Skip to main content
×
Home
    • Aa
    • Aa

The clinical context of copy number variation in the human genome

  • Charles Lee (a1) and Stephen W. Scherer (a2) (a3)
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.

Copyright
Corresponding author
*Corresponding author: Stephen W. Scherer, The Hospital for Sick Children, MaRS Centre - East Tower, 101 College Street, Room 14-701, Toronto, Ontario, M5G 1L7, Canada. E-mail: stephen.scherer@sickkids.ca
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2 A.J. Iafrate (2004) Detection of large-scale variation in the human genome. Nature Genetics 36, 949-951

3 J. Sebat (2004) Large-scale copy number polymorphism in the human genome. Science 305, 525-528

5 P.A. Jacobs and J.A. Strong (1959) A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183, 302-303

6 L. Feuk , A.R. Carson and S.W. Scherer (2006) Structural variation in the human genome. Nature Reviews Genetics 7, 85-97

7 S.W. Scherer (2007) Challenges and standards in integrating surveys of structural variation. Nature Genetics 39, S7-15

8 C. Lee , A.J. Iafrate and A.R. Brothman (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nature Genetics 39, S48-54

9 D.F. Conrad (2006) A high-resolution survey of deletion polymorphism in the human genome. Nature Genetics 38, 75-81

10 R. Khaja (2006) Genome assembly comparison identifies structural variants in the human genome. Nature Genetics 38, 1413-1418

11 J.S. Beckmann , X. Estivill and S.E. Antonarakis (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature Reviews Genetics 8, 639-646

12 L.V. Wain , J.A. Armour and M.D. Tobin (2009) Genomic copy number variation, human health, and disease. Lancet 374, 340-350

14 J.A. Buchanan and S.W. Scherer (2008) Contemplating effects of genomic structural variation. Genetics in Medicine 10, 639-647

15 A. Varki , D.H. Geschwind and E.E. Eichler (2008) Explaining human uniqueness: genome interactions with environment, behaviour and culture. Nature Reviews Genetics 9, 749-763

16 R. Redon (2006) Global variation in copy number in the human genome. Nature 444, 444-454

17 B.S. Emanuel and T.H. Shaikh (2001) Segmental duplications: an ‘expanding’ role in genomic instability and disease. Nature Reviews Genetics 2, 791-800

18 S.W. Scherer (2003) Human chromosome 7: DNA sequence and biology. Science 300, 767-772

19 D. Fredman (2004) Complex SNP-related sequence variation in segmental genome duplications. Nature Genetics 36, 861-866

21 P.M. Kim (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, 1865-1874

22 P. Stankiewicz and J.R. Lupski (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18, 74-82

23 J.R. Lupski (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219-232

24 B.S. Emanuel and S.C. Saitta (2007) From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nature Reviews Genetics 8, 869-883

25 J.K. Moore and J.E. Haber (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, 2164-2173

26 D.F. Conrad and M.E. Hurles (2007) The population genetics of structural variation. Nature Genetics 39, S30-36

27 F. Zhang (2009) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genetics 41, 849-853

28 J.A. Lee , C.M. Carvalho and J.R. Lupski (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235-1247

29 C.M. Carvalho (2009) Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Human Molecular Genetics 18, 2188-2203

30 P.J. Hastings (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10, 551-564

31 P.J. Hastings , G. Ira and J.R. Lupski (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genetics 5, e1000327

32 D.A. Koolen (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nature Genetics 38, 999-1001

33 C. Shaw-Smith (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nature Genetics 38, 1032-1037

34 H. Stefansson (2005) A common inversion under selection in Europeans. Nature Genetics 37, 129-137

35 R. Visser (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, 52-67

36 L.R. Osborne (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nature Genetics 29, 321-325

37 S.W. Scherer and L.R. Osborne (2006) Williams-Beuren syndrome. In Genomic Disorders: The Genomic Basis of Disease ( J.R. Lupski and P. Stankiewicz , eds), pp. 221-236, Humana Press, Totowa, NJ, USA

38 S.A. McCarroll (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genetics 40, 1166-1174

39 J. Zhang (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, 205-214

40 S. Levy (2007) The diploid genome sequence of an individual human. PLoS Biology 5, e254

41 D.A. Wheeler (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872-876

42 E.S. Lander (2001) Initial sequencing and analysis of the human genome. Nature 409, 860-921

43International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431, 931-945

44 J.C. Venter (2001) The sequence of the human genome. Science 291, 1304-1351

45 B. Maher (2008) Personal genomes: the case of the missing heritability. Nature 456, 18-21

46 T.A. Manolio (2009) Finding the missing heritability of complex diseases. Nature 461, 747-753

47 E.H. Cook Jr, and S.W. Scherer (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919-923

48 N.P. Carter (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nature Genetics 39, S16-21

49 J. Wang (2008) The diploid genome sequence of an Asian individual. Nature 456, 60-65

50 D.R. Bentley (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53-59

51 S.M. Ahn (2009) The first Korean genome sequence and analysis: full genome sequencing for a socio-ethnic group. Genome Research 19, 1622-1629

53 K.J. McKernan (2009) Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Research 19, 1527-1541

54 R. Drmanac Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78-81

55 C. Alkan (2009) Personalized copy number and segmental duplication maps using next-generation sequencing. Nature Genetics 41, 1061-1067

56 D.Y. Chiang (2009) High-resolution mapping of copy-number alterations with massively parallel sequencing. Nature Methods 6, 99-103

57 J.R. Lupski (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends in Genetics 14, 417-422

59 R. de Cid (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genetics 41, 211-215

60 A. Shlien (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, 11264-11269

61 S.J. Diskin (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459, 987-991

62 J.R. Lupski (2007) Genomic rearrangements and sporadic disease. Nature Genetics 39, S43-47

63 P. Cahan (2009) The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nature Genetics 41, 430-437

64 C.N. Henrichsen , E. Chaignat and A. Reymond (2009) Copy number variants, diseases and gene expression. Human Molecular Genetics 18, R1-8

65 K. Dathe (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. American Journal of Human Genetics 84, 483-492

66 B.E. Stranger (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes.Science 315, 848-853

67 G. Merla (2006) Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. American Journal of Human Genetics 79, 332-341

68 H.V. Firth (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. American Journal of Human Genetics 84, 524-533

69 D.T. Miller (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. Journal of Medical Genetics 46, 242-248

70 A.J. Sharp (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40, 322-328

71 M.C. O'Donovan , G. Kirov and M.J. Owen (2008) Phenotypic variations on the theme of CNVs. Nature Genetics 40, 1392-1393

72 N. Brunetti-Pierri (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics 40, 1466-1471

73 H.C. Mefford (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359, 1685-1699

74 C. Carlson (1997) Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. American Journal of Human Genetics 61, 620-629

75 D.A. Driscoll (1992) Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. American Journal of Medical Genetics 44, 261-268

76 J. Coppinger (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, 1377-1383

77 E. Klopocki (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. American Journal of Human Genetics 80, 232-240

78 S. Uhrig (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, 866-868

79 T.W. Prior (2007) Spinal muscular atrophy diagnostics. Journal of Child Neurology 22, 952-956

80 N. Schonherr (2007) The centromeric 11p15 imprinting centre is also involved in Silver-Russell syndrome. Journal of Medical Genetics 44, 59-63

81 L. Feuk (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. American Journal of Human Genetics 79, 965-972

82 C.E. Bruder (2008) Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. American Journal of Human Genetics 82, 763-771

83 A. Piotrowski (2008) Somatic mosaicism for copy number variation in differentiated human tissues. Human Mutation 29, 1118-1124

84 C. Gervasini (2007) High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics 90, 567-573

86 E.K. Schorry (2008) Genotype-phenotype correlations in Rubinstein-Taybi syndrome. American Journal of Medical Genetics Part A 146A, 2512-2519

87 P. Kozlowski (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Human Genetics 121, 389-400

88 D.O. Robinson (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, 558-569

89 G. Kirov (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics 18, 1497-1503

90 S.C. Greenway (2009) De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nature Genetics 41, 931-935

91 A.C. Need (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics 5, e1000373

92 R. Lyle (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, 454-466

93 J.O. Korbel (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, 12031-12036

95 A.K. Ewart (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genetics 5, 11-16

97 J.R. Lupski (2009) Genomic disorders ten years on. Genome Medicine 1, 42

98 M.J. Somerville (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. New England Journal of Medicine 353, 1694-1701

99 M. Kriek (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, 180-189

100 C. Torniero (2008) Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. European Journal of Human Genetics 16, 880-887

101 A.J. Sharp (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genetics 38, 1038-1042

102 S.L. Christian (1999) Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Human Molecular Genetics 8, 1025-1037

103 C. Mignon-Ravix (2007) Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations. European Journal of Human Genetics 15, 432-440

104 T. Sahoo (2005) Array-based comparative genomic hybridization analysis of recurrent chromosome 15q rearrangements. American Journal of Medical Genetics A 139A, 106-113

106 H. Stefansson (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236

107 A.T. Pagnamenta (2009) A 15q13.3 microdeletion segregating with autism. European Journal of Human Genetics 17, 687-692

108 M. Shinawi (2009) A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nature Genetics 41, 1269-1271

110 S. Ben-Shachar (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. Journal of Medical Genetics 46, 382-388

112 B.W. van Bon (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, 511-523

114 I. Helbig (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics 41, 160-162

115 J.A. Buchanan (2009) The cycle of genome-directed medicine. Genome Medicine 1, 16

116 S.E. Ali-Khan (2009) Whole genome scanning: resolving clinical diagnosis and management amidst complex data. Pediatric Research 66, 357-363

117 J. Christiansen (2004) Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circulation Research 94, 1429-1435

118 P. Szatmari (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics 39, 319-328

119 H.C. Mefford (2009) A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Research 19, 1579-1585

120 D. Pinto (2007) Copy-number variation in control population cohorts. Human Molecular Genetics 16 (Spec No. 2), R168-173

121 L. Armengol , R. Rabionet and X. Estivill (2008) The emerging role of structural variations in common disorders: initial findings and discovery challenges. Cytogenetic and Genome Research 123, 108-117

122 H. Schaschl , T.J. Aitman and T.J. Vyse (2009) Copy number variation in the human genome and its implication in autoimmunity. Clinical and Experimental Immunology 156, 12-16

123 I. Ionita-Laza (2009) Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics 93, 22-26

124 E.J. Hollox , J.C. Detering and T. Dehnugara (2009) An integrated approach for measuring copy number variation at the FCGR3 (CD16) locus. Human Mutation 30, 477-484

125 H. Nuytten (2009) Accurate determination of copy number variations (CNVs): application to the alpha- and beta-defensin CNVs. Journal of Immunological Methods 344, 35-44

126 S.A. McCarroll (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nature Genetics 40, 1107-1112

127 E. Gonzalez (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434-1440

128 H. Kulkarni (2008) CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals. PLoS One 3, e3165

130 C. McKinney (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, 409-413

131 R. Colobran (2009) Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation. Genes and Immunity 10, 254-259

132 S.A. McCarroll (2009) Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nature Genetics 41, 1341-1344

133 A. Shlien and D. Malkin (2009) Copy number variations and cancer. Genome Medicine 1, 62

134 V. Marcel (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, 766-772

135 T. Schwarzbraun (2009) Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing. Journal of Medical Genetics 46, 341-344

136 M.P. Adam (2009) Clinical utility of array comparative genomic hybridization: uncovering tumor susceptibility in individuals with developmental delay. Journal of Pediatrics 154, 143-146

137 S.A. Adams (2009) Impact of genotype-first diagnosis: the detection of microdeletion and microduplication syndromes with cancer predisposition by aCGH. Genetics in Medicine 11, 314-322

138 M.R. Speicher and N.P. Carter (2005) The new cytogenetics: blurring the boundaries with molecular biology. Nature Reviews Genetics 6, 782-792

139 M. Stuhrmann (2009) Testing the parents to confirm genotypes of CF patients is highly recommended: report of two cases. European Journal of Human Genetics 17, 417-419

140 A. Girardet (2007) Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements. Clinical Genetics 72, 374-377

141 R. Tomaiuolo (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, 347-351

143 L.E. Vissers (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature Genetics 36, 955-957

145 R.A. Kumar (2008) Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics 17, 628-638

146 C.R. Marshall (2008) Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics 82, 477-488

147 L.A. Weiss (2008) Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667-675

149 S.E. McCarthy (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics 41, 1223-1227

150 E.G. Bochukova (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666-670

151 G.H. Perry (2008) The fine-scale and complex architecture of human copy-number variation. American Journal of Human Genetics 82, 685-695

152 G. Zogopoulos (2007) Germ-line DNA copy number variation frequencies in a large North American population. Human Genetics 122, 345-353

153 M. Jakobsson (2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451, 998-1003

154 L. Armengol (2009) Identification of copy number variants defining genomic differences among major human groups. PLoS One 4, e7230

155 H. Matsuzaki (2009) High resolution discovery and confirmation of copy number variants in 90 Yoruba Nigerians. Genome Biology 10, R125

156 S.H. Yim (2010) Copy number variations in East-Asian population and their evolutionary and functional implications. Human Molecular Genetics Jan 15; [Epub ahead of print]

157 A.J. Brookes (2009) Genomic variation in a global village: report of the 10th annual Human Genome Variation Meeting 2008. Human Mutation 30, 1134-1138

158 P. Stankiewicz and J.R. Lupski (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61, 437-455

161 T. Caspersson (1969) Chemical differentiation with fluorescent alkylating agents in Vicia faba metaphase chromosomes. Experimental Cell Research 58, 128-140

162 S.H. Orkin (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, 5950-5954

163 A.R. Wyman and R. White (1980) A highly polymorphic locus in human DNA. Proceedings of the National Academy of Sciences of the United States of America 77, 6754-6758

164 J.G. Bauman (1980) A new method for fluorescence microscopical localization of specific DNA sequences by in situ hybridization of fluorochromelabelled RNA. Experimental Cell Research 128, 485-490

165 A.C. Van Prooijen-Knegt (1982) In situ hybridization of DNA sequences in human metaphase chromosomes visualized by an indirect fluorescent immunocytochemical procedure. Experimental Cell Research 141, 397-407

166 A.J. Jeffreys , V. Wilson and S.L. Thein (1985) Individual-specific ‘fingerprints’ of human DNA. Nature 316, 76-79

167 A.P. Monaco (1985) Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment. Nature 316, 842-845

168 P.N. Ray (1985) Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy. Nature 318, 672-675

169 R.D. Schmickel (1986) Contiguous gene syndromes: a component of recognizable syndromes. Journal of Pediatrics 109, 231-241

170 A. Kallioniemi (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818-821

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, 86-89

172 D. Pinkel (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genetics 20, 207-211

173 T.L. Stockley (2006) Strategy for comprehensive molecular testing for Duchenne and Becker muscular dystrophies. Genetic Testing 10, 229-243

174 S.J. White and J.T. den Dunnen (2006) Copy number variation in the genome; the human DMD gene as an example. Cytogenetic and Genome Research 115, 240-246

175 A. De Luca (2007) Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. Journal of Medical Genetics 44, 800-808

176 T.D. Raedt (2006) Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion. Nature Genetics 38, 1419-1423

177 K. Wimmer (2006) Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes, Chromosomes & Cancer 45, 265-276

178 P. Saugier-Veber (2007) Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. Human Mutation 28, 1098-1107

179 C. Fagali (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, 333-336

181 N. Brouwers (2006) Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain 129, 2984-2991

182 A. Rovelet-Lecrux (2006) APP locus duplication causes autosomal dominant early-onset al.zheimer disease with cerebral amyloid angiopathy. Nature Genetics 38, 24-26

183 K. Sleegers (2006) APP duplication is sufficient to cause early onset al.zheimer's dementia with cerebral amyloid angiopathy. Brain 129, 2977-2983

184 C.M. Durand (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 39, 25-27

185 R. Moessner (2007) Contribution of SHANK3 mutations to autism spectrum disorder. American Journal of Human Genetics 81, 1289-1297

186 J. Gauthier (2009) Novel de novo SHANK3 mutation in autistic patients. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics 150B, 421-424

187 J. Fantes (1995) Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Human Molecular Genetics 4, 415-422

188 E. Klopocki (2008) A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. Journal of Medical Genetics 45, 370-375

189 M. Sun (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, 589-595

190 K. Fellermann (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, 439-448

191 E.J. Hollox (2008) Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1. Genome Research 18, 1686-1697

192 T.J. Aitman (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851-855

193 M. Fanciulli (2007) FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nature Genetics 39, 721-723

194 P. Ibanez (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Archives of Neurology 66, 102-108

195 J.C. Burns (2005) Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. Journal of Infectious Diseases 192, 344-349

196 S.C. Saitta (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Human Molecular Genetics 13, 417-428

197 T.H. Shaikh (2007) Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Research 17, 482-491

198 J.S. Berg (2007) Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genetics in Medicine 9, 427-441

199 I. Cusco (2008) Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion. Genome Research 18, 683-694

200 B. Grisart (2009) 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. Journal of Medical Genetics 46, 524-530

201 M. Kirchhoff (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, 256-263

202 L.G. Shaffer (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, 607-616

203 B.C. Ballif (2007) Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nature Genetics 39, 1071-1073

204 N. Ghebranious (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, 1462-1471

205 B.C. Ballif (2008) Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Molecular Cytogenetics 1, 8

206 S. Goobie (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, 65-78

207 L. Potocki (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, 633-649

208 H.K. Tabor and M.K. Cho (2007) Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research. Genetics in Medicine 9, 626-631

209 R. Ullmann (2007) Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Human Mutation 28, 674-682

210 G.B. Schaefer and N.J. Mendelsohn (2008) Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genetics in Medicine 10, 4-12

211 J.T. Glessner (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569-573

212 B.S. Abrahams and D.H. Geschwind (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nature Reviews Genetics 9, 341-355

213 H.M. Lachman (2007) Increase in GSK3beta gene copy number variation in bipolar disorder. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics 144B, 259-265

214 M. Burmeister , M.G. McInnis and S. Zollner (2008) Psychiatric genetics: progress amid controversy. Nature Reviews Genetics 9, 527-540

215 M. Alaerts and J. Del-Favero (2009) Searching genetic risk factors for schizophrenia and bipolar disorder: learn from the past and back to the future. Human Mutation 30, 1139-1152

216 T. Walsh (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539-543

217 B. Xu (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics 40, 880-885

219 A.E. Hughes (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genetics 38, 1173-1177

220 J. Maller (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature Genetics 38, 1055-1059

221 J.C. Barber (2008) 8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH. European Journal of Human Genetics 16, 18-27

222 B.C. Hendrickson (2009) Differences in SMN1 allele frequencies among ethnic groups within North America. Journal of Medical Genetics 46, 641-644

223 L. Alias (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, 29-39

224 K.K. Mantripragada (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, 897-907

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Full text views

Total number of HTML views: 15
Total number of PDF views: 90 *
Loading metrics...

Abstract views

Total abstract views: 406 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 26th September 2017. This data will be updated every 24 hours.