Structural variation in the human genome and its role in disease

Annual Review of Medicine

Volumn 61, Issue , 2010, Pages 437-455

  Stankiewicz, Pawel ^a   Lupski, James R ^a,b  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b TEXAS CHILDREN S HOSPITAL   (United States)

Author keywords

Array CGH; Copy number variants; Genomic disorders; Microdeletions and microduplications; Molecular mechanisms of genomic rearrangements

Indexed keywords

NUCLEOTIDE;

ALZHEIMER DISEASE; AUTISM; CHROMOSOME 15Q; CHROMOSOME 15Q13.3; CHROMOSOME 17Q; CHROMOSOME 17Q21.31; CHROMOSOME DELETION; CHROMOSOME DISORDER; COPY NUMBER VARIATION; DEVELOPMENTAL DISORDER; DISEASE PREDISPOSITION; EPILEPSY; ERROR; EVOLUTION; GENE DELETION; GENE REARRANGEMENT; GENE REPLICATION; GENE STRUCTURE; GENETIC DISORDER; GENETIC RECOMBINATION; GENETIC TRAIT; GENETIC VARIABILITY; GENOMICS; HEREDITARY MOTOR SENSORY NEUROPATHY; HIGH THROUGHPUT SCREENING; HOMOLOGOUS RECOMBINATION; HUMAN; HUMAN GENOME; MENTAL DEFICIENCY; NEUROPATHY; PANCREATITIS; PARKINSON DISEASE; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; SMITH MAGENIS SYNDROME; GENETIC PREDISPOSITION; GENETICS; MUTATION; PHYSIOLOGY;

GENETIC PREDISPOSITION TO DISEASE; GENOME, HUMAN; GENOMIC STRUCTURAL VARIATION; HUMANS; MUTATION; PHENOTYPE;

EID: 77949831756     PISSN: 00664219     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev-med-100708-204735     Document Type: Review

References (134)

1. Lupski JR. 1998. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14:417-422
2. Lupski JR. 2009. Genomic disorders ten years on. Genome Med. 24:1:42
3. Lupski JR, Wise CA, Kuwano A, et al. 1992. Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat. Genet. 1:29-33
4. Lupski JR. 2007. Genomic rearrangements and sporadic disease. Nat. Genet. 39:S43-47
5. Sebat J, Lakshmi B, Troge J, et al. 2004. Large-scale copy number polymorphism in the human genome. Science 305:525-528
6. Iafrate AJ, Feuk L, Rivera MN, et al. 2004. Detection of large-scale variation in the human genome. Nat. Genet. 36:949-951
7. Redon R, Ishikawa S, Fitch KR, et al. 2006. Global variation in copy number in the human genome. Nature 444:444-454 (Pubitemid 44809057)
8. Hurles ME, Dermitzakis ET, Tyler-Smith C. 2008. The functional impact of structural variation in humans. Trends Genet. 24:238-245
9. Conrad DF, Pinto D, Redon R, et al. 2009. Origins and functional impact of copy number variation in the human genome. Nature. In press
10. Korbel JO, Urban AE, Affourtit JP, et al. 2007. Paired-end mapping reveals extensive structural variation in the human genome. Science 318:420-426
11. Kidd JM, Cooper GM, Donahue WF, et al. 2008. Mapping and sequencing of structural variation from eight human genomes. Nature 453:56-64
12. Lupski JR. 2007. Structural variation in the human genome. N. Engl. J. Med. 356:1169-1171
13. Firth HV, Richards SM, Bevan AP, et al. 2009. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84:524-533
14. Bailey JA, Yavor AM, Massa HF, et al. 2001. Segmental duplications: organization and impact within the current Human Genome Project assembly. Genome Res. 11:1005-1017
15. Gu W, Zhang F, Lupski JR. 2008. Mechanisms for human genomic rearrangements. PathoGenetics 1:4.1-4.17
16. Stankiewicz P, Inoue K, Bi W, et al. 2003. Genomic disorders\genome architecture results in susceptibility to DNA rearrangements causing common human traits. Cold Spring Harb. Symp. Quant. Biol. LXVIII:445-454
17. Stankiewicz P, Lupski JR. 2002. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18:74-82
18. Weterings E, van Gent DC. 2004. The mechanism of non-homologous end-joining: a synopsis of synap-sis. DNA Repair (Amst.) 3:1425-1435
19. Lee JA, Carvalho CM, Lupski JR. 2007. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235-1247
20. Zhang F, Khajavi M, Connolly AM, et al. 2009. The DNA replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exonic complex rearrangements. Nat. Genet. 41:849-853
21. Slack A, Thornton PC, Magner DB, et al. 2006. On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2:e48
22. Hastings PJ, Ira G, Lupski JR. 2009. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5:e1000327
23. Carvalho CM, Zhang F, Liu P, et al. 2009. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum. Mol. Genet. 18:2188-2203
24. Bi W, Sapir T, Shchelochkov OA, et al. 2008. LIS1 increased expression affects human and mouse brain development. Nat. Genet. 41:168-177
25. Nagamani SCS, ZhangF,Shchelochkov OA,etal. 2009. Microdeletions includingYWHAEin the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J. Med. Genet. In press
26. Yatsenko SA, Brundage EK, Roney EK, et al. 2009. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum. Mol. Genet. 18:1924-1936
27. Zhang F,Carvalho CMB, Lupski JR. 2009. Complex human chromosomal and genomic rearrangements. Trends Genet. 25:298-307
28. Hastings PJ, Lupski JR, Rosenberg SM, et al. 2009. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10:551-564
29. Kleinjan DA, van Heyningen V. 2005. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76:8-32
30. Lee JA, Madrid RE, Sperle K, et al. 2006. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59:398-403
31. Smyk M,Berg JS, PursleyA, et al. 2007. Male-to-female sex reversal associated with an ∼250 Kbdeletion upstream of NR0B1 (DAX1). Hum. Genet. 122:63-70
32. Dathe K, Kjaer KW, Brehm A, et al. 2009. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am. J. Hum. Genet. 84:483-492
33. Klopocki E, Ott C-E, Benatar N, et al. 2008. A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J. Med. Genet. 45:370-375
34. Kurth I, Klopocki E, Stricker S, et. al. 2009. Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia. Nat. Genet. 41:862-863
35. Kurotaki N, Shen JJ, Touyama M, et al. 2005. Phenotypic consequences of genetic variation at hem-izygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med. 7:479-483
36. Lupski JR, Stankiewicz P. 2005. Genomic disorder mechanisms elucidated by breakpoint analysis of 17p rearrangements. PLoS Genet. 1:e49
37. Cheung SW, Yu W, Shaw CA, et al. 2005. Development and validation of chromosome microarray analysis (CMA) for clinical diagnosis. Genet. Med. 7:422-432
38. Stankiewicz P, Beaudet AL. 2007. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr. Opin. Genet. Dev. 17:182-192
39. Beaudet AL, Belmont JW. 2008. Array-based DNA diagnostics: let the revolution begin. Annu. Rev. Med. 59:113-129
40. Schmickel RD. 1986. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 109:231-241
41. Ledbetter DH, Riccardi VM, Airhart SD, et al. 1981. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N. Engl. J. Med. 304:325-329
42. Flint J, Hill AV, Bowden DK, et al. 1986. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 321:744-750
43. Francke U, Ochs HD, deMartinville B, et al. 1985. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, andMcLeod syndrome. Am. J. Hum. Genet. 37:250-267
44. Nathans J, Thomas D, Hogness DS. 1986. Molecular genetics of human color vision: the genes encoding blue, green, and red pigments. Science 232:193-202
45. Ballabio A, Bardoni B, Carrozzo R, et al. 1989. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc. Natl. Acad. Sci. USA 86:10001-10005
46. Yen PH, Li XM, Tsai SP, et al. 1990. Frequent deletions of the human X chromosome distal short arm result from recombination between low copy repetitive elements. Cell 61:603-610
47. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. 1991. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219-232
48. Hoogendijk JE, Hensels GW, Gabreels-Festen AA, et al. 1992. De-novo mutation in hereditary motor and sensory neuropathy type I. Lancet 339:1081-1082
49. Lee JA, Lupski JR. 2006. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52:103-121
50. Gu W, Lupski JR. 2008. CNV and nervous system diseases\what's new? Cytogenet. Genome Res. 123:54-64
51. Peoples R, Franke Y, Wang YK, et al. 2000. A physical map, including a BAC/PAC clone contig, of the Williams-Beuren syndrome\deletion region at 7q11.23. Am. J. Hum. Genet. 66:47-68
52. Berg JS, Brunetti-Pierri N, Peters SU, et al. 2007. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet. Med. 9:427-441
53. Matsuura T, Sutcliffe JS, Fang P, et al. 1997. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 15:74-77
54. Amos-Landgraf JM, Ji Y, Gottlieb W, et al. 1999. Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65:370-386
55. Bolton PF, Dennis NR, Browne CE, et al. 2001. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am. J. Med. Genet. 105:675-685
56. Long FL, Duckett DP, Billam LJ, et al. 1998. Triplication of 15q11-q13 with inv dup(15) in a female with developmental delay. J. Med. Genet. 5:425-428
57. Cardoso C, Leventer RJ, Ward HL, et al. 2003. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am. J. Hum. Genet. 72:918-930
58. Chen KS, Manian P, Koeuth T, et al. 1997. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat. Genet. 17:154-163
59. Potocki L, Bi W, Treadwell-Deering D, 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. Am. J. Hum. Genet. 80:633-649
60. López Correa C, Brems H, Lázaro C, et al. 2000. Unequal meiotic crossover: a frequent cause of NF1 microdeletions. Am. J. Hum. Genet. 66:1969-1974
61. Koolen DA, Vissers LE, Pfundt R, et al. 2006. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38:999-1001
62. Shaw-Smith C, Pittman AM, Willatt L, et al. 2006. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38:1032-1037
63. Sharp AJ, Hansen S, Selzer RR, et al. 2006. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38:1038-1042
64. Edelmann L, Pandita RK, Spiteri E, et al. 1999. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8:1157-1167
65. Ensenauer RE, Adeyinka A, Flynn HC, et al. 2003. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am. J. Hum. Genet. 73:1027-1040
66. Durand CM, Betancur C, Boeckers TM, et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39:25-27
67. Amir RE, Van den Veyver IB, Wan M, et al. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:185-188
68. Van Esch H, Bauters M, Ignatius J, et al. 2005. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.Am. J. Hum. Genet.77:442-453
69. Lee H, Bauters M, Ignatius J, et al. 2006. Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum. Mol. Genet. 15:2250-2265
70. Polymeropoulos MH, Higgins JJ, Golbe LI, et al. 1996. Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:1197-1199
71. Lefebvre S, Bürglen L, Reboullet S, et al. 1995. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155-165
72. Padiath QS, Saigoh K, Schiffmann R, et al. 2006. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38:1114-1123
73. Chance PF, Abbas N, Lensch MW, et al. 1994. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum. Mol. Genet. 3:223-228
74. Reiter LT, Murakami T, Koeuth T, et al. 1996. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat. Genet. 12:288-297
75. Rovelet-Lecrux A, Hannequin D, Raux G, et al. 2006. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38:24-26
76. Slager RE, Newton TL, Vlangos CN, et al. 2003. Mutations in RAI1 associated with Smith-Magenis syndrome. Nat. Genet. 33:466-468
77. Park SS, Stankiewicz P, Bi W, et al. 2002. Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res. 12:729-738
78. Sharp AJ, Locke DP, McGrath SD, et al. 2005. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77:78-88
79. Shao L, Shaw CA, Lu X-Y, et al. 2008. Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5380 cases. Am. J. Med. Genet. Part A 146A:2242-2251
80. del Gaudio D, Fang P, Scaglia F, et al. 2006. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8:784-792
81. Ramocki MB, Peters SU, TavyevJ,etal. 2009. Autism and other neuropsychiatric symptoms are prevalent in individuals with MECP2 duplication syndrome. Ann. Neurol. In press
82. van Ommen GJ. 2005. Frequency of new copy number variation in humans. Nat. Genet. 37:333-334
83. Autism Genome Project Consortium (AGPC), Szatmari P, Paterson AD, et al. 2007. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39:319-328
84. Marshall CR, Noor A, Vincent JB, et al. 2008. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82:477-488
85. Abrahams BS, Geschwind DH. 2008. Advances in autism genetics: on the threshold of a new neurobi-ology. Nat. Rev. Genet. 9:341-355
86. Sebat J, Lakshmi B, Malhotra D, et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445-449
87. Christian SL, Brune CW, Sudi J, et al. 2008. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol. Psychiatry 63:1111-1117
88. Morrow EM, Yoo SY, Flavell SW, et al. 2008. Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218-223
89. Weiss LA, Shen Y, Korn JM, et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667-675
90. Kumar RA, KaraMohamed S, Sudi J, et al. 2008. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17:628-638
91. Kim HG, KishikawaS, Higgins AW,etal. 2008. Disruptionofneurexin1associated with autism spectrum disorder. Am. J. Hum. Genet. 82:199-207
92. Glessner JT, Wang K, Cai G, et al. 2009. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569-573
93. Shinawi M, Schaaf CP, Bhatt SS, et al. 2009. A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat. Genet. In press
94. Sharp AJ, Mefford HC, Li K, et al. 2008. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat. Genet. 40:322-328
95. Helbig I, Mefford HC, Sharp AJ, et al. 2009. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41:160-162
96. Ben-Shachar S, Lanpher B, German JR, et al. 2009. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J. Med. Genet. 46:382-388
97. Miller DT, Shen Y, Weiss LA, et al. 2009. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J. Med. Genet. 46:242-248
98. van Bon BW, Mefford HC, Menten B, et al. 2009. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J. Med. Genet. 46:511-523
99. Brunetti-Pierri N, Berg JS, Scaglia F, et al. 2008. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat. Genet. 40:1466-1471
100. Mefford HC, Sharp AJ, Baker C, et al. 2008. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359:1685-1699
101. Popesco MC, Maclaren EJ, Hopkins J, et al. 2006. Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains. Science 313:1304-1307
102. The International Schizophrenia Consortium. 2008. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237-241
103. Stefansson H, Rujescu D, Cichon S, et al. 2008. Large recurrent microdeletions associated with schizophrenia. Nature 455:232-236
104. Pulver AE, Nestadt G, Goldberg R, et al. 1994. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J. Nerv. Ment. Dis. 182:476-478
105. Karayiorgou M, Morris MA, Morrow B, et al. 1995. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92:7612-7616
106. Kirov G, Gumus D, Chen W, et al. 2008. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17:458-465
107. Rujescu D, Ingason A, Cichon S, et al. 2009. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18:988-996
108. Vrijenhoek T, Buizer-Voskamp JE, Van Der Stelt I, et al. 2008. Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am. J. Hum. Genet. 83:504-510
109. Polymeropoulos MH, Higgins JJ, Golbe LI, et al. 1996. Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:1197-1199
110. Singleton AB, Farrer M, Johnson J, et al. 2003. Alpha-synuclein locus triplication causes Parkinson's disease. Science 302:841
111. Chartier-Harlin MC, Kachergus J, Roumier C, et al. 2004. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364:1167-1169
112. Ibáñez P, Bonnet AM, Debarges B, et al. 2004. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364:1169-1171
113. Ibáñez P, Lesage S, Janin S, et al. 2009. Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch. Neurol. 66:102-108
114. Maraganore DM, de Andrade M, Elbaz A, et al. 2006. Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. JAMA 296:661-670
115. Rovelet-Lecrux A, Hannequin D, Raux G, et al. 2006. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38:24-26
116. Theuns J, Brouwers N, Engelborghs S, et al. 2006. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am. J. Hum. Genet. 78:936-946
117. Suls A, Claeys KG, Goossens D, et al. 2006. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum. Mutat. 27:914-920
118. Erez A, Patel AJ, Wang X, et al. 2009. Alu-specific microhomology- mediated deletions in CDKL5 in females with early-onset seizure disorder. Neurogenetics 10:363-439
119. Hollox EJ, Huffmeier U, Zeeuwen PL, et al. 2008. Psoriasis is associated with increased beta-defensin genomic copy number. Nat. Genet. 40:23-25
120. Choi JS, Lee WJ, Baik SH, et al. 2009. Array CGH reveals genomic aberrations in human emphysema. Lung 187:165-172
121. Blaskó B, Kolka R, Thorbjornsdottir P, et al. 2008. Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction. Int. Immunol. 20:31-37
122. Stankiewicz P, Sen P, Bhatt SS, et al. 2009. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 84:780-791
123. SunM,LiN,DongW,etal.2009.Copy-numbermutationsonchromosome17q24.2-q24. 3incongenital generalized hypertrichosis terminalis with or without gingival hyperplasia. Am. J. Hum. Genet. 84:807-813
124. Le Maréchal C, Masson E, Chen JM, et al. 2006. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat. Genet. 38:1372-1374
125. Aitman TJ, Dong R, Vyse TJ, et al. 2006. Copy number polymorphism in Fcgr3 predisposes to glomeru-lonephritis in rats and humans. Nature 439:851-855
126. Fellermann K, Stange DE, Schaeffeler E, 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. Am. J. Hum. Genet. 79:439-448
127. McCarroll SA, Huett A, Kuballa P, et al. 2008. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat. Genet. 40:1107-1112
128. Pollex RL, Hegele RA. 2007. Genomic copy number variation and its potential role in lipoprotein and metabolic phenotypes. Curr. Opin. Lipidol. 18:174-180
129. Lakich Kazazian HH Jr, Antonarakis SE, Gitschier J. 1993. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat. Genet. 5:236-241
130. Flint J, Hill AV, Bowden DK, et al. 1986. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 321:744-750
131. Fanciulli M, Norsworthy PJ, Petretto E, et al. 2007. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39:721-723
132. Willcocks LC, Lyons PA, Clatworthy MR, et al. 2008. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J. Exp. Med. 205:1573-1582
133. Gonzalez E, Kulkarni H, Bolivar H, et al. 2005. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434-1440
134. Lu X, Phun MT, Shaw CA, et al. 2008. Genomic imbalance in neonates with birth defects: high detection rates using chromosomal microarray analyses. Pediatrics 122:1310-1318