. American Journal of Medical Genetics Part A 146A, 558-569CrossRefGoogle Scholar
89Kirov, G. et al. (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics 18, 1497-1503CrossRefGoogle ScholarPubMed
90Greenway, S.C. et al. (2009) De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nature Genetics 41, 931-935CrossRefGoogle ScholarPubMed
91Need, A.C. et al. (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics 5, e1000373CrossRefGoogle Scholar
92Lyle, R. et al. (2009) Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. European Journal of Human Genetics 17, 454-466CrossRefGoogle ScholarPubMed
93Korbel, J.O. et al. (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proceedings of the National Academy of Sciences of the United States of America 106, 12031-12036CrossRefGoogle ScholarPubMed
94Reisman, L.E. et al. (1966) Anti-mongolism. Studies in an infant with a partial monosomy of the 21 chromosome. Lancet 1, 394-397CrossRefGoogle Scholar
95Ewart, A.K. et al. (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genetics 5, 11-16CrossRefGoogle Scholar
96Osborne, L.R. and Mervis, C.B. (2007) Rearrangements of the Williams-Beuren syndrome locus: molecular basis and implications for speech and language development. Expert Reviews in Molecular Medicine 9, 1-16CrossRefGoogle ScholarPubMed
97Lupski, J.R. (2009) Genomic disorders ten years on. Genome Medicine 1, 42CrossRefGoogle Scholar
98Somerville, M.J. et al. (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. New England Journal of Medicine 353, 1694-1701CrossRefGoogle ScholarPubMed
99Kriek, M. et al. (2006) Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications. European Journal of Human Genetics 14, 180-189CrossRefGoogle ScholarPubMed
100Torniero, C. et al. (2008) Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. European Journal of Human Genetics 16, 880-887CrossRefGoogle ScholarPubMed
101Sharp, A.J. et al. (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genetics 38, 1038-1042CrossRefGoogle ScholarPubMed
102Christian, S.L. et al. (1999) Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Human Molecular Genetics 8, 1025-1037CrossRefGoogle Scholar
103Mignon-Ravix, C. et al. (2007) Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations. European Journal of Human Genetics 15, 432-440CrossRefGoogle ScholarPubMed
104Sahoo, T. et al. (2005) Array-based comparative genomic hybridization analysis of recurrent chromosome 15q rearrangements. American Journal of Medical Genetics A 139A, 106-113CrossRefGoogle ScholarPubMed
105Sharp, A.J. et al. (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40, 322-328CrossRefGoogle ScholarPubMed
106Stefansson, H. et al. (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236CrossRefGoogle ScholarPubMed
107Pagnamenta, A.T. et al. (2009) A 15q13.3 microdeletion segregating with autism. European Journal of Human Genetics 17, 687-692CrossRefGoogle ScholarPubMed
108Shinawi, M. et al. (2009) A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nature Genetics 41, 1269-1271CrossRefGoogle ScholarPubMed
109Helbig, I. et al. (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics 41, 160-162CrossRefGoogle ScholarPubMed
110Ben-Shachar, S. et al. (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. Journal of Medical Genetics 46, 382-388CrossRefGoogle ScholarPubMed
111Pagnamenta, A.T. et al. (2009) A 15q13.3 microdeletion segregating with autism. European Journal of Human Genetics 17, 687-692CrossRefGoogle ScholarPubMed
112van Bon, B.W. et al. (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. Journal of Medical Genetics 46, 511-523CrossRefGoogle ScholarPubMed
113Consortium, I.S. (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237-241Google Scholar
114Helbig, I. et al. (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics 41, 160-162CrossRefGoogle ScholarPubMed
115Buchanan, J.A. et al. (2009) The cycle of genome-directed medicine. Genome Medicine 1, 16CrossRefGoogle ScholarPubMed
116Ali-Khan, S.E. et al. (2009) Whole genome scanning: resolving clinical diagnosis and management amidst complex data. Pediatric Research 66, 357-363CrossRefGoogle ScholarPubMed
117Christiansen, J. et al. (2004) Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circulation Research 94, 1429-1435CrossRefGoogle ScholarPubMed
118Szatmari, P. et al. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics 39, 319-328CrossRefGoogle ScholarPubMed
119Mefford, H.C. et al. (2009) A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Research 19, 1579-1585CrossRefGoogle ScholarPubMed
120Pinto, D. et al. (2007) Copy-number variation in control population cohorts. Human Molecular Genetics 16 (Spec No. 2), R168-173CrossRefGoogle ScholarPubMed
121Armengol, L., Rabionet, R. and Estivill, X. (2008) The emerging role of structural variations in common disorders: initial findings and discovery challenges. Cytogenetic and Genome Research 123, 108-117CrossRefGoogle ScholarPubMed
122Schaschl, H., Aitman, T.J. and Vyse, T.J. (2009) Copy number variation in the human genome and its implication in autoimmunity. Clinical and Experimental Immunology 156, 12-16CrossRefGoogle ScholarPubMed
123Ionita-Laza, I. et al. (2009) Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics 93, 22-26CrossRefGoogle Scholar
124Hollox, E.J., Detering, J.C. and Dehnugara, T. (2009) An integrated approach for measuring copy number variation at the FCGR3 (CD16) locus. Human Mutation 30, 477-484CrossRefGoogle ScholarPubMed
125Nuytten, H. et al. (2009) Accurate determination of copy number variations (CNVs): application to the alpha- and beta-defensin CNVs. Journal of Immunological Methods 344, 35-44CrossRefGoogle ScholarPubMed
126McCarroll, S.A. et al. (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nature Genetics 40, 1107-1112CrossRefGoogle ScholarPubMed
127Gonzalez, E. et al. (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434-1440CrossRefGoogle ScholarPubMed
128Kulkarni, H. et al. (2008) CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals. PLoS One 3, e3165CrossRefGoogle ScholarPubMed
129Shostakovich-Koretskaya, L. et al. (2009) Combinatorial content of CCL3L and CCL4L gene copy numbers influence HIV-AIDS susceptibility in Ukrainian children. AIDS 23, 679-688Google ScholarPubMed
130McKinney, C. et al. (2008) Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Annals of the Rheumatic Diseases 67, 409-413CrossRefGoogle ScholarPubMed
131Colobran, R. et al. (2009) Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation. Genes and Immunity 10, 254-259CrossRefGoogle ScholarPubMed
132McCarroll, S.A. et al. (2009) Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nature Genetics 41, 1341-1344CrossRefGoogle ScholarPubMed
133Shlien, A. and Malkin, D. (2009) Copy number variations and cancer. Genome Medicine 1, 62CrossRefGoogle ScholarPubMed
134Marcel, V. et al. (2009) TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. Journal of Medical Genetics 46, 766-772CrossRefGoogle ScholarPubMed
135Schwarzbraun, T. et al. (2009) Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing. Journal of Medical Genetics 46, 341-344CrossRefGoogle ScholarPubMed
136Adam, M.P. et al. (2009) Clinical utility of array comparative genomic hybridization: uncovering tumor susceptibility in individuals with developmental delay. Journal of Pediatrics 154, 143-146CrossRefGoogle ScholarPubMed
137Adams, S.A. et al. (2009) Impact of genotype-first diagnosis: the detection of microdeletion and microduplication syndromes with cancer predisposition by aCGH. Genetics in Medicine 11, 314-322CrossRefGoogle ScholarPubMed
138Speicher, M.R. and Carter, N.P. (2005) The new cytogenetics: blurring the boundaries with molecular biology. Nature Reviews Genetics 6, 782-792CrossRefGoogle ScholarPubMed
139Stuhrmann, M. et al. (2009) Testing the parents to confirm genotypes of CF patients is highly recommended: report of two cases. European Journal of Human Genetics 17, 417-419CrossRefGoogle ScholarPubMed
140Girardet, A. et al. (2007) Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements. Clinical Genetics 72, 374-377CrossRefGoogle ScholarPubMed
141Tomaiuolo, R. et al. (2008) Epidemiology and a novel procedure for large scale analysis of CFTR rearrangements in classic and atypical CF patients: a multicentric Italian study. Journal of Cystic Fibrosis 7, 347-351CrossRefGoogle Scholar
142McDevitt, T. and Barton, D. (2009) When good CF tests go bad. European Journal of Human Genetics 17, 403-405Google Scholar
143Vissers, L.E. et al. (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature Genetics 36, 955-957CrossRefGoogle Scholar
144Fernandez, B.A. et al. (2009) Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. Journal of Medical Genetics Sep 24; [Epub ahead of print]Google ScholarPubMed
145Kumar, R.A. et al. (2008) Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics 17, 628-638CrossRefGoogle ScholarPubMed
146Marshall, C.R. et al. (2008) Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics 82, 477-488CrossRefGoogle ScholarPubMed
147Weiss, L.A. et al. (2008) Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667-675CrossRefGoogle ScholarPubMed
148Shinawi, M. et al. (2009) Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioral problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics Nov 12; [Epub ahead of print]Google Scholar
149McCarthy, S.E. et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics 41, 1223-1227CrossRefGoogle ScholarPubMed
150Bochukova, E.G. et al. (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666-670CrossRefGoogle ScholarPubMed
151Perry, G.H. et al. (2008) The fine-scale and complex architecture of human copy-number variation. American Journal of Human Genetics 82, 685-695CrossRefGoogle ScholarPubMed
152Zogopoulos, G. et al. (2007) Germ-line DNA copy number variation frequencies in a large North American population. Human Genetics 122, 345-353CrossRefGoogle Scholar
153Jakobsson, M. et al. (2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451, 998-1003CrossRefGoogle ScholarPubMed
154Armengol, L. et al. (2009) Identification of copy number variants defining genomic differences among major human groups. PLoS One 4, e7230CrossRefGoogle ScholarPubMed
155Matsuzaki, H. et al. (2009) High resolution discovery and confirmation of copy number variants in 90 Yoruba Nigerians. Genome Biology 10, R125CrossRefGoogle ScholarPubMed
156Yim, S.H. et al. (2010) Copy number variations in East-Asian population and their evolutionary and functional implications. Human Molecular Genetics Jan 15; [Epub ahead of print]CrossRefGoogle ScholarPubMed
157Brookes, A.J. et al. (2009) Genomic variation in a global village: report of the 10th annual Human Genome Variation Meeting 2008. Human Mutation 30, 1134-1138CrossRefGoogle Scholar
158Stankiewicz, P. and Lupski, J.R. (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61, 437-455CrossRefGoogle Scholar
159Ilbery, P.L., Lee, C.W. and Winn, S.M. (1961) Incomplete trisomy in a mongoloid child exhibiting minimal stigmata. Medical Journal of Australia 48, 182-184Google Scholar
160Lejeune, J. et al. (1963) [3 cases of partial deletion of the short arm of a 5 chromosome.] Comptes rendus hebdomadaires des séances de l'Académie des sciences 257, 3098-3102 [Article in French]Google Scholar
161Caspersson, T. et al. (1969) Chemical differentiation with fluorescent alkylating agents in Vicia faba metaphase chromosomes. Experimental Cell Research 58, 128-140CrossRefGoogle ScholarPubMed
162Orkin, S.H. (1978) The duplicated human alpha globin genes lie close together in cellular DNA. Proceedings of the National Academy of Sciences of the United States of America 75, 5950-5954CrossRefGoogle ScholarPubMed
163Wyman, A.R. and White, R. (1980) A highly polymorphic locus in human DNA. Proceedings of the National Academy of Sciences of the United States of America 77, 6754-6758CrossRefGoogle ScholarPubMed
164Bauman, J.G. et al. (1980) A new method for fluorescence microscopical localization of specific DNA sequences by in situ hybridization of fluorochromelabelled RNA. Experimental Cell Research 128, 485-490CrossRefGoogle ScholarPubMed
165Van Prooijen-Knegt, A.C. et al. (1982) In situ hybridization of DNA sequences in human metaphase chromosomes visualized by an indirect fluorescent immunocytochemical procedure. Experimental Cell Research 141, 397-407CrossRefGoogle ScholarPubMed
166Jeffreys, A.J., Wilson, V. and Thein, S.L. (1985) Individual-specific ‘fingerprints’ of human DNA. Nature 316, 76-79CrossRefGoogle ScholarPubMed
167Monaco, A.P. et al. (1985) Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment. Nature 316, 842-845CrossRefGoogle ScholarPubMed
168Ray, P.N. et al. (1985) Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy. Nature 318, 672-675CrossRefGoogle ScholarPubMed
169Schmickel, R.D. (1986) Contiguous gene syndromes: a component of recognizable syndromes. Journal of Pediatrics 109, 231-241CrossRefGoogle ScholarPubMed
170Kallioniemi, A. et al. (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818-821CrossRefGoogle ScholarPubMed
171 [No authors listed] (1996) A complete set of human telomeric probes and their clinical application. National Institutes of Health and Institute of Molecular Medicine collaboration. Nature Genetics 14, 86-89CrossRefGoogle ScholarPubMed
172Pinkel, D. et al. (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genetics 20, 207-211CrossRefGoogle ScholarPubMed
173Stockley, T.L. et al. (2006) Strategy for comprehensive molecular testing for Duchenne and Becker muscular dystrophies. Genetic Testing 10, 229-243CrossRefGoogle ScholarPubMed
174White, S.J. and den Dunnen, J.T. (2006) Copy number variation in the genome; the human DMD gene as an example. Cytogenetic and Genome Research 115, 240-246CrossRefGoogle ScholarPubMed
175De Luca, A. et al. (2007) Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. Journal of Medical Genetics 44, 800-808CrossRefGoogle ScholarPubMed
176Raedt, T.D. et al. (2006) Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion. Nature Genetics 38, 1419-1423CrossRefGoogle ScholarPubMed
177Wimmer, K. et al. (2006) Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes, Chromosomes & Cancer 45, 265-276CrossRefGoogle Scholar
178Saugier-Veber, P. et al. (2007) Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. Human Mutation 28, 1098-1107CrossRefGoogle ScholarPubMed
179Fagali, C. et al. (2009) MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported. European Journal of Medical Genetics 52, 333-336CrossRefGoogle Scholar
180Woodward, K.J. (2008) The molecular and cellular defects underlying Pelizaeus-Merzbacher disease. Expert Reviews in Molecular Medicine 10, e14CrossRefGoogle ScholarPubMed
181Brouwers, N. et al. (2006) Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain 129, 2984-2991CrossRefGoogle ScholarPubMed
182Rovelet-Lecrux, A. et al. (2006) APP locus duplication causes autosomal dominant early-onset al.zheimer disease with cerebral amyloid angiopathy. Nature Genetics 38, 24-26CrossRefGoogle ScholarPubMed
183Sleegers, K. et al. (2006) APP duplication is sufficient to cause early onset al.zheimer's dementia with cerebral amyloid angiopathy. Brain 129, 2977-2983CrossRefGoogle ScholarPubMed
184Durand, C.M. et al. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 39, 25-27CrossRefGoogle ScholarPubMed
185Moessner, R. et al. (2007) Contribution of SHANK3 mutations to autism spectrum disorder. American Journal of Human Genetics 81, 1289-1297CrossRefGoogle ScholarPubMed
186Gauthier, J. et al. (2009) Novel de novo SHANK3 mutation in autistic patients. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics 150B, 421-424CrossRefGoogle ScholarPubMed
187Fantes, J. et al. (1995) Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Human Molecular Genetics 4, 415-422CrossRefGoogle ScholarPubMed
188Klopocki, E. et al. (2008) A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. Journal of Medical Genetics 45, 370-375CrossRefGoogle Scholar
189Sun, M. et al. (2008) Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. Journal of Medical Genetics 45, 589-595CrossRefGoogle Scholar
190Fellermann, K. et al. (2006) A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. American Journal of Human Genetics 79, 439-448CrossRefGoogle ScholarPubMed
191Hollox, E.J. et al. (2008) Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1. Genome Research 18, 1686-1697CrossRefGoogle ScholarPubMed
192Aitman, T.J. et al. (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851-855CrossRefGoogle ScholarPubMed
193Fanciulli, M. et al. (2007) FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nature Genetics 39, 721-723CrossRefGoogle Scholar
194Ibanez, P. et al. (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Archives of Neurology 66, 102-108CrossRefGoogle ScholarPubMed
195Burns, J.C. et al. (2005) Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. Journal of Infectious Diseases 192, 344-349CrossRefGoogle ScholarPubMed
196Saitta, S.C. et al. (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Human Molecular Genetics 13, 417-428CrossRefGoogle ScholarPubMed
197Shaikh, T.H. et al. (2007) Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Research 17, 482-491CrossRefGoogle ScholarPubMed
198Berg, J.S. et al. (2007) Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genetics in Medicine 9, 427-441CrossRefGoogle ScholarPubMed
199Cusco, I. et al. (2008) Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion. Genome Research 18, 683-694CrossRefGoogle ScholarPubMed
200Grisart, B. et al. (2009) 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. Journal of Medical Genetics 46, 524-530CrossRefGoogle ScholarPubMed
201Kirchhoff, M. et al. (2007) A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. European Journal of Medical Genetics 50, 256-263CrossRefGoogle Scholar
202Shaffer, L.G. et al. (2007) The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genetics in Medicine 9, 607-616CrossRefGoogle ScholarPubMed
203Ballif, B.C. et al. (2007) Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nature Genetics 39, 1071-1073CrossRefGoogle ScholarPubMed
204Ghebranious, N. et al. (2007) A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. American Journal of Medical Genetics Part A 143A, 1462-1471CrossRefGoogle ScholarPubMed
205Ballif, B.C. et al. (2008) Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Molecular Cytogenetics 1, 8CrossRefGoogle ScholarPubMed
206Goobie, S. et al. (2008) Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting. Cytogenetic and Genome Research 123, 65-78CrossRefGoogle ScholarPubMed
207Potocki, L. et al. (2007) Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. American Journal of Human Genetics 80, 633-649CrossRefGoogle ScholarPubMed
208Tabor, H.K. and Cho, M.K. (2007) Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research. Genetics in Medicine 9, 626-631CrossRefGoogle ScholarPubMed
209Ullmann, R. et al. (2007) Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Human Mutation 28, 674-682CrossRefGoogle ScholarPubMed
210Schaefer, G.B. and Mendelsohn, N.J. (2008) Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genetics in Medicine 10, 4-12CrossRefGoogle ScholarPubMed
211Glessner, J.T. et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569-573CrossRefGoogle ScholarPubMed
212Abrahams, B.S. and Geschwind, D.H. (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nature Reviews Genetics 9, 341-355CrossRefGoogle ScholarPubMed
213Lachman, H.M. et al. (2007) Increase in GSK3beta gene copy number variation in bipolar disorder. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics 144B, 259-265CrossRefGoogle ScholarPubMed
214Burmeister, M., McInnis, M.G. and Zollner, S. (2008) Psychiatric genetics: progress amid controversy. Nature Reviews Genetics 9, 527-540CrossRefGoogle ScholarPubMed
215Alaerts, M. and Del-Favero, J. (2009) Searching genetic risk factors for schizophrenia and bipolar disorder: learn from the past and back to the future. Human Mutation 30, 1139-1152CrossRefGoogle ScholarPubMed
216Walsh, T. et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539-543CrossRefGoogle Scholar
217Xu, B. et al. (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics 40, 880-885CrossRefGoogle ScholarPubMed
218Rujescu, D. et al. (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics 18, 988-996CrossRefGoogle ScholarPubMed
219Hughes, A.E. et al. (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genetics 38, 1173-1177CrossRefGoogle ScholarPubMed
220Maller, J. et al. (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature Genetics 38, 1055-1059CrossRefGoogle ScholarPubMed
221Barber, J.C. et al. (2008) 8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH. European Journal of Human Genetics 16, 18-27CrossRefGoogle ScholarPubMed
222Hendrickson, B.C. et al. (2009) Differences in SMN1 allele frequencies among ethnic groups within North America. Journal of Medical Genetics 46, 641-644CrossRefGoogle ScholarPubMed
223Alias, L. et al. (2009) Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Human Genetics 125, 29-39CrossRefGoogle ScholarPubMed
224Mantripragada, K.K. et al. (2009) Genome-wide high-resolution analysis of DNA copy number alterations in NF1-associated malignant peripheral nerve sheath tumors using 32K BAC array. Genes, Chromosomes & Cancer 48, 897-907CrossRefGoogle ScholarPubMed
118
Cited by